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Clinical Practice Guideline for the Therapeutic Drug Monitoring of Voriconazole in Non-Asian and Asian Adult Patients: Consensus Review by the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring

Open AccessPublished:November 22, 2022DOI:https://doi.org/10.1016/j.clinthera.2022.10.005

      Abstract

      Purpose

      Voriconazole, an antifungal drug, is metabolized by a cytochrome P450 isozyme. Increased adverse effects are observed in Asians because of the high rate of poor metabolizers. In this therapeutic drug monitoring (TDM) guideline, recommendations were made according to ethnic group.

      Methods

      Five clinical questions were used. For the preparation of the guideline, the performance of TDM in multicenter studies was surveyed (study 1). We also conducted a systematic review and meta-analysis (study 2) to establish recommendations for non-Asians and Asians.

      Findings

      In study 1, 401 patients were surveyed. A risk of supratherapeutic concentrations was found in Japanese patients who adhered to the recommended dose. Target trough levels were achieved in 87% of patients with dose reductions. Although the trough level measured at the onset of adverse effects (AEs) was significantly associated with hepatotoxicity, no significant correlation was found between the initial trough level and hepatotoxicity, which indicated that hepatotoxicity was successfully prevented by the trough-guided dosing. In study 2, 22 studies (11 Asian locations and 11 non-Asian locations) were included in meta-analysis for the relationship between trough cutoff level (3, 4, 5, 5.5, and 6 µg/mL) and AEs. Significant differences were found for all cutoff levels, with the highest odds ratio for 4.0 µg/mL in Asian locations. In contrast, in non-Asian locations, no more than 1 study was available for any trough cutoff level, except for 5.5 µg/mL, at which level a significant increase in AEs was found. These findings indicate that TDM is strongly recommended to prevent AEs in Asians, and TDM is generally recommended for non-Asians to address subtherapeutic concentrations. TDM on day 3 is recommended to assess pharmacokinetic properties, including loading and maintenance doses. If the patient condition permits, delaying until day 5 is suggested for Asians because of the prolonged t½ in poor metabolizers. A trough level ≥1.0 µg/mL is strongly recommended to improve efficacy. Trough levels ≥2.0 µg/mL are suggested for invasive aspergillosis. To decrease adverse effects, trough levels <4.0 µg/mL are strongly recommended in Asians, whereas trough levels <5.5 µg/mL are generally recommended in non-Asians. Maintenance doses of 4 and 3 mg/kg twice daily are recommended in non-Asians and Asians, respectively.

      Implications

      Different indications, timings, and target trough levels for TDM and different regimens are suggested for Asians and non-Asians.

      Keywords

      Introduction

      Voriconazole is an antifungal drug used in the treatment or prophylaxis of invasive aspergillosis and candidiasis.
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      Voriconazole is mainly metabolized in the liver by the cytochrome P450 isozyme (CYP) 2C19 and, to a lesser extent, by CYP2C9 and CYP3A4. Compared with normal metabolizers of voriconazole, intermediate or poor metabolizers have significantly higher serum levels of voriconazole.
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      Because the incidence of poor metabolizers is higher in Asian populations than in White populations,
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      a higher hepatotoxicity rate has been observed in Asian populations.
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      Low serum concentrations of voriconazole are observed in non-Asian patients with rapid or ultrarapid metabolizers.
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      Bioinformatics research on inter-racial difference in drug metabolism I. Analysis on frequencies of mutant alleles and poor metabolizers on CYP2D6 and CYP2C19.
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      the serum concentrations of voriconazole can have considerable interpatient variability.
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      Hence, therapeutic drug monitoring (TDM) is required to optimize the dosing regimen to prevent adverse effects and increase clinical efficacy.
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      Previous practice guidelines for the TDM of voriconazole have been reported by the Japanese Society of Chemotherapy (JSC) and the Japanese Society of Therapeutic Drug Monitoring (JSTDM) in 2013,
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      and several guidelines have been published worldwide.
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      To prepare an updated guideline, the guideline committee conducted a multicenter study to evaluate the performance of TDM in the clinical setting to investigate the problems with the previous guidelines for the use of voriconazole in Japanese patients.
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      We recognized that there are several limitations in the use of identical guidelines for the treatment of Asian and non-Asian populations. The guideline committee performed a systematic review and meta-analysis of studies conducted in non-Asian and Asian locations to make separate evidence-based recommendations for non-Asian and Asian populations.

      Methods

      Preparation of the Guideline

      Development Policy for the Updated Guideline

      The guideline was developed based on the Minds Manual for Guideline Development 2017 established by the Medical Information Network Distribution Service (Minds) in Japan.

      Minds Manual Developing Committee ed. Minds Manual for Guideline Development 2017. Tokyo: Japan Council for Quality Health Care, 2017 (in Japanese).

      The committee agreed on 5 clinical questions (CQs) regarding voriconazole TDM. Original articles related to each CQ were identified in general databases. Systematic reviews of the CQs were performed by several guideline committee members to assess the current evidence, and recommendations were formulated. Because randomized controlled trials (RCTs) are difficult to perform for TDM, recommendations for each CQ were made using the modified Minds classification (Table I).
      Table ICategory for ranking recommendations adopted in the guidelines.
      CategoryDefinition
      IStrong recommendation with strong evidence for efficacy with clinical benefit
      IIGeneral recommendation with moderate evidence for efficacy with clinical benefit
      III-ASuggestion to encourage use by expert opinion without sufficient evidence
      III-BInsufficient evidence to make any suggestion
      III-CSuggestion to discourage use because of insufficient evidence
      IVRecommendation against use with sufficient evidence of no clinical efficacy or increased adverse outcome
      Referenced from the report

      Minds Manual Developing Committee ed. Minds Manual for Guideline Development 2017. Tokyo: Japan Council for Quality Health Care, 2017 (in Japanese).

      ,
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      developed by this committee, Oxford University Press, 2022
      Table IIRecommendations for voriconazole TDM in non-Asian and Asian patients.
      CQNon-AsiansAsians
      CQ1. PK/PD parameterTrough level (II)Trough level (II)
      CQ2. Indication for TDMTDM is generally recommended mainly to prevent subtherapeutic concentrations (II)TDM is strongly recommended, mainly because of the risk for supratherapeutic concentrations (I)
      CQ3. TDM timingDay 3 after start of therapy (III-A)Days 3–5 after start of therapy (III-A); if patient condition allows, delaying TDM until day 5 is suggested
      CQ4. Target trough level
      To improve efficacy outcome≥1 µg/mL (I)≥1 µg/mL (I)
      To prevent adverse effects<5.5 µg/mL is generally recommended (II)<4 .0 µg/mL is strongly recommended (I)
      CQ5. Dosing regimen
      Loading dose for initial day6.0 mg/kg q12h (I)6.0 mg/kg q12h (I)
      Maintenance dose4 mq/kg q12h (II)3 mq/kg q12h is suggested to prevent overdose (III-A)
      CQ = clinical question; PK/PD = pharmacokinetic/pharmacodynamic; q12h = every 12 hoursTDM = therapeutic drug monitoring.

      Monitoring the Performance of TDM in Accordance With the Previous Guidelines

      A multicenter retrospective study was conducted at 5 hospitals in Japan between April 2015 and March 2018 to evaluate the adherence to the previous TDM guidelines in patients aged ≥18 years who received voriconazole therapy with supervision by an antimicrobial stewardship team.
      • Hamada Y
      • Ueda T
      • Miyazaki Y
      • et al.
      Effects of antifungal stewardship using therapeutic drug monitoring in voriconazole therapy on the prevention and control of hepatotoxicity and visual symptoms: A multicentre study conducted in Japan.
      Patients who used voriconazole prophylactically were excluded. For evaluation of adherence to the recommendations, an adequate voriconazole dose was defined as a loading dose of 5 to 6 mg/kg every 12 hours (q12h) followed by a maintenance dose of 3 to 4 mg/kg q12h. A rounding dose with 50-mg and 200-mg tablets was used for weight-based dosing in patients with oral administration. The target trough level range was defined as 1 to 5 µg/mL.

      Systematic Review and Meta-analysis (for CQ2 and CQ4)

      Five electronic databases were searched for clinical studies published up to June 8, 2022, on safety profiles and up to February 1, 2021, on all-cause mortality and treatment success
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      using a combined Medical Subject Headings and text search strategy. Studies were included for analysis if they assessed the relationship between the voriconazole concentration and treatment success, all-cause mortality, or safety profile and if all participants were adults (≥15 years old).
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      Stepwise cutoff levels of 3.0, 4.0, 5.0, 5.5, and 6.0 µg/mL of voriconazole were set for safety (hepatotoxicity and neurotoxicity, including visual symptoms),
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      • Johnson EM
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      Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology.
      ,
      • Hamada Y
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      Investigation and threshold of optimum blood concentration of voriconazole: A descriptive statistical meta-analysis.
      ,
      • Luong ML
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      and stepwise cutoff levels of 0.5, 1.0, and 2.0 µg/mL voriconazole were set for all-cause mortality and treatment success. We analyzed the odds ratios (ORs) and 95% CIs. Safety profiles were assessed according to the study location (Asia and non-Asia). Risk of bias was assessed using the Cochrane Handbook for Systematic Reviews of Interventions.
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      Process Before Publication

      A draft summary of the guideline was uploaded to the home pages of the JSC and JSTDM between June 2, 2021, and July 2, 2021, to obtain external public comments. After corrections, the Japanese version of the guideline was approved by the JSC and JSTDM Board of Directors. All members of the clinical practice guideline committee complied with the JSC policy.

      Results

      Executive Summary (Table II)

      CQ 1. What Are the Recommended PK/Pharmacodynamic (PD) Parameters for Voriconazole TDM in Clinical Practice?
      The AUC/MIC ratio is a plausible therapeutic index (III-A).
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      A physiologically based pharmacokinetic model for voriconazole disposition predicts intestinal first-pass metabolism in children.
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      However, genotyping CYP2C19 to identify intermediate/poor and rapid/ultrarapid metabolizers of voriconazole and intensive sampling should be considered to increase the estimation accuracy.
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      Different from vancomycin, in which AUC-guided dosing is recommended,
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      a clear correlation between the AUC values and trough concentrations has been found for voriconazole.
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      Optimization of Voriconazole Therapy for the Treatment of Invasive Fungal Infections in Adults.
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      Pharmacokinetics of intravenous voriconazole in patients with liver dysfunction: A prospective study in the intensive care unit.
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      The efficacy (I) and tolerability (II) of treatment with voriconazole using trough-guided dosing have been found in non-Asians and Asians.
      • Hamada Y
      • Ueda T
      • Miyazaki Y
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      Effects of antifungal stewardship using therapeutic drug monitoring in voriconazole therapy on the prevention and control of hepatotoxicity and visual symptoms: A multicentre study conducted in Japan.
      ,
      • Park WB
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      • et al.
      The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in inva-sive fungal infections: a randomized controlled trial.
      ,
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      Favorable Effects of Voriconazole Trough Concentrations Exceeding 1 µg/mL on Treatment Success and All-Cause Mortality: A Systematic Review and Meta-Analysis.
      The guideline committee recommended using the trough concentration as a marker until the development of user-friendly validated software that can predict AUC values using limited sample numbers (II).

      CQ 2. What Are the Indications for TDM in Voriconazole?

      TDM is strongly recommended to prevent adverse effects in Asian patients undergoing voriconazole therapy because a higher proportion of Asian patients are poor metabolizers, compared with non-Asians, because of genetic polymorphisms of CYP2C19 (I).
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      Efficacy and safety of voriconazole in the treatment of chronic pulmonary aspergillosis: experience in Japan.
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      Risk factors for voriconazole hepatotoxicity at 12 weeks in lung transplant recipients.
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      Meta-analysis of the safety of voriconazole in definitive, empirical, and prophylactic therapies for invasive fungal infections.
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      Monitoring trough voriconazole plasma concentrations in haematological patients: real life multicentre experience.
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      Correlation between voriconazole trough plasma concentration and hepatotoxicity in patients with different CYP2C19 genotypes.
      TDM is generally recommended for non-Asians to address subtherapeutic concentrations in rapid metabolizers (II).
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      Serial plasma voriconazole concentrations after allogeneic hematopoietic stem cell transplantation.
      ,
      • Pascual A
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      • Bolay S
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      Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes.
      TDM is recommended in the following adult patients: patients with serious fungal infections, such as invasive pulmonary aspergillosis, to increase treatment success (II)
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      Voriconazole therapeutic drug monitoring.
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      Impact of Voriconazole Plasma Concentrations on Treatment Response in Critically Ill Patients.
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      ; critically ill patients admitted to intensive care units (II)
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      • et al.
      Voriconazole Therapeutic Drug Monitoring Practices in Intensive Care.
      ,
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      • et al.
      Risk Factors for Voriconazole-Associated Hepatotoxicity in Patients in the Intensive Care Unit.
      ; patients with liver cirrhosis or hyperbilirubinemia because of the reduced clearance of voriconazole (I)
      • Wang T
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      • Tang D
      • et al.
      A retrospective, multicenter study of voriconazole trough concentrations and safety in patients with Child-Pugh class C cirrhosis.

