Clinical Therapeutics

Review of Linagliptin for the Treatment of Type 2 Diabetes Mellitus

Joshua J. Neumiller, Stephen M. Setter — 2012-03-23

Abstract: Background: Linagliptin is a dipeptidyl peptidase-4 inhibitor that was approved in 2011 by the US Food and Drug Administration as a treatment adjunctive to diet and exercise for the improvement of glycemic control in adults with type 2 diabetes mellitus (T2DM). Objective: The purpose of this article is to review the pharmacology, pharmacokinetic properties, efficacy, tolerability including drug–drug interactions, contraindications/precautions, and dosage and administration of linagliptin, and the potential role of linagliptin in the management of glycemia in adults with T2DM. Methods: MEDLINE (1966–January 12, 2012), PubMed (1950–January 12, 2012), Science Direct (1994–January 12, 2012), Web of Science (1980–January 12, 2012), and the American Diabetes Association Scientific Abstracts (2008–2011) were searched using the term linagliptin. Articles and abstracts published in English, both original research and review articles, were identified for review. Reference lists from identified articles were also searched for additional references of interest. Manufacturers' prescribing information was additionally examined. Results: Data from clinical trials of linagliptin suggest clinical efficacy in terms of reductions in hemoglobin A1c (A1c), fasting plasma glucose, and postprandial glucose when linagliptin was administered as monotherapy or in combination with other oral antidiabetic agents, with placebo-subtracted A1c changes ranging from −0.47% to −0.69% in placebo-controlled trials. Adverse events that occurred in ≥2% of patients treated with linagliptin and at a prevalence of ≥2-fold greater compared with placebo were nasopharyngitis, hyperlipidemia, cough, hypertriglyceridemia, and weight increase (when used in combination with a thiazolidinedione [TZD]). Although linagliptin administered as monotherapy or in combination with metformin or a TZD may convey a low risk for hypoglycemia (0%–1.2%), caution is warranted when linagliptin is administered in combination with insulin secretagogues due to an increased risk for hypoglycemic events. Dosage adjustments based on renal or hepatic function are not required. Additionally, according to the currently approved prescribing information, the efficacy of linagliptin may be limited in patients receiving concurrent inducers of the cytochrome P450 3A4 isozyme or P-glycoprotein (eg, rifampin). Conclusions: Based on the findings from the present review, patients and clinicians should be aware of the risk for hypoglycemia when linagliptin is prescribed as a treatment adjunctive to a regimen of an insulin secretagogue. An initial dose decrease in the secretagogue should be considered to prevent hypoglycemic events. Dosage adjustment of linagliptin is not required in patients with renal impairment.

Belimumab: Review of Use in Systemic Lupus Erythematosus

Eric G. Boyce, Bryan E. Fusco — 2012-04-05

Abstract: Background: Belimumab, a monoclonal antibody that inhibits B-lymphocyte stimulating protein, was the first biologic agent approved for, and the first drug approved in 55 years for, the treatment of systemic lupus erythematosus (SLE) by the US Food and Drug Administration (FDA). Objective: This article reviews the current research on belimumab and provides recommendations on its use in the treatment of SLE. Methods: The Cochrane Library, EBSCO, IPA, MEDLINE, and SCOPUS were searched for research published from January 2000 to November 2011, using the search terms belimumab, Benlysta, and Lympho-Stat B. Selection criteria included peer-reviewed original research articles on the pharmacology, pharmacokinetic properties, drug interactions, and clinical efficacy and tolerability of belimumab in the treatment of SLE. Abstracts from the annual meetings of major rheumatology medical organizations and societies were searched and reviewed for new content. Additional information on belimumab was obtained from the manufacturer, from the FDA, and from other sources. MEDLINE was also used to select clinical studies and therapeutic guidelines on SLE therapy. Results: The literature search identified 1 Phase II and 2 Phase III studies that compared belimumab (1, 4, and 10 mg/kg/dose IV on days 0, 14, and 28; then every 28 days) to placebo in patients with active SLE on concurrent therapies. Patients with active lupus nephritis or neuropsychiatric lupus were excluded. In a Phase II, 52-week study, 24-week mean Safety of Estrogens in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) scores were decreased by 19.5% with belimumab versus 17.2% with placebo (P = NS). Median time to first flare was 67 days with belimumab versus 83 days with placebo (P = NS). In seropositive patients, 52-week mean SELENA-SLEDAI scores were decreased by 28.8% with belimumab versus 14.2% with placebo (P < 0.05), and physician's global assessment scores were improved by 32.7% with belimumab versus 10.7% with placebo (P < 0.05). Two Phase III studies were performed in seropositive SLE patients. In a Phase III, 52-week study, the rates of response (a reduction of ≥4 points on the SLE Response Index [SRI]) at week 52 were 51% and 58% with belimumab 1 and 10 mg/kg/dose, respectively, versus 44% with placebo (both, P < 0.05). In a Phase III, 76-week study, the rates of response, as measured using SRI, at week 52 were 42.8% and 46.5% with belimumab 1 and 10 mg/kg/dose versus 35.3% with placebo (P = NS and P < 0.001); at 76 weeks, response rates were 42.1% and 41.4% with belimumab 1 and 10 mg/kg/dose versus 33.8% with placebo (P < 0.05 and P = NS). The tolerability data from these studies did not suggest any overall differences between belimumab and placebo. Conclusions: Based on the findings from the present review, belimumab appears to be efficacious and generally well-tolerated and in the treatment of SLE other than lupus nephritis or neuropsychiatric lupus. Additional clinical and economics studies are needed to determine the most appropriate place for belimumab in the treatment of SLE.