      Yamada T, Imai S, Koshizuka Y, et al. Necessity for a Significant Maintenance Dosage Reduction of Voriconazole in Patients With Severe Liver Cirrhosis (Child-Pugh Class C).Biol Pharm Bull. 2018; 41:1112–1118. doi: 10.1248/bpb.b18-00164.

      • Wang T
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      • et al.
      Therapeutic Drug Monitoring and Safety of Voriconazole Therapy in Patients With Child–Pugh Class B and C Cirrhosis: A Multicenter Study.
      ; transplant recipients receiving voriconazole for prophylaxis against fungal infections (II)
      • Trifilio SM
      • Yarnold PR
      • Scheetz MH
      • et al.
      Serial plasma voriconazole concentrations after allogeneic hematopoietic stem cell transplantation.
      ,
      • Trifilio S
      • Singhal S
      • Williams S
      • et al.
      Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole.
      ,
      • Trifilio S
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      Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients.
      ; and patients undergoing long-term outpatient treatment or prophylaxis (II).
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      Adverse Effects Associated with Long-Term Administration of Azole Antifungal Agents.
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      Efficacy and safety of isavuconazole compared with voriconazole as primary antifungal prophylaxis in allogeneic hematopoietic cell transplant recipients.
      TDM is recommended or suggested in the following situations: lack of clinical response (II)
      • Hamada Y
      • Seto Y
      • Yago K
      • et al.
      Investigation and threshold of optimum blood concentration of voriconazole: A descriptive statistical meta-analysis.
      ,
      • Luong ML
      • Al-Dabbagh M
      • Groll AH
      • et al.
      Utility of voriconazole therapeutic drug monitoring: a meta-analysis.
      ,
      • Pascual A
      • Calandra T
      • Bolay S
      • et al.
      Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes.
      ,
      • Smith J
      • Safdar N
      • Knasinski V
      • et al.
      Voriconazole therapeutic drug monitoring.
      ,
      • Trifilio S
      • Singhal S
      • Williams S
      • et al.
      Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole.
      ,
      • Bogler Y
      • Stern A
      • Su Y
      • et al.
      Efficacy and safety of isavuconazole compared with voriconazole as primary antifungal prophylaxis in allogeneic hematopoietic cell transplant recipients.
      • Miyakis S
      • van Hal SJ
      • Ray J.
      Voriconazole concentrations and outcome of invasive fungal infections.
      • Jin H
      • Wang T
      • Falcione BA
      • et al.
      Trough concentration of voriconazole and its relationship with efficacy and safety: A systematic review and meta-analysis.
      • Ueda K
      • Nannya Y
      • Kumano K
      • et al.
      Monitoring trough concentration of voriconazole is important to ensure successful antifungal therapy and to avoid hepatic damage in patients with hematological disorders.
      • Okuda T
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      • et al.
      Retrospective serological tests for determining the optimal blood concentration of voriconazole for treating fungal infection.
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      Role of therapeutic drug monitoring of voriconazole in the treatment of invasive fungal infections.
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      ; hepatotoxicity (II)
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      • Miyazaki Y
      • et al.
      Effects of antifungal stewardship using therapeutic drug monitoring in voriconazole therapy on the prevention and control of hepatotoxicity and visual symptoms: A multicentre study conducted in Japan.
      ,
      • Matsumoto K
      • Abematsu K
      • Shigemi A
      • et al.
      Therapeutic Drug Monitoring of Voriconazole in Japanese Patients: Analysis Based on Clinical Practice Data.
      or encephalopathy (III-A)
      • Imhof A
      • Schaer DJ
      • Schanz U
      • et al.
      Neurological adverse events to voriconazole: evidence for therapeutic drug monitoring.
      after starting voriconazole treatment; persistent visual symptoms and/or hallucinations (III-A)
      • Luong ML
      • Al-Dabbagh M
      • Groll AH
      • et al.
      Utility of voriconazole therapeutic drug monitoring: a meta-analysis.
      ,
      • Pascual A
      • Calandra T
      • Bolay S
      • et al.
      Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes.
      ,
      • Imhof A
      • Schaer DJ
      • Schanz U
      • et al.
      Neurological adverse events to voriconazole: evidence for therapeutic drug monitoring.
      ,
      • Tan K
      • Brayshaw N
      • Tomaszewski K
      • et al.
      Investigation of the potential relationships between plasma voriconazole concentrations and visual adverse events or liver function test abnormalities.
      ; dose alteration based on initial TDM (II)
      • Purkins L
      • Wood N
      • Greenhalgh K
      • et al.
      Voriconazole, a novel wide-spectrum triazole: oral pharmacokinetics and safety.
      ,
      • Purkins L
      • Wood N
      • Ghahramani P
      • et al.
      Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens.
      ; alteration of administration route (III-A)
      • Hamada Y
      • Ueda T
      • Miyazaki Y
      • et al.
      Effects of antifungal stewardship using therapeutic drug monitoring in voriconazole therapy on the prevention and control of hepatotoxicity and visual symptoms: A multicentre study conducted in Japan.
      ,
      • Purkins L
      • Wood N
      • Ghahramani P
      • et al.
      Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens.
      ; and introduction or discontinued use of an interacting drug (eg, omeprazole) (III-A).
      • Blanco Dorado S
      • Maroñas Amigo O
      • Latorre-Pellicer A
      • et al.
      A multicentre prospective study evaluating the impact of proton-pump inhibitors omeprazole and pantoprazole on voriconazole plasma concentrations.
      • Guinea J
      • Escribano P
      • Marcos-Zambrano LJ
      • et al.
      Therapeutic drug monitoring of voriconazole helps to decrease the percentage of patients with off-target trough serum levels.
      • Mikus G
      • Schöwel V
      • Drzewinska M
      • et al.
      Potent cytochrome P450 2C19 genotype-related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir.
      • Qi F
      • Zhu L
      • Li N
      • et al.
      Influence of different proton pump inhibitors on the pharmacokinetics of voriconazole.
      • Huang Q
      • Liu Q
      • Yin T
      • et al.
      Effect of proton pump inhibitors on voriconazole concentrations in Chinese patients with malignant hematological diseases.
      • Wood N
      • Tan K
      • Purkins L
      • et al.
      Effect of omeprazole on the steady-state pharmacokinetics of voriconazole.
      • Purkins L
      • Wood N
      • Ghahramani P
      • et al.
      Coadministration of voriconazole and phenytoin: pharmacokinetic interaction, safety, and toleration.
      • Marshall WL
      • McCrea JB
      • Macha S
      • et al.
      Pharmacokinetics and Tolerability of Letermovir Coadministered With Azole Antifungals (Posaconazole or Voriconazole) in Healthy Subjects.

      CQ 3. When Should TDM Be Performed in Voriconazole?

      A trough level close to the concentration at steady state is obtained after 2 to 5 days of therapy in patients with loading doses.
      • Hamada Y
      • Ueda T
      • Miyazaki Y
      • et al.
      Effects of antifungal stewardship using therapeutic drug monitoring in voriconazole therapy on the prevention and control of hepatotoxicity and visual symptoms: A multicentre study conducted in Japan.
      ,
      • Chau MM
      • Kong DC
      • van Hal SJ
      • et al.
      Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014.
      ,
      • Ullmann AJ
      • Aguado JM
      • Arikan-Akdagli S
      • et al.
      Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline.
      • Purkins L
      • Wood N
      • Greenhalgh K
      • et al.
      The pharmacokinetics and safety of intravenous voriconazole - a novel wide-spectrum antifungal agent.
      • Theuretzbacher U
      • Ihle F
      • Derendorf H.
      Pharmacokinetic/pharmacodynamic profile of voriconazole.
      • Imani S
      • Alffenaar JW
      • Cotta MO
      • et al.
      Therapeutic drug monitoring of commonly used anti-infective agents: A nationwide cross-sectional survey of Australian hospital practices.
      • Mellinghoff SC
      • Panse J
      • Alakel N
      • et al.
      Primary prophylaxis of invasive fungal infections in patients with haematological malignancies: 2017 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO).
      Because the trough level on day 2 (24 hours after the start of therapy) reflects only the concentration achieved via loading doses,
      • Purkins L
      • Wood N
      • Greenhalgh K
      • et al.
      The pharmacokinetics and safety of intravenous voriconazole - a novel wide-spectrum antifungal agent.
      initial TDM on day 3 (48 hours after the start of therapy) is suggested, especially in the treatment of serious fungal infections (III-A).
      • Chen K
      • Zhang X
      • Ke X
      • et al.
      Individualized Medication of Voriconazole: A Practice Guideline of the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society.
      ,
      • Stott KE
      • Hope WW.
      Therapeutic drug monitoring for invasive mould infections and disease: pharmacokinetic and pharmacodynamic considerations.
      The prolonged t½of voriconazole in patients who are poor metabolizers results in delaying the achievement of steady state; therefore, there is a risk of further increase in the trough level after TDM on day 3 in Asians.
      • Shimizu T
      • Ochiai H
      • Asell F
      • et al.
      Bioinformatics research on inter-racial difference in drug metabolism I. Analysis on frequencies of mutant alleles and poor metabolizers on CYP2D6 and CYP2C19.
      ,
      • Chen L
      • Qin S
      • Xie J
      • et al.
      Genetic polymorphism analysis of CYP2C19 in Chinese Han populations from different geographic areas of mainland China.
      If the patient condition allows, delaying TDM until day 5 is a reasonable policy for Asians (III-A). Subsequent TDM after 3 to 5 days is suggested according to the initial trough level in patients with liver cirrhosis (eg, within the target range but close to the upper limit) (III-A).
      • Wang T
      • Yan M
      • Tang D
      • et al.
      A retrospective, multicenter study of voriconazole trough concentrations and safety in patients with Child-Pugh class C cirrhosis.

      Yamada T, Imai S, Koshizuka Y, et al. Necessity for a Significant Maintenance Dosage Reduction of Voriconazole in Patients With Severe Liver Cirrhosis (Child-Pugh Class C).Biol Pharm Bull. 2018; 41:1112–1118. doi: 10.1248/bpb.b18-00164.

      • Wang T
      • Yan M
      • Tang D
      • et al.
      Therapeutic Drug Monitoring and Safety of Voriconazole Therapy in Patients With Child–Pugh Class B and C Cirrhosis: A Multicenter Study.
      In patients receiving voriconazole without loading doses (eg, for prophylaxis), the initial TDM is suggested to be performed after 5 to 8 days of therapy (III-A).
      • Purkins L
      • Wood N
      • Greenhalgh K
      • et al.
      The pharmacokinetics and safety of intravenous voriconazole - a novel wide-spectrum antifungal agent.
      Repeated sampling with short intervals (eg, every 3 days) until the patient's condition becomes stable is suggested in patients with worsening clinical status who have life-threatening fungal infections (III-A).
      • Wang Y
      • Wang T
      • Xie J
      • et al.
      Risk Factors for Voriconazole-Associated Hepatotoxicity in Patients in the Intensive Care Unit.
      • Wang T
      • Yan M
      • Tang D
      • et al.
      A retrospective, multicenter study of voriconazole trough concentrations and safety in patients with Child-Pugh class C cirrhosis.

      Yamada T, Imai S, Koshizuka Y, et al. Necessity for a Significant Maintenance Dosage Reduction of Voriconazole in Patients With Severe Liver Cirrhosis (Child-Pugh Class C).Biol Pharm Bull. 2018; 41:1112–1118. doi: 10.1248/bpb.b18-00164.

      ,
      • Espinel-Ingroff A
      • Diekema DJ
      • Fothergill A
      • et al.
      Wild-type MIC distributions and epidemiological cutoff values for the triazoles and six Aspergillus spp. for the CLSI broth microdilution method (M38-A2 document).
      For patients in whom prolonged voriconazole prophylaxis is anticipated,
      • Marks DI
      • Liu Q
      • Slavin M.
      Voriconazole for prophylaxis of invasive fungal infections after allogeneic hematopoietic stem cell transplantation.
      subsequent TDM after initial TDM is warranted; if similar concentration as in the initial TDM are obtained, further TDM might not be required unless hepatotoxicity develops or there is some uncertainty about the concentrations (III-A).