Asenapine: A Clinical Review of a Second-Generation Antipsychotic

Steven C. Stoner, Heather A. Pace — 2012-04-12

Abstract: Background: Schizophrenia and bipolar disorder are both prevalent types of psychiatric illness in the United States. As second-generation antipsychotics have become a more viable first-line treatment option, their use has been associated with a new era of adverse events (AEs), most notably metabolic and cardiovascular concerns. Although treatment options for schizophrenia and bipolar disorder have arguably improved, there continues to be a need for medications that achieve and maintain desired efficacy with minimal AEs. Objectives: This article serves as a comprehensive review of the pharmacologic profile of the second-generation antipsychotic asenapine, as well as a review of its efficacy and safety profiles based on the findings from clinical trials in schizophrenia and bipolar disorder. Methods: Searches of Ovid MEDLINE, EMBASE, and IDIS were conducted (January 1996 to November 2011) to identify clinical studies and other primary literature sources with the following search terms: asenapine, bipolar disorder, antipsychotic, psychosis, dopamine, and schizophrenia. Only studies of asenapine and placebo and/or active-comparator arms were included. Results: The literature search yielded 67 unique articles, including review articles, which were excluded. The efficacy of asenapine was reported in 3 clinical studies in patients with schizophrenia, 1 each in acute and long-term settings, measured as significant changes in Positive and Negative Syndrome Scale scores over 6 and 52 weeks. Asenapine also had reported efficacy in the prevention of relapse in schizophrenia during a 26-week extension study. In addition, efficacy of asenapine was reported in 2 studies in acute mania as well as extension phases of both 9 and 40 weeks, as determined by significant changes in Young Mania Rating Scale scores. The most commonly reported AEs in these studies were somnolence (13%–24%), extrapyramidal symptoms (EPS) (7%–12%), and dizziness (11%). Conclusions: The findings from multiple studies have suggested that asenapine is efficacious in the acute treatment of schizophrenia. Asenapine has reported long-term efficacy for this indication and the potential to reduce the incidence of relapse. Asenapine efficacy was also reported in the treatment of acute manic or mixed states associated with bipolar I disorder. Asenapine had an acceptable safety profile across the different disease states studied, although it was not devoid of metabolic and EPS-related AEs.

Utility of Interferon-γ Release Assay Results to Monitor Anti-Tubercular Treatment in Adults and Children

2012-04-19

Abstract: Background: Interferon-γ release assays (IGRAs), including the commercially available T-SPOT.TB, QuantiFERON-TB Gold (QFT-G), and QuantiFERON-TB Gold In-Tube (QTF-G-IT), enable detection of circulating T lymphocytes responsive to specific Mycobacterium tuberculosis antigens. Studies of the potential role of serial IGRAs for assessment of response to anti-tubercular therapy are accumulating. Objective: The objective of this systematic review was to evaluate the potential clinical utility of serial IGRAs in anti-tubercular therapy. Methods: We conducted a literature search of the Cochrane Library and MEDLINE by PubMed, from database inception through October 1, 2011, for serial IGRA results in anti-tubercular therapy, in adults and children, using commercial stardardized assays. All types of articles in the English language were included. Meta-analysis was performed to estimate the pooled percentage of reversion from a positive to a negative IGRA value at 3- to 6-month follow-up. Results: According to inclusion and exclusion criteria, three T-SPOT.TB–based (n = 319 patients), three QFT-G–based (n = 75 patients), and seven QFT-G-IT-based (n = 558 patients) longitudinal studies were included. The percentage of patients with reversion from a positive to a negative IGRA value ranged from 5.71% to 13.93% for T-SPOT.TB, 5.26% to 71.05% for QFT-G, and 14.28% to 41.89% for QFT-G-IT assays. Meta-analysis estimation of reversion was feasible only for the QFT-G-IT assay, at 30.54% (95% CI, 22.89–38.75). In two pediatric studies, which were QFT-G-IT based (n = 122 children), the reported reversion rates were 14.28% and 20.33%, respectively. Conclusions: Because IGRAs require time and cost resources, and reversion from positive to negative IGRA values occurs in a minority of treated patients, monitoring IGRA changes over time seems to have only speculative value in adults. Data in children are poor, but are in line with results reported in adults.

The Effect of Levodopa on Pulmonary Function in Parkinson's Disease: A Systematic Review and Meta-Analysis

Larissa Monteiro, Adelmir Souza-Machado, Silvia Valderramas, Ailton Melo — 2012-04-02

Abstract: Background: Levodopa is considered the gold standard therapy for Parkinson's disease (PD). Aspiration pneumonia is the most frequent cause of death among PD patients. Asymptomatic respiratory impairment can be detected even in the initial stages of the disease course; however, there is no conclusive evidence regarding the efficacy of levodopa, the main therapeutic drug for PD, to enhance pulmonary function in these patients. Objective: The aim of this systematic review and meta-analysis was to evaluate the effects of levodopa therapy on respiratory parameters in patients with PD. Methods: After a comprehensive and systematic literature search in the electronic databases MEDLINE, Embase, the Cochrane Library, and Web of Science, all trials referring to levodopa and respiratory function that met the eligibility criteria were included in the analysis. Considered outcomes were forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), the ratio between FEV1 and FVC (FEV1/FVC), and peak expiratory flow (PEF). The fixed effects model was used to assess the weighted mean difference, and heterogeneity between studies was calculated with the I2 test. Results: Four clinical trials comprising 73 patients and assessing the effects of levodopa on pulmonary function in patients with PD were included in the analysis. Pooled data showed that levodopa significantly improved FVC (SMD, 0.40; P = 0.02) and PEF (standard mean difference, 0.39; P = 0.03). No significant change was observed with FEV1 (SMD, 0.34; P = 0.05) or the FEV1/FVC ratio (standard mean difference, −0.08; P = 0.66) after levodopa therapy. Conclusions: The results of this systematic review suggest that levodopa therapy improved FVC and PEF, whereas no changes were observed in FEV1 and FEV1/FVC. These findings may provide some indirect evidence regarding the efficacy of levodopa in restrictive parameters of pulmonary function.

The Safety Profile of Dalfampridine Extended Release in Multiple Sclerosis Clinical Trials

David R. Cornblath, E. Jay Bienen, Andrew R. Blight — 2012-04-13

Abstract: Background: Dalfampridine (fampridine outside the United States) is a broad-spectrum potassium channel blocker. Dalfampridine extended-release tablets have been approved by the US Food and Drug Administration to improve walking in patients with multiple sclerosis (MS). Objective: The objective of this article is to review the safety profile of dalfampridine extended-release tablets with respect to its expected use in patients with MS. Methods: We reviewed published data relevant to patient safety profiles based on searches of articles in PubMed published up to December 31, 2010, using the search terms fampridine OR dalfampridine OR 4-aminopyridine AND (multiple sclerosis) in combination with toxicity, safety, clinical trial, pharmacokinetics, and seizures. These searches were supplemented with data derived from the approved package insert and relevant sections of the New Drug Application (22-250) as submitted to the US Food and Drug Administration. Results: The literature searches returned 58 unique citations, of which 26 were considered relevant for characterizing the safety profile of dalfampridine; excluded citations were as follows: reviews (19), evaluation of 3,4-diaminopyridine (4), intravenous dosing (2), inadequate information on patient doses (2), preclinical models (2), and “other” (3). Dalfampridine is nearly completely (approximately 96%) eliminated unchanged in urine, with limited transformation to 2 inactive metabolites and low risk for interaction with drugs metabolized by hepatic P450 cytochromes. However, in patients with renal impairment (creatinine clearance [CrCl], ≤80 mL/min), mean peak plasma concentrations were 68%–101% higher and apparent clearance was 43%–73% lower relative to those without impairment, precluding dalfampridine use in patients with moderate (CrCl, 30–50 mL/min) or severe renal impairment (CrCl, <30 mL/min). Dalfampridine has a narrow therapeutic range. At the therapeutic dose of 10 mg twice daily, adverse events were generally mild to moderate and, consistent with the mechanism of action of dalfampridine, were primarily related to stimulatory effects on the nervous system. A thorough QT study suggested a low risk of induction of QT prolongation and associated cardiac arrhythmias in healthy individuals at therapeutic (10 mg, twice daily) or supratherapeutic (30 mg, twice daily) doses. Although the incidence of seizures was dose related, data from the clinical trials of dalfampridine extended-release tablets suggest that the risk of seizure at the therapeutic dose, in patients with no history of seizure, is not likely to be higher than background rates in MS. Conclusion: In patients with MS, dalfampridine has a narrow therapeutic range but an acceptable safety profile when used at the therapeutic dose of 10 mg twice daily.