      CQ 4. What Is the Target Trough Level in Voriconazole?

      A trough level ≥1.0 µg/mL is strongly recommended to increase clinical efficacy and improve the prognosis (I).
      • Lee J
      • Ng P
      • Hamandi B
      • et al.
      Effect of Therapeutic Drug Monitoring and Cytochrome P450 2C19 Genotyping on Clinical Outcomes of Voriconazole: A Systematic Review.
      ,
      • Hanai Y
      • Hamada Y
      • Kimura T
      • et al.
      Favorable Effects of Voriconazole Trough Concentrations Exceeding 1 µg/mL on Treatment Success and All-Cause Mortality: A Systematic Review and Meta-Analysis.
      A trough level ≥2.0 µg/mL is suggested in the treatment of invasive aspergillosis (III-A).
      • Guinea J
      • Escribano P
      • Marcos-Zambrano LJ
      • et al.
      Therapeutic drug monitoring of voriconazole helps to decrease the percentage of patients with off-target trough serum levels.
      ,
      • Siopi M
      • Mavridou E
      • Mouton JW
      • et al.
      Susceptibility breakpoints and target values for therapeutic drug monitoring of voriconazole and Aspergillus fumigatus in an in vitro pharmacokinetic/pharmacodynamic model.
      Although a level ≥4.0 µg/mL might be required for the treatment of Candida glabrata or Candida krusei, infections, this concentration increases the risk of hepatotoxicity (III-C).
      • Espinel-Ingroff A
      • Diekema DJ
      • Fothergill A
      • et al.
      Wild-type MIC distributions and epidemiological cutoff values for the triazoles and six Aspergillus spp. for the CLSI broth microdilution method (M38-A2 document).
      To prevent adverse effects, a trough level <5.5 µg/mL is generally recommended for non-Asians (II),
      • Pascual A
      • Calandra T
      • Bolay S
      • et al.
      Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes.
      whereas a trough level of <4.0 µg/mL is strongly recommended for Asians (I) (Figures 1 and 2).
      • Pappas PG
      • Kauffman CA
      • Andes DR
      • et al.
      Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America.
      • Troke PF
      • Hockey HP
      • Hope WW.
      Observational study of the clinical efficacy of voriconazole and its relationship to plasma concentrations in patients.
      • Johnson LB
      • Kauffman CA.
      Voriconazole: a new triazole antifungal agent.
      • Hagiwara E
      • Shiihara J
      • Matsushima A
      • et al.
      Usefulness of monitoring plasma voriconazole concentration in patients with chronic necrotizing pulmonary aspergillosis.
      • Kim SH
      • Yim DS
      • Choi SM
      • et al.
      Voriconazole-related severe adverse events: clinical application of therapeutic drug monitoring in Korean patients.
      • Suzuki Y
      • Tokimatsu I
      • Sato Y
      • et al.
      As-sociation of sustained high plasma trough concentration of voriconazole with the incidence of hepatotoxicity.
      • Wang T
      • Zhu H
      • Sun J
      • et al.
      Efficacy and safety of voriconazole and CYP2C19 polymorphism for optimised dosage regimens in patients with invasive fungal infections.
      • Hashemizadeh Z
      • Badiee P
      • Malekhoseini SA
      • et al.
      Observational Study of Associations between Voriconazole Therapeutic Drug Monitoring, Toxicity, and Outcome in Liver Transplant Patients.
      • Hirata A
      • Noto K
      • Ota R
      • et al.
      Voriconazole trough concentration and hepatotoxicity in patients with low serum albumin.
      • Perez-Pitarch A
      • Guglieri-Lopez B
      • Ferriols-Lisart R
      • et al.
      Pharmacokinetic/Pharmacodynamic Analysis of Voriconazole Against Candida spp. and Aspergillus spp. in Allogeneic Stem Cell Transplant Recipients.
      • Veringa A
      • Geling S
      • Span LF
      • et al.
      Bioavailability of voriconazole in hospitalised patients.
      • Harada S
      • Niwa T
      • Hoshino Y
      • et al.
      Influence of switching from intravenous to oral administration on serum voriconazole concentration.
      • Hohmann N
      • Kocheise F
      • Carls A
      • et al.
      Dose-Dependent Bioavailability and CYP3A Inhibition Contribute to Non-Linear Pharmacokinetics of Voriconazole.
      • Koselke E
      • Kraft S
      • Smith J
      • et al.
      Evaluation of the effect of obesity on voriconazole serum concentrations.
      • Davies-Vorbrodt S
      • Ito JI
      • Tegtmeier BR
      • et al.
      Voriconazole serum concentrations in obese and overweight immunocompromised patients: a retrospective review.
      • Eljaaly K
      • Nix DE.
      Voriconazole Dosing in Obese Patients.
      • Richards PG
      • Dang KM
      • Kauffman CA
      • et al.
      Therapeutic drug monitoring and use of an adjusted body weight strategy for high-dose voriconazole therapy.
      • Burkhardt O
      • Thon S
      • Burhenne J
      • et al.
      Sulphobutylether-beta-cyclodextrin accumulation in critically ill patients with acute kidney injury treated with intravenous voriconazole under extended daily dialysis.
      • von Mach MA
      • Burhenne J
      • Weilemann LS.
      Accumulation of the solvent vehicle sulphobutylether beta cyclodextrin sodium in critically ill patients treated with intravenous voriconazole under renal replacement therapy.
      • Lin XB
      • Lui KY
      • Guo PH
      • et al.
      Population pharmacokinetic model-guided optimization of intravenous voriconazole dosing regimens in critically ill patients with liver dysfunction.
      • Cota JM
      • Burgess DS.
      Antifungal dose adjustment in renal and hepatic dysfunction: Pharmacokinetic and pharmacodynamic considerations.
      ,
      • Qi F
      • Zhu L
      • Li N
      • et al.
      Influence of different proton pump inhibitors on the pharmacokinetics of voriconazole.
      ,
      • Lee YJ
      • Lee SO
      • Choi SH
      • et al.
      Initial voriconazole trough blood levels and clinical outcomes of invasive aspergillosis in patients with hematologic malignancies.
      • Denning DW
      • Ribaud P
      • Milpied N
      • et al.
      Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis.
      • Chu HY
      • Jain R
      • Xie H
      • et al.
      Voriconazole therapeutic drug monitoring: retrospective cohort study of the relationship to clinical outcomes and adverse events.
      • Cabral-Galeano E
      • Ruiz-Camps I
      • Len-Abad O
      • et al.
      Clinical usefulness of therapeutic drug monitoring of voriconazole in a university hospital.
      • Gómez-López A
      • Cendejas-Bueno E
      • Cuesta I
      • et al.
      Voriconazole serum levels measured by high-performance liquid chromatography: a monocentric study in treated patients.
      • Sebaaly JC
      • MacVane SH
      • et al.
      Voriconazole concentration monitoring at an academic medical center.
      • Taghvaye-Masoumi H
      • Hadjibabaie M
      • Ghadimi M
      • et al.
      Association of Voriconazole Trough Plasma Concentration with Efficacy and Incidence of Hepatotoxicity in Iranian Patients with Hematological Malignancies.
      • Kara E
      • Ekinci PB
      • Metan G.
      Voriconazole therapeutic drug level monitoring: A university hospital experience.
      • Ren QX
      • Li XG
      • Mu JS
      • et al.
      Population Pharmacokinetics of Voriconazole and Optimization of Dosage Regimens Based on Monte Carlo Simulation in Patients With Liver Cirrhosis.
      • Bury D
      • Tissing WJE
      • Muilwijk EW
      • et al.
      Clinical Pharmacokinetics of Triazoles in Pediatric Patients.
      • Shi C
      • Xiao Y
      • Mao Y
      • et al.
      Voriconazole: A Review of Population Pharmacokinetic Analyses.
      • Li S
      • Wu S
      • Gong W
      • et al.
      Application of Population Pharmacokinetic Analysis to Characterize CYP2C19 Mediated Metabolic Mechanism of Voriconazole and Support Dose Optimization.
      • Takahashi T
      • Jaber MM
      • Smith AR
      • et al.
      Predictive Value of C-Reactive Protein and Albumin for Temporal Within-Individual Pharmacokinetic Variability of Voriconazole in Pediatric Patients Undergoing Hematopoietic Cell Transplantation.
      • Suetsugu K
      • Muraki S
      • Fukumoto J
      • et al.
      Effects of Letermovir and/or Methylprednisolone Coadministration on Voriconazole Pharmacokinetics in Hematopoietic Stem Cell Transplantation: A Population Pharmacokinetic Study.
      • Takahashi T
      • Mohamud MA
      • Smith AR
      • et al.
      CYP2C19 Phenotype and Body Weight-Guided Voriconazole Initial Dose in Infants and Children after Hematopoietic Cell Transplantation.
      • Wang T
      • Yan M
      • Tang D
      • et al.
      Using Child-Pugh Class to Optimize Voriconazole Dosage Regimens and Improve Safety in Patients with Liver Cirrhosis: Insights from a Population Pharmacokinetic Model-based Analysis.
      • Tang D
      • Yan M
      • Song BL
      • et al.
      Population pharmacokinetics, safety and dosing optimization of voriconazole in patients with liver dysfunction: A prospective observational study.
      • Chantharit P
      • Tantasawat M
      • Kasai H
      • et al.
      Population Pharmacokinetics of Voriconazole in Patients With Invasive Aspergillosis: Serum Albumin Level as a Novel Marker for Clearance and Dosage Optimization.
      • Khan-Asa B
      • Punyawudho B
      • Singkham N
      • et al.
      Impact of Albumin and Omeprazole on Steady-State Population Pharmacokinetics of Voriconazole and Development of a Voriconazole Dosing Optimization Model in Thai Patients with Hematologic Diseases.
      • Kim HY
      • Märtson AG
      • Dreesen E
      • et al.
      Saliva for Precision Dosing of Antifungal Drugs: Saliva Population PK Model for Voriconazole Based on a Systematic Review.
      • Liu Y
      • Qiu T
      • Liu Y
      • et al.
      Model-based Voriconazole Dose Optimization in Chinese Adult Patients With Hematologic Malignancies.
      • Chen C
      • Yang T
      • Li X
      • et al.
      Population Pharmacokinetics of Voriconazole in Chinese Patients with Hematopoietic Stem Cell Transplantation.
      • Kim Y
      • Rhee SJ
      • Park WB
      • et al.
      A Personalized CYP2C19 Phenotype-Guided Dosing Regimen of Voriconazole Using a Population Pharmacokinetic Analysis.
      • Tang D
      • Song BL
      • Yan M
      • Zou JJ
      • et al.
      Identifying factors affecting the pharmacokinetics of voriconazole in patients with liver dysfunction: A population pharmacokinetic approach.
      • Tsutsuura M
      • Moriyama H
      • Kojima N
      • et al.
      The monitoring of vancomycin: a systematic review and meta-analyses of area under the concentration-time curve-guided dosing and trough-guided dosing.
      ,
      • Saito T
      • Fujiuchi S
      • Tao Y
      • et al.
      Efficacy and safety of voriconazole in the treatment of chronic pulmonary aspergillosis: experience in Japan.
      ,
      • Yu G
      • Li GF
      • Atomoxetine Markowitz J.S.
      A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition.
      • Li-Wan-Po A
      • Girard T
      • Farndon P
      • et al.
      Pharmacogenetics of CYP2C19: Functional and clinical implications of a new variant CYP2C19*17.
      • Amsden JR
      • Gubbins P.O.
      Pharmacogenomics of triazole antifungal agents: Implications for safety, tolerability and efficacy.
      • Allegra S
      • Fatiguso G
      • Francia S
      • et al.
      Pharmacogenetic of voriconazole antifungal agent in pediatric patients.
      • Chan SY
      • Hughes RM
      • Woo K
      • et al.
      Reasons for voriconazole prophylaxis discontinuation in allogeneic hematopoietic cell transplant recipients: A real-life paradigm.
      • McCreary EK
      • Bayless M
      • Van AP
      • et al.
      Impact of Triazole Therapeutic Drug Monitoring Availability and Timing.
      • Brüggemann RJ
      • Donnelly JP
      • Aarnoutse RE
      • et al.
      Therapeutic drug monitoring of voriconazole.
      • Beredaki MI
      • Georgiou PC
      • Siopi M
      • et al.
      Voriconazole efficacy against Candida glabrata and Candida krusei: preclinical data using a validated in vitro pharmacokinetic/pharmacodynamic model.
      • Arendrup MC
      • Friberg N
      • Mares M
      • et al.
      How to interpret MICs of antifungal compounds according to the revised clinical breakpoints v. 10.0 European committee on antimicrobial susceptibility testing (EUCAST).
      • Hamada Y
      • Kawasumi N
      • Hirai J
      • et al.
      Evaluation of voriconazole oral dosage in Japan.
      • Hoenigl M
      • Duettmann W
      • Raggam RB
      • et al.
      Potential factors for inadequate voriconazole plasma concentrations in intensive care unit patients and patients with hematological malignancies.
      • Berge M
      • Guillemain R
      • Trégouet DA
      • et al.
      Effect of cytochrome P450 2C19 genotype on voriconazole exposure in cystic fibrosis lung transplant patients.
      Sufficient data were not available to determine the cutoff trough level, except 5.5 µg/mL, in non-Asians.
      • Jin H
      • Wang T
      • Falcione BA
      • et al.
      Trough concentration of voriconazole and its relationship with efficacy and safety: A systematic review and meta-analysis.
      A trough level >3.0 µg/mL is a reasonable concentration for the consideration of additional TDM within a few days in patients with liver cirrhosis or early blood sampling before reaching steady state, especially in Asian patients (III-A).
      • Wang T
      • Yan M
      • Tang D
      • et al.
      A retrospective, multicenter study of voriconazole trough concentrations and safety in patients with Child-Pugh class C cirrhosis.