Are Selective Serotonin Reuptake Inhibitors Safe for Drivers? What is the Evidence?

2012-05-03

Abstract: Background: Selective serotonin reuptake inhibitors (SSRIs) are widely used medications to treat several psychiatric diseases and, above all, depression. They seem to be as effective as older antidepressants but have a different adverse effect profile. Despite their favorable safety profile, little is known about their influence on traffic safety. Objective: To conduct a literature review to summarize the current evidence on the role of SSRIs in traffic safety, particularly concerning undesirable effects that could potentially impair fitness to drive, experimental and pharmacoepidemiologic studies on driving impairment, 2 existing categorization systems for driving-impairing medications, and the European legislative procedures for assessing fitness to drive before issuing a driver's license and driving under the influence of medicines. Methods: The article search was performed in the following electronic databases: MEDLINE, PsycINFO, ScienceDirect, and SafetyLit. The English-language scientific literature was searched using key words such as SSRIs and psychomotor performance, car crash or traffic accident, and adverse effects. For inclusion in this review, papers had to be full-text articles, refer to possible driving-related adverse effects, and be experimental or pharmacoepidemiologic studies on SSRIs and traffic accident risks. No restrictions concerning publication year were applied. Results: Ten articles were selected as background information on driving-related adverse effects, and 15 articles were selected regarding experimental and pharmacoepidemiologic work. Regarding SSRI adverse effects, the most reported undesirable effects referring to driving impairment were anxiety, agitation, sleep disturbances, headache, increased risk of suicidal behavior, and deliberate self-harm. Regarding the remaining issues addressed in this article, inconsistencies were found between the outcomes of the selected experimental and epidemiologic studies and between the 2 existing categorization systems under evaluation. Some pitfalls of the current legislative scenario were identified as well. Conclusions: Based on the current evidence, it was concluded that more experimental and epidemiologic research is needed to elucidate the relationship between SSRI use and traffic safety. Furthermore, a revision of the existing categorization systems and harmonized European legislation in the field of medication use and driving were highly recommended.

Impact of a Text Messaging Pilot Program on Patient Medication Adherence

2012-05-03

Abstract: Background: Medication nonadherence is a well-recognized challenge associated with poor health outcomes and increased utilization of health care resources. Although many different behavioral and educational strategies are available to improve patient medication adherence, technological advances, including cell phone text messaging, represent new and innovative modalities to improve adherence and overall health outcomes. Objective: To evaluate medication adherence among patients opting to receive text message medication reminders and a well-matched control cohort. Methods: This retrospective, observational cohort analysis compared medication adherence of members who opted-in to the text message medication reminder program and a matched control cohort using data from a member portal database and electronic pharmacy claims of a national pharmacy benefit manager with commercial and Medicare membership. Continuously enrolled members who opted to receive at least 1 medication-specific dosage reminder for a chronic oral medication of interest and had at least 1 pharmacy claim for the same chronic oral medication of interest were included. Matching was based on medication therapeutic class, then on propensity score (including variables of age, sex, health plan, Chronic Disease Score, distinct medication count, average baseline medication adherence, and duration of therapy). The primary outcome was chronic oral medication adherence, measured as the proportion of days covered (PDC), between January 1, 2011, and August 31, 2011. Analyses comparing cohorts were conducted using paired t tests and the McNemar test. Results: After implementation of the text messaging program, the mean (SD) PDC was significantly higher for the text message cohort (n = 290) than for the control cohort (n = 290) (0.85 [0.20] vs 0.77 [0.28], respectively; P < 0.001). Of those members identified with a chronic oral antidiabetes medication, the mean PDC was significantly higher in the text message cohort than in the control cohort (0.91 [0.14] vs 0.82 [0.21]; P = 0.029). Significant differences in mean PDC were also seen in members who opted to receive text message reminders for β-blocker therapy over members in the control cohort (0.88 [0.18] vs 0.71 [0.29]; P = 0.006). Conclusions: Findings suggest that members opting into a text message reminder program have significantly higher chronic oral medication adherence compared with members not opting to receive medication-specific text message reminders, and that the use of a text message reminder program assists in preserving higher rates of adherence over time.

Safety Profile and Tolerability of Up to 1 Year of Pregabalin Treatment in 3 Open-Label Extension Studies in Patients With Fibromyalgia

2012-04-16

Abstract: Background: Pain relief and an acceptable safety profile have been reported in randomized controlled trials (RCTs) of pregabalin in the treatment of fibromyalgia (FM) for up to 14 weeks. Objective: To evaluate the safety profile and tolerability of pregabalin (75–300 mg BID) treatment for up to 1 year in patients with FM. Methods: Twelve-week data were pooled from 3 open-label extension studies of pivotal RCTs. Study 1 was a 1-year extension of a 13-week RCT, and studies 2 and 3 were 12-week extensions of 14-week RCTs. The 1-year data were separately evaluated. The open-label data are summarized using descriptive statistics. Results: Overall, 1206 patients (92.4% female) with a mean (SD) age of 48.8 (10.7) years received open-label extended pregabalin treatment. A total of 119 of 1206 patients (9.9%) permanently discontinued study participation due to treatment-emergent adverse events (all causality) at 12 weeks (pooled data) and 53 of 429 (12.4%) within 1 year. Consistent with previous RCTs, the most commonly reported treatment-emergent adverse events with open-label pregabalin treatment were dizziness, somnolence, headache, peripheral edema, and increased weight. The highest incidence rates in the pooled 12-week data were for dizziness (214 of 1206; 17.7%) and somnolence (96 of 1206; 8.0%). In ratings of severity (mild, moderate, severe), most were reported as mild to moderate. The mean (SD) change in patient-reported visual analog scale pain scores (0–100) from the open-label baseline to the end of treatment was −21 (30.5) in study 1 (1 year), −26.7 (28.8) in study 2 (12 weeks), and −20.1 (26.8) in study 3 (12 weeks). Conclusions: The data from these extension studies suggest that the adverse event safety profile and tolerability of patients with FM treated with open-label pregabalin (75–300 mg BID) for up to 1 year were stable and were consistent with those of previous studies. ClinicalTrials.gov identifiers: NCT00151528 (A0081057 [study 1]), NCT00282997 (A0081078 [study 2]), and NCT00346034 (A0081101 [study 3]).

Efficacy and Tolerability of a 20-mg Dose of Methylphenidate for the Treatment of Daytime Sleepiness in Adult Patients With Myotonic Dystrophy Type 1: A 2-Center, Randomized, Double-Blind, Placebo-Controlled, 3-Week Crossover Trial