      Yamada T, Imai S, Koshizuka Y, et al. Necessity for a Significant Maintenance Dosage Reduction of Voriconazole in Patients With Severe Liver Cirrhosis (Child-Pugh Class C).Biol Pharm Bull. 2018; 41:1112–1118. doi: 10.1248/bpb.b18-00164.

      • Wang T
      • Yan M
      • Tang D
      • et al.
      Therapeutic Drug Monitoring and Safety of Voriconazole Therapy in Patients With Child–Pugh Class B and C Cirrhosis: A Multicenter Study.
      A target trough level ≥0.5 µg/mL may be applicable for prophylaxis. However, a higher cutoff level is required to decrease the occurrence of breakthrough invasive candidiasis (III-B).
      • Trifilio S
      • Singhal S
      • Williams S
      • et al.
      Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole.
      Figure 1
      Figure 1Risk of hepatotoxicity and neurotoxicity at a cutoff trough level of 4.0 µg/mL in studies conducted in Asian locations.
      Figure 2
      Figure 2Risk of hepatotoxicity and neurotoxicity at a cutoff trough level of 5.5 µg/mL in studies conducted in non-Asian locations

      CQ 5. What Is the Dosing Regimen to Achieve the Target Trough Level in Voriconazole?

      Standard Dose Regimen

      A loading dose of 6 mg/kg q12h on the initial day is strongly recommended for intravenous use (I).
      • Chau MM
      • Kong DC
      • van Hal SJ
      • et al.
      Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014.
      ,
      • Chen K
      • Zhang X
      • Ke X
      • et al.
      Individualized Medication of Voriconazole: A Practice Guideline of the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society.
      ,
      • Ullmann AJ
      • Aguado JM
      • Arikan-Akdagli S
      • et al.
      Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline.
      ,
      • Mellinghoff SC
      • Panse J
      • Alakel N
      • et al.
      Primary prophylaxis of invasive fungal infections in patients with haematological malignancies: 2017 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO).
      A maintenance dose of 4 mg/kg q12h is generally recommended for intravenous use in non-Asians (II).
      • Ullmann AJ
      • Aguado JM
      • Arikan-Akdagli S
      • et al.
      Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline.
      ,
      • Pappas PG
      • Kauffman CA
      • Andes DR
      • et al.
      Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America.
      • Troke PF
      • Hockey HP
      • Hope WW.
      Observational study of the clinical efficacy of voriconazole and its relationship to plasma concentrations in patients.
      • Johnson LB
      • Kauffman CA.
      Voriconazole: a new triazole antifungal agent.
      Considering the tendency toward high trough concentrations and high rates of adverse effects in Asian patients,
      • Matsumoto K
      • Ikawa K
      • Abematsu K
      • et al.
      Correlation between voriconazole trough plasma concentration and hepatotoxicity in patients with different CYP2C19 genotypes.
      ,
      • Ueda K
      • Nannya Y
      • Kumano K
      • et al.
      Monitoring trough concentration of voriconazole is important to ensure successful antifungal therapy and to avoid hepatic damage in patients with hematological disorders.
      ,
      • Okuda T
      • Okuda A
      • Watanabe N
      • et al.
      Retrospective serological tests for determining the optimal blood concentration of voriconazole for treating fungal infection.
      ,
      • Matsumoto K
      • Abematsu K
      • Shigemi A
      • et al.
      Therapeutic Drug Monitoring of Voriconazole in Japanese Patients: Analysis Based on Clinical Practice Data.
      ,
      • Hagiwara E
      • Shiihara J
      • Matsushima A
      • et al.
      Usefulness of monitoring plasma voriconazole concentration in patients with chronic necrotizing pulmonary aspergillosis.
      • Kim SH
      • Yim DS
      • Choi SM
      • et al.
      Voriconazole-related severe adverse events: clinical application of therapeutic drug monitoring in Korean patients.
      • Suzuki Y
      • Tokimatsu I
      • Sato Y
      • et al.
      As-sociation of sustained high plasma trough concentration of voriconazole with the incidence of hepatotoxicity.
      • Wang T
      • Zhu H
      • Sun J
      • et al.
      Efficacy and safety of voriconazole and CYP2C19 polymorphism for optimised dosage regimens in patients with invasive fungal infections.
      • Hashemizadeh Z
      • Badiee P
      • Malekhoseini SA
      • et al.
      Observational Study of Associations between Voriconazole Therapeutic Drug Monitoring, Toxicity, and Outcome in Liver Transplant Patients.
      • Hirata A
      • Noto K
      • Ota R
      • et al.
      Voriconazole trough concentration and hepatotoxicity in patients with low serum albumin.
      a maintenance dose of 3 mg/kg is suggested to prevent adverse effects in this group (III-A). A loading dose of 400 mg q12h is recommended for oral administration (II).
      • Johnson LB
      • Kauffman CA.
      Voriconazole: a new triazole antifungal agent.
      A maintenance oral dose of 200 mg q12h is recommended for the treatment of infections with Candida species, except for C glabrata, and C krusei (II).
      • Perez-Pitarch A
      • Guglieri-Lopez B
      • Ferriols-Lisart R
      • et al.
      Pharmacokinetic/Pharmacodynamic Analysis of Voriconazole Against Candida spp. and Aspergillus spp. in Allogeneic Stem Cell Transplant Recipients.
      A maintenance dose of 300 mg q12h is suggested for the treatment of invasive aspergillosis (III-A).
      • Mangal N
      • Hamadeh IS
      • Arwood MJ
      • et al.
      Optimization of Voriconazole Therapy for the Treatment of Invasive Fungal Infections in Adults.
      For oral step-down, the oral dose is suggested to be adjusted with reference to the adjacent dose for intravenous administration, considering the bioavailability of voriconazole is 80% to 90% (III-A).
      • Hamada Y
      • Ueda T
      • Miyazaki Y
      • et al.
      Effects of antifungal stewardship using therapeutic drug monitoring in voriconazole therapy on the prevention and control of hepatotoxicity and visual symptoms: A multicentre study conducted in Japan.
      ,
      • Veringa A
      • Geling S
      • Span LF
      • et al.
      Bioavailability of voriconazole in hospitalised patients.
      • Harada S
      • Niwa T
      • Hoshino Y
      • et al.
      Influence of switching from intravenous to oral administration on serum voriconazole concentration.
      • Hohmann N
      • Kocheise F
      • Carls A
      • et al.
      Dose-Dependent Bioavailability and CYP3A Inhibition Contribute to Non-Linear Pharmacokinetics of Voriconazole.

      Dosing Regimen for Special Conditions

      In patients with underweight or overweight/obesity, because dosing based on actual weight causes supratherapeutic levels, dosing based on ideal weight or adjusted weight are suggested (III-A).
      • Koselke E
      • Kraft S
      • Smith J
      • et al.
      Evaluation of the effect of obesity on voriconazole serum concentrations.
      • Davies-Vorbrodt S
      • Ito JI
      • Tegtmeier BR
      • et al.
      Voriconazole serum concentrations in obese and overweight immunocompromised patients: a retrospective review.
      • Eljaaly K
      • Nix DE.
      Voriconazole Dosing in Obese Patients.
      Weight-based dosing for oral administration using a rounding dose with 50- and 200-mg tablets is suggested in patients who are underweight or overweight/obese (III-A).
      • Davies-Vorbrodt S
      • Ito JI
      • Tegtmeier BR
      • et al.
      Voriconazole serum concentrations in obese and overweight immunocompromised patients: a retrospective review.
      • Eljaaly K
      • Nix DE.
      Voriconazole Dosing in Obese Patients.
      • Richards PG
      • Dang KM
      • Kauffman CA
      • et al.
      Therapeutic drug monitoring and use of an adjusted body weight strategy for high-dose voriconazole therapy.
      • Burkhardt O
      • Thon S
      • Burhenne J
      • et al.
      Sulphobutylether-beta-cyclodextrin accumulation in critically ill patients with acute kidney injury treated with intravenous voriconazole under extended daily dialysis.
      • von Mach MA
      • Burhenne J
      • Weilemann LS.
      Accumulation of the solvent vehicle sulphobutylether beta cyclodextrin sodium in critically ill patients treated with intravenous voriconazole under renal replacement therapy.
      In patients with liver cirrhosis, a loading dose of 5 to 6 mg/kg q12h on the initial day followed by half of the standard daily maintenance dose (q12h or every 24 hours [q24h]) is recommended for patients with Child-Pugh classes A and B (II).
      • Lin XB
      • Lui KY
      • Guo PH
      • et al.
      Population pharmacokinetic model-guided optimization of intravenous voriconazole dosing regimens in critically ill patients with liver dysfunction.
      ,
      • Cota JM
      • Burgess DS.
      Antifungal dose adjustment in renal and hepatic dysfunction: Pharmacokinetic and pharmacodynamic considerations.
      Although halved standard loading doses followed by a quarter of the standard maintenance dose have been reported in patients with Child-Pugh class C in a simulation study,
      • Oda K.
      Development of Software for Antimicrobial PK/PD Simulation incorporating Montecarlo Simulation Based on Microsoft® Office Excel.
      the tolerability has not been confirmed in a clinical study (III-B).
      In patients with hyperbilirubinemia, a loading dose of 200 mg q12h on the initial day followed by maintenance doses of 50 mg q12h is suggested in patients with total bilirubin levels of 3 to 10 mg/dL, and a loading dose of 100 mg q24h followed by 50 mg q24h is suggested in patients with total bilirubin levels ≥10 mg/dL (III-A).
      • Wang T
      • Yan M
      • Tang D
      • et al.
      A retrospective, multicenter study of voriconazole trough concentrations and safety in patients with Child-Pugh class C cirrhosis.

      Yamada T, Imai S, Koshizuka Y, et al. Necessity for a Significant Maintenance Dosage Reduction of Voriconazole in Patients With Severe Liver Cirrhosis (Child-Pugh Class C).Biol Pharm Bull. 2018; 41:1112–1118. doi: 10.1248/bpb.b18-00164.

      • Wang T
      • Yan M
      • Tang D
      • et al.
      Therapeutic Drug Monitoring and Safety of Voriconazole Therapy in Patients With Child–Pugh Class B and C Cirrhosis: A Multicenter Study.
      In patients with impaired renal function, oral voriconazole can be used without dose adjustment (II).
      • Johnson LB
      • Kauffman CA.
      Voriconazole: a new triazole antifungal agent.
      Intravenous administration should be avoided in patients with creatinine clearance <50 mL/min because of the accumulation of sulfobutylether β-cyclodextrin (III-A).
      • Koselke E
      • Kraft S
      • Smith J
      • et al.
      Evaluation of the effect of obesity on voriconazole serum concentrations.
      ,
      • Davies-Vorbrodt S
      • Ito JI
      • Tegtmeier BR
      • et al.
      Voriconazole serum concentrations in obese and overweight immunocompromised patients: a retrospective review.
      However, there is insufficient evidence that the incidence of acute kidney injury is increased by intravenous formulation with sulfobutylether β-cyclodextrin.
      In patients with concomitant use of proton pump inhibitors (PPIs), increased voriconazole exposure with PPIs has been found because of the inhibition of CYP2C19.
      • Blanco Dorado S
      • Maroñas Amigo O
      • Latorre-Pellicer A
      • et al.
      A multicentre prospective study evaluating the impact of proton-pump inhibitors omeprazole and pantoprazole on voriconazole plasma concentrations.
      ,
      • Qi F
      • Zhu L
      • Li N
      • et al.
      Influence of different proton pump inhibitors on the pharmacokinetics of voriconazole.
      However, changing the dosage for initial voriconazole therapy might be unnecessary when a PPI is coadministered, until the TDM result is known (III-A).

      Studies Conducted by the Committee

      Monitoring the Performance of TDM in Accordance With the Previous Guidelines
      • Hamada Y
      • Ueda T
      • Miyazaki Y
      • et al.
      Effects of antifungal stewardship using therapeutic drug monitoring in voriconazole therapy on the prevention and control of hepatotoxicity and visual symptoms: A multicentre study conducted in Japan.

      In total, 401 patients receiving voriconazole were included in the study. Loading doses were administered in 66% of patients. The median maintenance dose was 3.8 mg/kg q12h. A reduced dose was administered in 3 of 13 patients with liver cirrhosis. Voriconazole was intravenously administered in 2 of 26 patients with estimated glomerular filtration rates <30 mL/min/1.73 m2 and in 6 of 35 patients who underwent intermittent hemodialysis or continuous renal replacement therapy. Oral step-down dosing was performed in 40% of patients who were initially administered intravenous voriconazole.
      TDM was performed a median of 6 days after the start of therapy. The median trough level of voriconazole was 3.9 µg/mL. In patients who adhered to the recommended dose, including loading doses, 30% of patients had high trough levels (≥5 µg/mL) and 7% had low levels (<1 µg/mL). Dose modification was performed in 95% of patients with high trough levels (discontinuation: 32 patients; dose reduction: 71 patients) and in 52% of patients with low initial trough levels (discontinuation: 4 patients; dose reduction: 19 patients). Subsequent TDM was performed in 90% of patients who underwent a dose reduction and 100% of patients who underwent a dose increase. TDM was also performed in 70% of patients who did not have a dose adjustment. Because of the dose adjustment, target trough levels were achieved in 87% of patients with dose reductions and in 88% of patients with dose increases.
      Hepatotoxicity occurred in 24 patients (6%), and visual symptoms were experienced in 38 patients (9%). Visual symptoms occurred earlier than hepatotoxicity (median days after the start of therapy: 4 vs 10; P < 0.001). No significant correlation was found between the initial trough level and hepatotoxicity, which indicated that hepatotoxicity was successfully prevented by dose optimization using the initial TDM result. In contrast, a high initial trough level was associated with visual symptoms, possibly because of the early onset of visual symptoms before obtaining the TDM results. As an inevitable consequence, the trough level measured at the onset of adverse effects was significantly associated with hepatotoxicity (AUC = 0.725, P < 0.001) and visual symptoms (AUC = 0.684, P < 0.001). The trough cutoff levels for predicting the occurrence of adverse effects were 3.5 µg/mL for hepatotoxicity and 4.2 µg/mL for visual symptoms.

      Systematic Review and Meta-analysis of Voriconazole Target Trough Levels in Adult Patients

      Safety

      We obtained 2242 articles, and 316 articles were retrieved for full-text review. Finally, 22 studies (Asian locations: 11; non-Asian locations: 11) were included in the meta-analysis (Supplemental Table I).
      • Dolton MJ
      • Ray JE
      • Chen SC
      • et al.
      Multicenter study of voriconazole pharmacokinetics and therapeutic drug monitoring.
      ,
      • Hamada Y
      • Ueda T
      • Miyazaki Y
      • et al.
      Effects of antifungal stewardship using therapeutic drug monitoring in voriconazole therapy on the prevention and control of hepatotoxicity and visual symptoms: A multicentre study conducted in Japan.
      ,
      • Matsumoto K
      • Ikawa K
      • Abematsu K
      • et al.
      Correlation between voriconazole trough plasma concentration and hepatotoxicity in patients with different CYP2C19 genotypes.
      ,
      • Pascual A
      • Calandra T
      • Bolay S
      • et al.
      Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes.
      ,
      • Ruiz J
      • Gordon M
      • Villarreal E
      • et al.
      Impact of Voriconazole Plasma Concentrations on Treatment Response in Critically Ill Patients.
      ,
      • Wang T
      • Yan M
      • Tang D
      • et al.
      A retrospective, multicenter study of voriconazole trough concentrations and safety in patients with Child-Pugh class C cirrhosis.
      ,
      • Ueda K
      • Nannya Y
      • Kumano K
      • et al.
      Monitoring trough concentration of voriconazole is important to ensure successful antifungal therapy and to avoid hepatic damage in patients with hematological disorders.
      ,
      • Okuda T
      • Okuda A
      • Watanabe N
      • et al.
      Retrospective serological tests for determining the optimal blood concentration of voriconazole for treating fungal infection.
      ,
      • Matsumoto K
      • Abematsu K
      • Shigemi A
      • et al.
      Therapeutic Drug Monitoring of Voriconazole in Japanese Patients: Analysis Based on Clinical Practice Data.
      ,
      • Imhof A
      • Schaer DJ
      • Schanz U
      • et al.
      Neurological adverse events to voriconazole: evidence for therapeutic drug monitoring.
      ,
      • Hagiwara E
      • Shiihara J
      • Matsushima A
      • et al.
      Usefulness of monitoring plasma voriconazole concentration in patients with chronic necrotizing pulmonary aspergillosis.
      • Kim SH
      • Yim DS
      • Choi SM
      • et al.
      Voriconazole-related severe adverse events: clinical application of therapeutic drug monitoring in Korean patients.
      • Suzuki Y
      • Tokimatsu I
      • Sato Y
      • et al.
      As-sociation of sustained high plasma trough concentration of voriconazole with the incidence of hepatotoxicity.
      • Wang T
      • Zhu H
      • Sun J
      • et al.
      Efficacy and safety of voriconazole and CYP2C19 polymorphism for optimised dosage regimens in patients with invasive fungal infections.
      • Hashemizadeh Z
      • Badiee P
      • Malekhoseini SA
      • et al.
      Observational Study of Associations between Voriconazole Therapeutic Drug Monitoring, Toxicity, and Outcome in Liver Transplant Patients.
      • Hirata A
      • Noto K
      • Ota R
      • et al.
      Voriconazole trough concentration and hepatotoxicity in patients with low serum albumin.
      ,
      • Koselke E
      • Kraft S
      • Smith J
      • et al.
      Evaluation of the effect of obesity on voriconazole serum concentrations.
      ,
      • Denning DW
      • Ribaud P
      • Milpied N
      • et al.
      Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis.
      • Chu HY
      • Jain R
      • Xie H
      • et al.
      Voriconazole therapeutic drug monitoring: retrospective cohort study of the relationship to clinical outcomes and adverse events.
      • Cabral-Galeano E
      • Ruiz-Camps I
      • Len-Abad O
      • et al.
      Clinical usefulness of therapeutic drug monitoring of voriconazole in a university hospital.
      ,
      • Taghvaye-Masoumi H
      • Hadjibabaie M
      • Ghadimi M
      • et al.
      Association of Voriconazole Trough Plasma Concentration with Efficacy and Incidence of Hepatotoxicity in Iranian Patients with Hematological Malignancies.
      ,
      • Kara E
      • Ekinci PB
      • Metan G.
      Voriconazole therapeutic drug level monitoring: A university hospital experience.
      Because of racial and ethnic differences in the populations, studies conducted in Iran and Turkey were classified as non-Asian locations. The numbers of studies that evaluated safety parameters at each trough cutoff level were 8 (3.0 µg/mL), 11 (4.0 µg/mL), 9 (5.0 µg/mL), 14 (5.5 µg/mL), and 9 (6.0 µg/mL). The assessment of risk of bias is presented in Figure 3.
      Figure 3
      Figure 3Risk of bias for each study included in the meta-analysis. (A) Review authors’ judgments concerning each risk of bias item for each included study. (B) Review authors’ judgments concerning each risk of bias item presented as percentages across all included studies. ? = unclear risk of bias; − = high risk of bias; + = low risk of bias.
      In the analysis of all included studies, significantly higher incidences of hepatotoxicity and nephrotoxicity in patients with higher trough levels of voriconazole were found for all cutoff levels (Supplemental Figures 1 and 2). The risk of adverse effects at each trough cutoff level in studies conducted in Asian and non-Asian locations is given in Table III. A sufficient number of studies (6–8 for hepatotoxicity and 4–5 for neurotoxicity) for meta-analysis was obtained at each trough cutoff level in Asian locations, and significant differences were found for all trough cutoff levels in both hepatotoxicity and neurotoxicity, with the highest OR for 4.0 µg/mL (OR = 7.39; 95% CI, 3.81–14.36 and OR = 5.41; 95% CI, 2.87–10.21, respectively) (Figure 1). In contrast, in non-Asian locations, no more than 1 study was available for any trough cutoff level, except for 5.5 µg/mL (6 studies for hepatotoxicity and 5 studies for neurotoxicity), at which level a significant increase in adverse effects was found for both hepatotoxicity and neurotoxicity (OR = 4.56; 95% CI, 2.31–8.99 and OR = 6.51; 95% CI, 2.25–18.85, respectively) (Figure 2).

      Treatment Success and All-cause Mortality
      • Hanai Y
      • Hamada Y
      • Kimura T
      • et al.
      Favorable Effects of Voriconazole Trough Concentrations Exceeding 1 µg/mL on Treatment Success and All-Cause Mortality: A Systematic Review and Meta-Analysis.

      Most patients had hematologic disorders or a history of solid organ transplantation. Four studies were obtained for all-cause mortality (cutoff trough level of 0.5 µg/mL [1 study], 1.0 µg/mL [4 studies], and 2.0 µg/mL [2 studies]). For treatment success, 14 studies at the cutoff trough level of 1.0 µg/mL, 8 studies at 0.5 µg/mL, and 9 studies at 2.0 µg/mL were evaluated. The rates of all-cause mortality were significantly decreased at trough levels ≥1.0 µg/mL compared with levels <1.0 µg/mL (OR = 0.34; 95% CI, 0.16–0.80). A significantly higher success rate was observed in patients with voriconazole levels above the cutoff trough level than below the cutoff trough level at 0.5 µg/mL and 1.0 µg/mL (OR = 3.48; 95% CI, 1.45–8.34 and OR = 3.35; 95% CI, 1.52–7.38, respectively). However, a significant difference was not found at the cutoff trough level of 2.0 µg/mL.