Jack Puymirat, Jean-Pierre Bouchard, Jean Mathieu — 2012-05-01

Abstract: Background: Despite the fact that excessive daytime sleepiness (EDS) is one of the most common manifestations in patients with myotonic dystrophy type 1 (DM1), no treatment is yet available. Methylphenidate is being studied for prospective use in the treatment of EDS. Objective: The aim of this investigator-initiated study was to evaluate the efficacy and tolerability of a single 20-mg morning dose of methylphenidate for the treatment of EDS in adults with DM1. Methods: This randomized, double-blind, placebo-controlled, 3-week crossover trial was conducted at 2 sites in Quebec. French-Canadian patients with DM1 with an Epworth Sleepiness Scale score ≥10 were invited to participate in this crossover trial of 20 mg/d of methylphenidate versus placebo, with 3 weeks in each arm of the study separated by a 2-week washout period. The primary efficacy end points were the Daytime Sleepiness Scale and the Epworth Sleepiness Scale at week 3. Secondary end points included the energy/vitality scale of the RAND 36-Item Health Survey, the Profile of Mood States questionnaire, and the mean sleep latency test. Assessment of tolerability profile included a physical examination, measurement of blood pressure, standard 12-lead ECG, and laboratory tests. Adverse event assessments were recorded based on patient reporting at each visit on clinical report forms. Results: In a total of 24 patients (12 men, 12 women; mean [SD] age, 46 [13] years), 17 completed the study. Treatment with methylphenidate showed a significant change in median scores on the Daytime Sleepiness Scale (–3.0 vs –0.5; P = 0.003) and the Epworth Sleepiness Scale (–3.0 vs –1.5; P = 0.039). The Profile of Mood States and the energy/vitality scale from the RAND 36-Item Health Survey showed no significant changes. Likewise, there was no significant change in mean sleep latency test results. One patient died during the trial, but the autopsy results eliminated methylphenidate as cause of death. Three patients discontinued methylphenidate due to treatment-emergent adverse events (1, diarrhea; 2, nervousness and irritability). Loss of appetite, nausea, and palpitations were the most common adverse events reported by more patients treated with methylphenidate than those receiving placebo. Conclusion: A single 20-mg dose of methylphenidate significantly reduced daytime sleepiness in this small selected population of patients with DM1. ClinicalTrials.gov identifier: NCT01421992.

Tacrolimus Versus Intravenous Pulse Cyclophosphamide Therapy in Chinese Adults With Steroid-Resistant Idiopathic Minimal Change Nephropathy: A Multicenter, Open-Label, Nonrandomized Cohort Trial

2012-04-16

Abstract: Background: The treatment of steroid-resistant minimal change nephropathy (SR-MCN) in adults remains a challenge to nephrologists. Although immunosuppressants such as cyclophosphamide (CTX), chlorambucil, and cyclosporin A have been used in these patients, their use has been limited by low remission rates and severe adverse effects. Alternative immunosuppressive treatments for SR-MCN are therefore needed. Objective: The aim of this study was to compare the efficacy of tacrolimus (TAC) with that of intravenous (IV) pulse CTX therapy in the management of SR-MCN and to assess the tolerability of those treatments. Methods: This was a nonrandomized, case-matched trial in Chinese adults with SR-MCN. Patients were self-assigned to either: (1) combination therapy with prednisone and oral TAC; or (2) combination therapy with prednisone and IV CTX. TAC was initiated at 0.05 mg/kg/d and was adjusted to maintain a trough blood level of 5 to 10 ng/mL for 1 year. CTX was initiated at 1 g/1.73 m2 for a total dosage of 10 g/1.73 m2 over 1 year. In both groups, oral prednisone was initiated at 0.5 mg/kg/d for 3 months but was tapered off to complete cessation by 6 months. Results: A total of 37 patients were enrolled (21 in the TAC group; 16 in the CTX group), of whom 33 (19 in the TAC group; 14 in the CTX group) completed the study. There were no significant difference in baseline demographic characteristics between the two treatment groups (The TAC group-mean age at onset, 28.8 [11.3]; mean age at trial, 29.6 [11.0]; male, 63.16%; The CTX group-mean age at onset, 34.4 [12.7]; mean age at trial, 35.9 [12.7]; male, 57.14%). The remission rates were 57.9%, 73.7%, and 78.9% in the TAC group and 14.3%, 42.9%, and 50.0% in the CTX group after 2, 4, and 6 months, respectively. The remission rate at 2 months was significantly higher in the TAC group than in the CTX group (P < 0.05). The remission rates during the 1-year therapy and the 1-year follow-up were higher in the TAC group than in the CTX group (Kaplan-Meier curve, log-rank test, P < 0.001). For patients who achieved remission, the mean (SD) time needed for remission was 48.7 (36.0) days in the TAC group and 85.3 (40.6) days in the CTX group (P < 0.05). During the 1-year therapy and 1-year follow-up periods, 6 of the 15 TAC-treated patients and 1 of the 7 CTX-treated patients relapsed (P = 0.35). Conclusions: These findings suggest that TAC therapy was effective compared with IV pulse CTX therapy in treating this select group of Chinese adults with SR-MCN. Both agents were well tolerated although TAC seemed to induce remission more rapidly than IV pulse CTX therapy. Australian New Zealand Clinical Trials Registry: study number ACTR 00362050.