      Discussion

      Literature Review

      CQ 1. What Are the Recommended PK/PD Parameters for Voriconazole TDM in Clinical Practice?
      In a rat model of Candida infection, nonlinear regression analysis indicated that the AUC/MIC ratio is the PK/PD parameter that predicts treatment outcome.
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      The free fraction can be used to indicate antifungal activity and voriconazole clearance. In a mouse model of disseminated candidiasis, a free AUC/MIC value >25 produced the maximum effect.
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      In patients with hematologic disorders, the clinical efficacy was highly consistent with the cumulative fraction of the response value of the free AUC/MIC ratio.
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      Nearly 40 different population PK models have been reported in adult and pediatric patients.
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      Predictive Value of C-Reactive Protein and Albumin for Temporal Within-Individual Pharmacokinetic Variability of Voriconazole in Pediatric Patients Undergoing Hematopoietic Cell Transplantation.
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      Effects of Letermovir and/or Methylprednisolone Coadministration on Voriconazole Pharmacokinetics in Hematopoietic Stem Cell Transplantation: A Population Pharmacokinetic Study.
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      Population pharmacokinetics, safety and dosing optimization of voriconazole in patients with liver dysfunction: A prospective observational study.
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      Population Pharmacokinetics of Voriconazole in Patients With Invasive Aspergillosis: Serum Albumin Level as a Novel Marker for Clearance and Dosage Optimization.
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      • et al.
      Impact of Albumin and Omeprazole on Steady-State Population Pharmacokinetics of Voriconazole and Development of a Voriconazole Dosing Optimization Model in Thai Patients with Hematologic Diseases.
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      Population Pharmacokinetics of Voriconazole in Chinese Patients with Hematopoietic Stem Cell Transplantation.
      • Kim Y
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      • Park WB
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      A Personalized CYP2C19 Phenotype-Guided Dosing Regimen of Voriconazole Using a Population Pharmacokinetic Analysis.
      • Tang D
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      • et al.
      Identifying factors affecting the pharmacokinetics of voriconazole in patients with liver dysfunction: A population pharmacokinetic approach.
      Ideally, a model should be able to be varied for different races and ethnicities
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      ,
      • Wang J
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      Model-Oriented Dose Optimization of Voriconazole in Critically Ill Children.
      because of differences in the frequency of genetic polymorphisms of CYP2C19 between racial and ethnic groups (15.8% in Asians vs 2.2% in Whites).
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      • et al.
      Bioinformatics research on inter-racial difference in drug metabolism I. Analysis on frequencies of mutant alleles and poor metabolizers on CYP2D6 and CYP2C19.
      Physiologic PK models for voriconazole have also been reported and are expected to be useful for precise dosing.
      • Li X
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      A Physiologically Based Pharmacokinetic Model of Voriconazole Integrating Time-Dependent Inhibition of CYP3A4, Genetic Polymorphisms of CYP2C19 and Predictions of Drug-Drug Interactions.
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      Assessing pharmacokinetic differences in Caucasian and East Asian (Japanese, Chinese and Korean) populations driven by CYP2C19 polymorphism using physiologically-based pharmacokinetic modelling.
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      A physiologically based pharmacokinetic model for voriconazole disposition predicts intestinal first-pass metabolism in children.
      Several types of software for the analysis of voriconazole have been developed.
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      • et al.
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      ,
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      Voriconazole: an audit of hospital-based dosing and monitoring and evaluation of the predictive performance of a dose-prediction software package.
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      Hope et al
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      reported that the target trough level was achieved at 120 hours in 85.7% of patients with software-guided dosing for trough concentrations, which was higher than the expected achievement rate of 33% without using the software. However, a polymorphism test is required with use of this software and the delay in initiation of dosing until receipt of the test results should be considered. The frequency of sampling required for correct evaluation because of the inherent PK variability of voriconazole is another concern.
      As an alternative marker for AUC, the trough concentration has been used in guided dosing. A logistic regression model found a high correlation between the voriconazole trough concentration/MIC and clinical response, and a trough level/MIC of 2 to 5 was reported as the target PK parameter.
      • Ashbee HR
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      • et al.
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      Mangal et al
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      found that both these PK/PD indexes for efficacy (free AUC/MIC ≥25 and trough level/MIC of 2–5) yielded a similar probability of target attainment.
      • Mangal N
      • Hamadeh IS
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      Optimization of Voriconazole Therapy for the Treatment of Invasive Fungal Infections in Adults.
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      Pharmacokinetics of intravenous voriconazole in patients with liver dysfunction: A prospective study in the intensive care unit.
      reported coefficients of determination of 0.951 for the trough concentration and 0.963 for the peak concentration. A relatively broader target range of trough levels has been found for voriconazole
      • Hanai Y
      • Hamada Y
      • Kimura T
      • et al.
      Favorable Effects of Voriconazole Trough Concentrations Exceeding 1 µg/mL on Treatment Success and All-Cause Mortality: A Systematic Review and Meta-Analysis.
      compared with vancomycin for which a target trough level range that ensures both efficacy and tolerability could not be determined.
      • Tsutsuura M
      • Moriyama H
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      • et al.
      The monitoring of vancomycin: a systematic review and meta-analyses of area under the concentration-time curve-guided dosing and trough-guided dosing.
      The effect of trough-guided dosing on tolerability and efficacy was found in an RCT in a Korean population.
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      • et al.
      The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in inva-sive fungal infections: a randomized controlled trial.
      The CYP2C19 genotypes were comparable between the study group and control group. The proportion of patients that discontinued receiving voriconazole treatment because of adverse events was significantly lower in the trough-guided dosing group than in the non-TDM group (4% vs 17%). The response rate was 81% in the trough-guided dosing group, which was significantly higher than the rate of 57% in the non-TDM group. Successful antifungal stewardship using trough-guided dosing of voriconazole for the prevention of hepatotoxicity was reported in a study of Japanese patients conducted by the committee.
      • Hamada Y
      • Ueda T
      • Miyazaki Y
      • et al.
      Effects of antifungal stewardship using therapeutic drug monitoring in voriconazole therapy on the prevention and control of hepatotoxicity and visual symptoms: A multicentre study conducted in Japan.
      With dose adjustments based on the trough level, only 6% of patients experienced hepatotoxicity, which was much lower than previously reported rates.
      • Dolton MJ
      • Ray JE
      • Chen SC
      • et al.
      Multicenter study of voriconazole pharmacokinetics and therapeutic drug monitoring.
      ,
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      • Singer LG
      • et al.
      Risk factors for voriconazole hepatotoxicity at 12 weeks in lung transplant recipients.
      ,
      • Matsumoto K
      • Ikawa K
      • Abematsu K
      • et al.
      Correlation between voriconazole trough plasma concentration and hepatotoxicity in patients with different CYP2C19 genotypes.
      ,
      • Saito T
      • Fujiuchi S
      • Tao Y
      • et al.
      Efficacy and safety of voriconazole in the treatment of chronic pulmonary aspergillosis: experience in Japan.
      CQ 2. What Are the Indications for TDM With Voriconazole?

      Influence of Genetic Polymorphisms of CYP2C19 in Asian and Non-Asian Populations

      In a systematic review and meta-analysis, being an ultrarapid/rapid metabolizer was a significant risk factor for lower trough levels, compared with an intermediate/poor metabolizer, and was associated with reduced treatment success.
      • Li X
      • Yu C
      • Wang T
      • et al.
      Effect of Cytochrome P450 2C19 Polymorphisms on the Clinical Outcomes of Voriconazole: A Systematic Review and Meta-Analysis.
      A Spanish pharmacogenetic/PK multicenter study found that, compared with patients who had other phenotypes, rapid metabolizers and ultrarapid metabolizers had lower voriconazole plasma concentrations; this finding suggests the possible clinical efficacy of CYP2C19 genotype–guided voriconazole dosing to achieve therapeutic concentrations early in treatment.
      • Blanco-Dorado S
      • Maroñas O
      • Latorre-Pellicer A
      • et al.
      Impact of CYP2C19 Genotype and Drug Interactions on Voriconazole Plasma Concentrations: A Spain Pharmacogenetic-Pharmacokinetic Prospective Multicenter Study.
      The median initial trough level was only 1.8 µg/mL, and low voriconazole concentrations (<1.0 µg/mL) were observed in 42% of patients in a study conducted in the United States.
      • Trifilio SM
      • Yarnold PR
      • Scheetz MH
      • et al.
      Serial plasma voriconazole concentrations after allogeneic hematopoietic stem cell transplantation.
      In a study conducted in Switzerland,
      • Pascual A
      • Calandra T
      • Bolay S
      • et al.
      Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes.
      the median trough level was 1.7 µg/mL in patients with a maintenance dose of 3.5 mg/kg q12h and 2.9 µg/mL in patients with a maintenance dose ≥4.0 mg/kg q12h; the proportion of patients with low trough concentrations (<1 µg/mL) was 25%.
      Poor metabolizers are susceptible to having greater trough concentrations, compared with other types of metabolizers, and are at risk of adverse effects. Asian populations have a higher proportion of poor metabolizers (13%–23%) than White (2%–5%) or African (6%) populations.
      • Shimizu T
      • Ochiai H
      • Asell F
      • et al.
      Bioinformatics research on inter-racial difference in drug metabolism I. Analysis on frequencies of mutant alleles and poor metabolizers on CYP2D6 and CYP2C19.
      ,
      • Park WB
      • Kim NH
      • Kim KH
      • et al.
      The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in inva-sive fungal infections: a randomized controlled trial.
      ,
      • Chen L
      • Qin S
      • Xie J
      • et al.
      Genetic polymorphism analysis of CYP2C19 in Chinese Han populations from different geographic areas of mainland China.
      ,
      • Yu G
      • Li GF
      • Atomoxetine Markowitz J.S.
      A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition.
      • Li-Wan-Po A
      • Girard T
      • Farndon P
      • et al.
      Pharmacogenetics of CYP2C19: Functional and clinical implications of a new variant CYP2C19*17.
      • Amsden JR
      • Gubbins P.O.
      Pharmacogenomics of triazole antifungal agents: Implications for safety, tolerability and efficacy.
      • Allegra S
      • Fatiguso G
      • Francia S
      • et al.
      Pharmacogenetic of voriconazole antifungal agent in pediatric patients.
      In a multicenter study conducted in Japan,
      • Hamada Y
      • Ueda T
      • Miyazaki Y
      • et al.
      Effects of antifungal stewardship using therapeutic drug monitoring in voriconazole therapy on the prevention and control of hepatotoxicity and visual symptoms: A multicentre study conducted in Japan.
      the median trough level was 3.9 µg/mL in patients with adequate dosing, including the loading dose, and 30% of patients had high initial trough levels (≥5 µg/mL); only 7% of patients had low initial trough levels (<1.0 µg/mL). Similarly, in a multicenter study conducted in Korea, the mean (SD) initial trough level was 4.7 (3.0) µg/mL, and the proportion of patients with high trough levels (≥5.5 µg/mL) was 38%. The proportion of patients with low trough levels (<1.0 µg/mL) was only 11%, with a mean loading dose of 5.8 mg/kg q12h on the initial day and a mean maintenance dose of 3.9 mg/kg q12h.
      • Park WB
      • Kim NH
      • Kim KH
      • et al.
      The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in inva-sive fungal infections: a randomized controlled trial.

      Patients With Liver Cirrhosis

      Although the tolerability of voriconazole has not been confirmed for patients with Child-Pugh class C, in a retrospective, multicenter study in which the dose of voriconazole was reduced to 200 mg/d as a maintenance dose in 34 patients with Child-Pugh class C, the mean (SD) trough values were as high as 4.4 (2.1) µg/mL for 2 divided doses and 5.4 (2.0) µg/mL for a once-daily dose.
      • Wang T
      • Yan M
      • Tang D
      • et al.
      A retrospective, multicenter study of voriconazole trough concentrations and safety in patients with Child-Pugh class C cirrhosis.
      A retrospective analysis of patients with Child-Pugh class C found that an adequate trough concentration was obtained with a decreased dose of 2.1 mg/kg/d.

      Yamada T, Imai S, Koshizuka Y, et al. Necessity for a Significant Maintenance Dosage Reduction of Voriconazole in Patients With Severe Liver Cirrhosis (Child-Pugh Class C).Biol Pharm Bull. 2018; 41:1112–1118. doi: 10.1248/bpb.b18-00164.

      Wang et al
      • Wang T
      • Yan M
      • Tang D
      • et al.
      Therapeutic Drug Monitoring and Safety of Voriconazole Therapy in Patients With Child–Pugh Class B and C Cirrhosis: A Multicenter Study.
      reported that 78 patients with cirrhosis and Child-Pugh classes B and C had elevated trough levels of voriconazole, even at half the usual maintenance dose.

      Patients With Invasive Aspergillosis and Critically Ill Patients

      A classification and regression tree analysis of patients with deep-seated fungal infections, including invasive pulmonary aspergillosis, found an association between the clinical response to voriconazole and the serum concentration.
      • Smith J
      • Safdar N
      • Knasinski V
      • et al.
      Voriconazole therapeutic drug monitoring.
      In a study of patients admitted to the intensive care unit, 27.3% had concentrations above the target and 18.2% below.
      • Ruiz J
      • Gordon M
      • Villarreal E
      • et al.
      Impact of Voriconazole Plasma Concentrations on Treatment Response in Critically Ill Patients.
      Similarly, 129 of 349 serum points measured (37%) were outside the therapeutic concentrations in patients admitted to the intensive care unit.
      • van Wanrooy MJ
      • Rodgers MG
      • Span LF
      • et al.
      Voriconazole Therapeutic Drug Monitoring Practices in Intensive Care.

      Patients With Adverse Effects After the Start of Voriconazole Treatment

      Matsumoto et al
      • Matsumoto K
      • Abematsu K
      • Shigemi A
      • et al.
      Therapeutic Drug Monitoring of Voriconazole in Japanese Patients: Analysis Based on Clinical Practice Data.
      reported that 15 patients who developed hepatotoxicity after treatment with voriconazole were able to complete treatment with a dose adjustment using TDM, and liver function improved during the subsequent treatment. In a Japanese multicenter study,
      • Hamada Y
      • Ueda T
      • Miyazaki Y
      • et al.
      Effects of antifungal stewardship using therapeutic drug monitoring in voriconazole therapy on the prevention and control of hepatotoxicity and visual symptoms: A multicentre study conducted in Japan.
      voriconazole treatment discontinuation or dose reduction was more frequently performed in patients with hepatotoxicity than in those with visual symptoms. All patients with hepatotoxicity subsequently achieved a target trough range with dose reduction, and the hepatotoxicity improved in 89% of patients. In contrast, visual symptoms improved irrespective of dose adjustment in most patients.
      An increase in the serum voriconazole concentration by 1 µg/mL is predicted to increase the risk of visual symptoms by 4.7%.
      • Tan K
      • Brayshaw N
      • Tomaszewski K
      • et al.
      Investigation of the potential relationships between plasma voriconazole concentrations and visual adverse events or liver function test abnormalities.
      Imhof et al
      • Imhof A
      • Schaer DJ
      • Schanz U
      • et al.
      Neurological adverse events to voriconazole: evidence for therapeutic drug monitoring.
      found that in all patients with neuropathy, the neuropathy resolved during voriconazole treatment or within 4 days after stopping therapy. Because visual symptoms are usually transient and improvement is obtained without dose adjustment,
      • Hamada Y
      • Ueda T
      • Miyazaki Y
      • et al.
      Effects of antifungal stewardship using therapeutic drug monitoring in voriconazole therapy on the prevention and control of hepatotoxicity and visual symptoms: A multicentre study conducted in Japan.
      TDM is recommended only when visual disturbances persist.

      Transplant Recipients Receiving Voriconazole for Prophylaxis

      Primary antifungal prophylaxis is recommended during the first 75 days after a hematopoietic cell transplant (HCT). High-risk patients usually receive antifungal prophylaxis beyond 100 days after an HCT.
      • Marks DI
      • Liu Q
      • Slavin M.
      Voriconazole for prophylaxis of invasive fungal infections after allogeneic hematopoietic stem cell transplantation.
      In allogeneic HCT recipients who received voriconazole for fungal infection prophylaxis, breakthrough infection occurred in 6 of 43 patients with blood levels ˂2 µg/mL, and no infection occurred in 24 patients who received higher levels of voriconazole.
      • Miyakis S
      • van Hal SJ
      • Ray J.
      Voriconazole concentrations and outcome of invasive fungal infections.
      In addition, a study of voriconazole prophylaxis in allogeneic hematopoietic stem cell transplantation found that serum concentrations fluctuated even at standard doses.
      • Matsumoto K
      • Ikawa K
      • Abematsu K
      • et al.
      Correlation between voriconazole trough plasma concentration and hepatotoxicity in patients with different CYP2C19 genotypes.
      Trifilio et al
      • Trifilio S
      • Pennick G
      • Pi J
      • et al.
      Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients.
      found that undetectable levels of voriconazole (<0.2 µg/mL) were observed in 15% of HCT recipients receiving prophylactic voriconazole. Chan et al
      • Chan SY
      • Hughes RM
      • Woo K
      • et al.
      Reasons for voriconazole prophylaxis discontinuation in allogeneic hematopoietic cell transplant recipients: A real-life paradigm.
      reported that hepatotoxicity during the first 2 weeks after HCT is a significant predictor of early voriconazole antifungal prophylaxis discontinuation; the authors suspected that a lack of routine TDM in their series could have affected the results. Although beneficial effects of TDM for successful outcomes were not found among patients receiving voriconazole for prophylaxis in a meta-analysis,
      • Luong ML
      • Al-Dabbagh M
      • Groll AH
      • et al.
      Utility of voriconazole therapeutic drug monitoring: a meta-analysis.
      TDM appears to be a prudent approach when using voriconazole as prophylaxis against invasive fungal infections, particularly in Asian patients.

      CQ 3. When Should TDM Be Performed for Voriconazole?

      TDM was conducted a median of 6 days after the initiation of voriconazole treatment in a Japanese multicenter study.
      • Hamada Y
      • Ueda T
      • Miyazaki Y
      • et al.
      Effects of antifungal stewardship using therapeutic drug monitoring in voriconazole therapy on the prevention and control of hepatotoxicity and visual symptoms: A multicentre study conducted in Japan.
      McCreary et al
      • McCreary EK
      • Bayless M
      • Van AP
      • et al.
      Impact of Triazole Therapeutic Drug Monitoring Availability and Timing.
      reported that an in-house assay was conducted in only one-third of institutions, and the mean time for result availability was 67 hours for a second-out assay. At least 7 to 8 days were required before the result of TDM was known if a blood sample was taken on day 5 or later. Adverse effects occurred within 8 days after voriconazole therapy initiation in 50.0% of patients with hepatotoxicity and 81.6% of patients with visual symptoms.
      • Hamada Y
      • Ueda T
      • Miyazaki Y
      • et al.
      Effects of antifungal stewardship using therapeutic drug monitoring in voriconazole therapy on the prevention and control of hepatotoxicity and visual symptoms: A multicentre study conducted in Japan.
      In addition, early dose optimization is mandatory in critically ill patients, such as those with invasive Aspergillus infections.
      • Imani S
      • Alffenaar JW
      • Cotta MO
      • et al.
      Therapeutic drug monitoring of commonly used anti-infective agents: A nationwide cross-sectional survey of Australian hospital practices.
      Hence, to prevent adverse effects and increase clinical efficacy, TDM started earlier than 5 days after the initiation of voriconazole treatment is ideal if proper assessment of the voriconazole concentration can be obtained at that time.
      Trough concentration-time profiles indicate that oral voriconazole reaches steady-state concentrations after 5 to 8 days of treatment using a regimen without a loading dose.
      • Purkins L
      • Wood N
      • Greenhalgh K
      • et al.
      The pharmacokinetics and safety of intravenous voriconazole - a novel wide-spectrum antifungal agent.
      However, trough levels reach concentrations close to the steady-state level within 5 days with a loading dose.
      • Purkins L
      • Wood N
      • Greenhalgh K
      • et al.
      The pharmacokinetics and safety of intravenous voriconazole - a novel wide-spectrum antifungal agent.
      ,
      • Theuretzbacher U
      • Ihle F
      • Derendorf H.
      Pharmacokinetic/pharmacodynamic profile of voriconazole.
      Several guidelines
      • Chau MM
      • Kong DC
      • van Hal SJ
      • et al.
      Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014.
      ,
      • Purkins L
      • Wood N
      • Greenhalgh K
      • et al.
      The pharmacokinetics and safety of intravenous voriconazole - a novel wide-spectrum antifungal agent.
      ,
      • Mellinghoff SC
      • Panse J
      • Alakel N
      • et al.
      Primary prophylaxis of invasive fungal infections in patients with haematological malignancies: 2017 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO).
      ,
      • Stott KE
      • Hope WW.
      Therapeutic drug monitoring for invasive mould infections and disease: pharmacokinetic and pharmacodynamic considerations.
      recommend that TDM should be performed on days 2 to 5. However, the results of TDM only reflect the loading dose on the initial day if a blood sample is obtained on day 2 before the start of maintenance dosing. In a previous report, with a loading dose regimen of 400 mg q12h on day 1 followed by a 200-mg q12 maintenance dose, the highest trough concentration was observed on day 2, and a concentration near the steady state was maintained after day 3 throughout the dosing period of 10 days.
      • Ullmann AJ
      • Aguado JM
      • Arikan-Akdagli S
      • et al.
      Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline.
      The Practice Guideline of the Division of TDM by the Chinese Pharmacological Society
      • Chen K
      • Zhang X
      • Ke X
      • et al.
      Individualized Medication of Voriconazole: A Practice Guideline of the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society.
      suggests that the initial blood sample should be taken on day 3 of treatment when a loading dose of voriconazole is given.

      CQ 4. What Is the Target Trough Level for Voriconazole?

      Although a target trough concentration of 1.0 to 5.5 mg/L is widely accepted,
      • Park WB
      • Kim NH
      • Kim KH
      • et al.
      The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in inva-sive fungal infections: a randomized controlled trial.
      ,
      • Pascual A
      • Calandra T
      • Bolay S
      • et al.
      Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes.
      ,
      • Brüggemann RJ
      • Donnelly JP
      • Aarnoutse RE
      • et al.
      Therapeutic drug monitoring of voriconazole.
      this value is derived from relatively low-quality evidence.
      • Chen L
      • Qin S
      • Xie J
      • et al.
      Genetic polymorphism analysis of CYP2C19 in Chinese Han populations from different geographic areas of mainland China.
      In our meta-analysis, the probability of mortality was significantly decreased only at a cutoff value ≥1.0 µg/mL (OR = 0.34; 95% CI, 0.16–0.80). A similar OR for treatment success was observed at concentrations ≥0.5 µg/mL (OR = 3.48; 95% CI, 1.45–8.34) and ≥1 µg/mL (OR = 3.35; 95% CI, 1.52–7.38).
      • Hanai Y
      • Hamada Y
      • Kimura T
      • et al.
      Favorable Effects of Voriconazole Trough Concentrations Exceeding 1 µg/mL on Treatment Success and All-Cause Mortality: A Systematic Review and Meta-Analysis.
      A recent systematic review and meta-analysis by Lee et al
      • Lee J
      • Ng P
      • Hamandi B
      • et al.
      Effect of Therapeutic Drug Monitoring and Cytochrome P450 2C19 Genotyping on Clinical Outcomes of Voriconazole: A Systematic Review.
      also found that voriconazole trough concentrations ≥1.0 mg/L were associated with treatment success. In the safety analysis, the upper threshold of trough levels was determined separately in non-Asian and Asian populations. Higher incidences of hepatotoxicity and neurotoxicity were observed at higher concentrations for all cutoff values in Asian patients, and the highest ORs for these adverse effects were observed when the cutoff value was set at a trough level of 4 µg/mL (Table III and Figure 1). The reported trough concentration cutoffs for predicting adverse effects in Japanese patients are 3.5 µg/mL for hepatotoxicity and 4.2 µg/mL for visual symptoms.
      • Hamada Y
      • Ueda T
      • Miyazaki Y
      • et al.
      Effects of antifungal stewardship using therapeutic drug monitoring in voriconazole therapy on the prevention and control of hepatotoxicity and visual symptoms: A multicentre study conducted in Japan.
      Table IIIRisk of hepatotoxicity and neurotoxicity at each trough cutoff level in the studies conducted in Asian locationsand non-Asian locations.
      Adverse EffectCut-off Trough Level (µg/mL)No. of StudiesNo. of PatientsOdds Ratio (95% CI)I2, %P
      Hepatotoxicity
      Asian location<3.0 vs ≥3.066675.66 (3.21–9.99)0<0.001
      <4.0 vs ≥4.087357.39 (3.81–14.36)33<0.001
      <5.0 vs ≥5.076964.35 (2.48–7.63)1<0.001
      <5.5 vs ≥5.566673.34 (1.76–6.35)3<0.001
      <6.0 vs ≥6.076924.54 (2.34–8.81)0<0.001
      Non-Asian location<3.0 vs ≥3.00
      <4.0 vs ≥4.013014.22 (2.32–87.03)0.004
      <5.0 vs ≥5.00
      <5.5 vs ≥5.564934.56 (2.31–8.99)2<0.001
      <6.0 vs ≥6.011162.14 (0.72–6.42)0.17
      Neurotoxicity
      Asian location<3.0 vs ≥3.044812.72 (1.43–5.19)00.002
      <4.0 vs ≥4.044815.41 (2.87–10.21)0<0.001
      <5.0 vs ≥5.044813.01 (0.92–9.83)350.07
      <5.5 vs ≥5.544813.58 (1.83–6.98)0<0.001
      <6.0 vs ≥6.055063.67 (1.87–7.18)0<0.001
      Non-Asian location<3.0 vs ≥3.01262.00 (0.30–13.51)0.48
      <4.0 vs ≥4.012611.33 (1.40–92.06)0.02
      <5.0 vs ≥5.0120140.00 (8.20–195.08)<0.001
      <5.5 vs ≥5.554036.51 (2.25–18.85)400.001
      <6.0 vs ≥6.00
      Jin et al
      • Jin H
      • Wang T
      • Falcione BA
      • et al.
      Trough concentration of voriconazole and its relationship with efficacy and safety: A systematic review and meta-analysis.
      observed a tendency toward an increased risk of hepatotoxicity at high cutoff concentrations (5.5 and 6.0 µg/mL) in a study conducted in non-Asian locations, although the difference was not significant. Our meta-analysis found that trough levels ≥5.5 µg/mL resulted in significant increases in both hepatotoxicity and neurotoxicity in a non-Asian location (Table III and Figure 2). Because sufficient data are not available for the cutoff trough levels in non-Asians, except for 5.5 µg/mL, the higher upper threshold concentration in non-Asians does not mean that non-Asian patients are less vulnerable to adverse effects than Asians.
      The MIC value has a substantial impact on exposure-response relationships. The probability of a clinical response is maximal with a trough level/MIC ratio of 2 to 5.
      • Troke PF
      • Hockey HP
      • Hope WW.
      Observational study of the clinical efficacy of voriconazole and its relationship to plasma concentrations in patients.
      This ratio is a useful guide for therapy when the MIC value is known and enables prompt dosage escalation or a change from voriconazole to another drug. Target trough levels were estimated to be 1 and 2 µg/mL against Aspergillus fumigatus isolates by the Clinical and Laboratory Standards Institute (CLSI) and MIC values of 0.5 and 1 µg/mL (European Committee on Antimicrobial Susceptibility Testing [EUCAST]: 1 and 2 µg/mL) against Candida species, respectively,
      • Siopi M
      • Mavridou E
      • Mouton JW
      • et al.
      Susceptibility breakpoints and target values for therapeutic drug monitoring of voriconazole and Aspergillus fumigatus in an in vitro pharmacokinetic/pharmacodynamic model.
      in an in vitro PK/PD model. The highest MIC value at which the PK/PD target was attained without exceeding the toxicity cutoff trough levels was 2 µg/mL in the CLSI study (4 µg/mL in the EUCAST study), and the use of voriconazole should be avoided against isolates with MIC values higher than these values. Considering that the MIC distribution of A fumigatus isolates was 48.0%, 39.3%, 10.5%, and 2.3% for MIC values of ≤0.25, 0.5, 1, and ≥2 µg/mL,
      • Espinel-Ingroff A
      • Diekema DJ
      • Fothergill A
      • et al.
      Wild-type MIC distributions and epidemiological cutoff values for the triazoles and six Aspergillus spp. for the CLSI broth microdilution method (M38-A2 document).
      respectively, in CLSI, a trough level of 2 µg/mL is recommended for PK/PD target attainment in the treatment of invasive aspergillosis in institutions where the MIC value is not routinely measured.
      Trough levels ≥4 µg/mL, which are not clinically feasible, are necessary for efficacy against C glabrata and C krusei isolates.
      • Beredaki MI
      • Georgiou PC
      • Siopi M
      • et al.
      Voriconazole efficacy against Candida glabrata and Candida krusei: preclinical data using a validated in vitro pharmacokinetic/pharmacodynamic model.
      In EUCAST, Arendrup et al
      • Arendrup MC
      • Friberg N
      • Mares M
      • et al.
      How to interpret MICs of antifungal compounds according to the revised clinical breakpoints v. 10.0 European committee on antimicrobial susceptibility testing (EUCAST).
      recommended a trough level of 0.5 µg/mL for the prophylactic use of voriconazole. Trifilio et al
      • Trifilio S
      • Singhal S
      • Williams S
      • et al.
      Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole.
      analyzed breakthrough infections after allogeneic HCT in patients receiving prophylactic voriconazole. Although prophylaxis could prevent Aspergillus infections, breakthrough candidiasis occurred caused by C glabrata and C krusei.
      • Trifilio S
      • Singhal S
      • Williams S
      • et al.
      Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole.