Failure to Intensify Hypertension Therapy After Rejected Aliskiren Claims

Feng Zeng, Jinhee Park, Craig A. Plauschinat, Bimal V. Patel — 2012-04-30

Abstract: Background: Failure to intensify therapy when indicated is a serious problem in the management of hypertension. Patients having an antihypertensive prescription rejected because of utilization management tools may be at a high risk of failing to intensify their therapy when it is warranted. Objective: The goal of this study was to investigate the patterns of therapy change after rejected aliskiren claims because of utilization management tools such as prior authorization, step therapy, and restrictive formulary. Methods: A retrospective study was conducted using data from a large national pharmacy benefits manager. Patients with a rejected aliskiren claim because of utilization management and who were naive to aliskiren treatment before having a rejected aliskiren claim were included. Patients were followed up for 6 months after the initial rejected aliskiren claim to see whether there was a therapy change. Therapy change was defined as titration of old regimens, fulfillment of aliskiren, or fulfillment of a new antihypertensive medication not used previously. Results: A total of 1955 patients were identified (mean age, 64.5 years; 54.4% female). Six months after having rejected aliskiren claims, 36.8% overcame the utilization management and filled aliskiren; 45.1% filled a new antihypertensive medication not used previously; and 10.8% patients titrated old antihypertensive medications. More than one quarter of patients (28.4%) had no change in their antihypertensive treatment. Logistic regression analysis revealed that patients rejected because of prior authorization (odds ratio = 4.00 [95% CI, 1.89–8.44]) or step therapy (odds ratio = 2.59 [95% CI, 1.26–5.32]) were more likely to have a therapy change compared with patients rejected because of a restrictive formulary. Conclusions: A significant number of patients had no therapy change 6 months after having rejected aliskiren claims because of utilization management tools, indicating potential clinical inertia or lack of therapy intensification in hypertension management. Patients with restrictive formularies were least likely to have a therapy change. More aggressive follow-up with patients with a rejected claim may be warranted to reduce treatment gaps.

Cost-Effectiveness Analysis of Interferon Beta-1b for the Treatment of Patients With a First Clinical Event Suggestive of Multiple Sclerosis

2012-04-30

Abstract: Objectives: To assess, from a Swedish societal perspective, the cost effectiveness of interferon β-1b (IFNB-1b) after an initial clinical event suggestive of multiple sclerosis (MS) (ie, early treatment) compared with treatment after onset of clinically definite MS (CDMS) (ie, delayed treatment). Methods: A Markov model was developed, using patient level data from the BENEFIT trial and published literature, to estimate health outcomes and costs associated with IFNB-1b for hypothetical cohorts of patients after an initial clinical event suggestive of MS. Health states were defined by Kurtzke Expanded Disability Status Scale (EDSS) scores. Model outcomes included quality-adjusted life years (QALYs), total costs (including both direct and indirect costs), and incremental cost-effectiveness ratios. Sensitivity analyses were performed on key model parameters to assess the robustness of model results. Results: In the base case scenario, early IFNB-1b treatment was economically dominant (ie, less costly and more effective) versus delayed IFNB-1b treatment when QALYs were used as the effectiveness metric. Sensitivity analyses showed that the cost-effectiveness results were sensitive to model time horizon. Compared with the delayed treatment strategy, early treatment of MS was also associated with delayed EDSS progressions, prolonged time to CDMS diagnosis, and a reduction in frequency of relapse. Conclusion: Early treatment with IFNB-1b for a first clinical event suggestive of MS was found to improve patient outcomes while controlling costs.

Effect of Exenatide, Pen Insulin, and Vial Insulin on Patient Outcomes: A Retrospective Database Analysis of Persistence and First-Year Costs in a Commercially Insured Population⁎