      CQ 5. What Is the Dosing Regimen to Achieve the Target Trough Level for Voriconazole?

      Trifilio et al
      • Trifilio S
      • Pennick G
      • Pi J
      • et al.
      Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients.
      reported that a median absolute daily dose of 400 mg of voriconazole corresponded to a median daily dose of only 5.4 mg/kg (2.7 mg/kg q12h), which is below the recommended daily dose (3–4 mg/kg q12h), and 44% of patients had trough levels <1 µg/mL. Fixed doses of oral voriconazole resulted in lower blood levels than weight-based dosing in overweight patients.
      • Hoenigl M
      • Duettmann W
      • Raggam RB
      • et al.
      Potential factors for inadequate voriconazole plasma concentrations in intensive care unit patients and patients with hematological malignancies.
      In obese/overweight patients, the blood concentrations of voriconazole were higher when the actual weight was used for weight-based dosing rather than dosing based on ideal weight or adjusted weight.
      • Koselke E
      • Kraft S
      • Smith J
      • et al.
      Evaluation of the effect of obesity on voriconazole serum concentrations.
      ,
      • Davies-Vorbrodt S
      • Ito JI
      • Tegtmeier BR
      • et al.
      Voriconazole serum concentrations in obese and overweight immunocompromised patients: a retrospective review.
      ,
      • Hoenigl M
      • Duettmann W
      • Raggam RB
      • et al.
      Potential factors for inadequate voriconazole plasma concentrations in intensive care unit patients and patients with hematological malignancies.
      A recent retrospective study indicated that there were no significant differences in achievement of the target trough concentrations in obese patients using an adjusted weight.
      • Richards PG
      • Dang KM
      • Kauffman CA
      • et al.
      Therapeutic drug monitoring and use of an adjusted body weight strategy for high-dose voriconazole therapy.
      Eljaaly et al
      • Eljaaly K
      • Nix DE.
      Voriconazole Dosing in Obese Patients.
      recommend dosing based on ideal weight in most obese patients, whereas more aggressive doses using adjusted weight are suggested in patients with serious invasive fungal infection. The standard dose results in higher blood levels of voriconazole in underweight patients than levels in patients with healthy weight.
      • Berge M
      • Guillemain R
      • Trégouet DA
      • et al.
      Effect of cytochrome P450 2C19 genotype on voriconazole exposure in cystic fibrosis lung transplant patients.
      Several authors have found that different doses of voriconazole might be required for patients with invasive candidiasis and invasive aspergillosis. Perez-Pitarch et al
      • Perez-Pitarch A
      • Guglieri-Lopez B
      • Ferriols-Lisart R
      • et al.
      Pharmacokinetic/Pharmacodynamic Analysis of Voriconazole Against Candida spp. and Aspergillus spp. in Allogeneic Stem Cell Transplant Recipients.
      conducted a PK/PD analysis in allogeneic stem cell transplant recipients to investigate the probability of target attainment. More than 90% probability of target attainment was achieved for all Candida species, except for C glabrata and C krusei, with 200-mg q12h administration. However, 300 mg q12h was required for Aspergillus infections with A fumigatus, Aspergillus flavus, Aspergillus nidulans, or Aspergillus terreus; 400 mg q12h was required for Aspergillus niger infections. The use of increased voriconazole doses (eg, 600 mg q12h) in patients who were rapid/ultrarapid metabolizers, compared with other metabolizers, has been reported for the treatment of invasive aspergillosis.
      • Mangal N
      • Hamadeh IS
      • Arwood MJ
      • et al.
      Optimization of Voriconazole Therapy for the Treatment of Invasive Fungal Infections in Adults.
      However, initial dose adjustments according to phenotype are not commonly performed in patients with invasive candidiasis.
      A study on voriconazole interactions
      • Mikus G
      • Schöwel V
      • Drzewinska M
      • et al.
      Potent cytochrome P450 2C19 genotype-related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir.
      found that concurrent administration of CYP3A4 inhibitors may lead to increased voriconazole exposure and the development of adverse effects. Studies of the interaction between voriconazole and PPIs
      • Blanco Dorado S
      • Maroñas Amigo O
      • Latorre-Pellicer A
      • et al.
      A multicentre prospective study evaluating the impact of proton-pump inhibitors omeprazole and pantoprazole on voriconazole plasma concentrations.
      ,
      • Qi F
      • Zhu L
      • Li N
      • et al.
      Influence of different proton pump inhibitors on the pharmacokinetics of voriconazole.
      ,
      • Huang Q
      • Liu Q
      • Yin T
      • et al.
      Effect of proton pump inhibitors on voriconazole concentrations in Chinese patients with malignant hematological diseases.
      found that blood levels of both voriconazole and PPI fluctuate, with omeprazole having the highest intensity of action. The use of omeprazole in patients receiving voriconazole increases trough voriconazole levels,
      • Guinea J
      • Escribano P
      • Marcos-Zambrano LJ
      • et al.
      Therapeutic drug monitoring of voriconazole helps to decrease the percentage of patients with off-target trough serum levels.
      and omeprazole has been used to augment subtherapeutic voriconazole concentrations for the treatment of aspergillosis.
      • Wood N
      • Tan K
      • Purkins L
      • et al.
      Effect of omeprazole on the steady-state pharmacokinetics of voriconazole.

      Limitations

      This guideline has several limitations. First, few RCTs were available to assess the recommendations because of the nature of TDM. Second, studies with target trough cutoff levels, other than 5.5 µg/mL, to prevent adverse effects are required in non-Asian locations. Third, the tolerability of loading doses q12h on the initial day followed by a maintenance dose of 3 mg/kg q12h in Asians should be confirmed in a prospective study. Finally, whether target trough levels ≥2 µg/mL improve the efficacy outcomes in patients with invasive aspergillosis should be investigated in prospective clinical studies.

      Conclusions

      We made recommendations using surveillance of TDM performance in a multicenter study, a systematic review comparing the incidence of adverse effects, and a systematic review and meta-analysis of the target trough level range in Asians and non-Asians. To our knowledge, this analysis was the first meta-analysis to indicate that a target trough cutoff level <5.5 µg/mL could be used to prevent adverse effects in non-Asians. In addition, the upper threshold of the trough level was lower in Asians (ie, <4.0 µg/mL) than non-Asians according to our meta-analysis. We emphasize the need for a decrease in the standard dose for Asian populations because of the high incidence of supratherapeutic concentrations observed in the analysis of TDM practice in Japan. In conclusion, different indications, timings, and target trough levels for TDM and different regimens to prevent overdose are required for Asian and non-Asian populations.

      Funding Sources

      This work was supported in part by the Research Program on Emerging and Re-emerging Infectious Diseases of the Japan Agency for Medical Research and Development grants 22fk0108135h0803 and 21fk0108135h0802. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

      Declaration of Interest

      Y. Takesue received grant support from Shionogi & Co Ltd and payment for lectures from Astellas Pharma Inc and MSD Japan. K. Matsumoto received grant support from Meiji Seika Pharma Co Ltd and Sumitomo Pharma Co Ltd and speaker honoraria from Meiji Seika Pharma Co Ltd. The authors have indicated that they have no other conflicts of interest regarding the content of this article.

      Acknowledgments

      We thank Victoria Muir, PhD, and Analisa Avila, MPH, ELS, from Edanz (https://jp.edanz.com/ac) for editing a draft of the manuscript. Author contributions are as follows: conceptualization: Yoshio Takesue, Yuki Hanai, Kazutaka Oda, and Yukihiro Hamada; data curation: Yoshio Takesue, Yuki Hanai, and Takashi Ueda; formal analysis: Yoshio Takesue, Yuki Hanai, and Takashi Ueda; funding acquisition: Yoshio Takesue and Yoshitsugu Miyazaki; investigation: Yuki Hanai, Kazutaka Oda, Yukihiro Hamada, Takashi Ueda, Toshihiko Mayumi, Kazuaki Matsumoto, Satoshi Fujii, Yoshiko Takahashi, and Toshimi Kimura; methodology: Yoshio Takesue, Yuki Hanai, Kazutaka Oda, Yukihiro Hamada, and Takashi Ueda; project administration: Yoshio Takesue, Yuki Hanai, and Toshimi Kimura Toshimi Kimura; resources: Yoshio Takesue, Yuki Hanai, Kazutaka Oda, Yukihiro Hamada, and Takashi Ueda; software: Yoshio Takesue and Yuki Hanai; supervision: Toshimi Kimura; validation: Yoshio Takesue and Yuki Hanai; visualization: Yoshio Takesue and Yuki Hanai; writing–original draft preparation: Yoshio Takesue, Yuki Hanai, Kazutaka Oda, Yukihiro Hamada, and Takashi Ueda; writing–review and editing: Yoshio Takesue, Yuki Hanai, Kazutaka Oda, Yukihiro Hamada, and Takashi Ueda. All authors have read and agreed to the published version of the manuscript.

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