Nazia Rashid, Jeffrey S. McCombs, Elizabeth Schwartz — 2012-03-30

Abstract: Objective: We compared health care costs and medication persistence for patients with type 2 diabetes initiating treatment using exenatide, pen insulin, or vial insulin. Methods: Commercial health plan data (2004–2008) were used to identify episodes of antidiabetic drug therapy, which were then classified according to treatment history: first observed treatment, restarting a previous therapy (90-day gap in all treatment), switching therapy, and augmentation therapy. Three time periods were defined for each episode: the month in which the episode was initiated (index month), 6 months before the index month (preindex period), and 12 months after the index month (postindex period). All exenatide and insulin episodes were selected for this analysis of persistence and first-year costs. Multivariate statistical methods were adjusted for demographic characteristics, drug use history, previous medical care use, comorbid medical conditions, and prescription drug profile. Several sensitivity analyses were conducted. Results: A total of 213,701 episodes of antidiabetic drug therapy were identified, of which 7031 patients were initiated using exenatide, 21,011 used vial insulin, and 422 used pen insulin. Time to all-cause discontinuation (TTAD) was measured for the index drug and all diabetic-related drugs. Pen insulin was discontinued 91 days earlier than exenatide, whereas vial insulin was continued 18 days longer than exenatide. Patients using pen insulin discontinued all antidiabetic drugs 34 days earlier than patients on exenatide, whereas patients using exenatide and vial insulin exhibited similar TTAD for all drugs. Exenatide use was estimated to significantly reduce medical costs of the first posttreatment year sufficient to offset higher prescription drug costs. These results were confirmed using propensity score matching estimation and were robust across episode type. Conclusions: Patients initiating drug therapy using exenatide might incur lower posttreatment costs than similar patients who initiated treatment using insulin.

Pharmacokinetic and Pharmacodynamic Properties of the Calcimimetic Agent Cinacalcet (KRN1493) in Healthy Male Korean Subjects: A Randomized, Open-Label, Single Ascending–Dose, Parallel-Group Study

2012-04-16

Abstract: Background: Cinacalcet (KRN1493) was developed to manage secondary hyperparathyroidism in patients with chronic kidney disease. The characteristics of cinacalcet have not been studied in the Korean population. Objective: The aim of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) properties and tolerability of single-dose cinacalcet 50 to 100 mg in healthy male Korean subjects for the purposes of a New Drug Application package for the Korean Food and Drug Administration. Methods: A randomized, open-label, single ascending–dose, parallel-group study was conducted in healthy male Korean subjects. Subjects were randomly assigned to receive a single oral dose of cinacalcet 50, 75, or 100 mg. Serial blood samples for PK/PD analysis were taken for up to 96 hours after administration. Plasma cinacalcet concentrations were analyzed by HPLC-MS/MS. PK parameters were determined using noncompartmental methods. Plasma intact parathyroid hormone (iPTH) concentrations, albumin-corrected serum calcium concentrations, and serum phosphorus concentrations were measured for PD evaluation. For the evaluation of tolerability, adverse events (AEs) were collected using investigators' questionnaires, subjects' spontaneous reports, clinical laboratory tests, ECG, and physical examinations including vital sign measurements. Results: Sixteen subjects in the 50-mg group, 16 in the 75-mg group, and 6 in the 100-mg group completed the study and were included in the PK/PD analysis. The mean (SD) age, height, and weight of the study population were 4.3 (3.0) years, 174.8 (4.9) cm, and 68.2 (7.5) kg, respectively. The median Tmax value in each of the 3 dose groups was 6.0 hours. Mean Cmax values in the 50-, 75-, and 100-mg dose groups were 12.0 (5.5), 17.2 (14.9), and 43.1 (15.5) μg/L; mean AUC0–∞ values were 126.6 (56.4), 184.3 (87.9), and 417.4 (169.9) μg · h/L. Characteristics were not linear, based on the data over the dose range of 50 to 100 mg. Mean plasma iPTH concentrations in the 50-, 75-, and 100-mg dose groups were decreased from baseline by 64.0% (11.7%), 63.1% (14.6%), and 70.6% (6.3%). Albumin-corrected serum calcium concentrations displayed patterns similar to those of the plasma iPTH concentrations. Sixteen AEs were reported in 11 subjects. No clinically significant abnormalities were observed in the tolerability assessments. Conclusions: A single oral dose of cinacalcet was well-tolerated up to 100 mg in this small, selected population of healthy male Korean subjects. In addition, the PK characteristics of cinacalcet and its accompanying PD changes—the decreases in the concentrations of plasma iPTH and albumin corrected serum calcium—were demonstrated in the same population. ClinicalTrials.gov identifier: NCT00942773.

Differences in the In Vitro and In Vivo Pharmacokinetic Profiles of Once-Daily Modified-Release Methylphenidate Formulations in Canada: Examination of Current Bioequivalence Criteria

2012-04-19

Abstract: Background: Current Canadian bioequivalence criteria rely on rate and extent of drug exposure, that is, Cmax and AUC. In the case of complex modified-release formulations, these criteria may not address pharmacokinetic differences with potential therapeutic and tolerability implications. Objective: This study was performed to characterize in vitro dissolution and in vivo pharmacokinetic profiles of three modified-release formulations of methylphenidate (MPH) marketed in Canada, two of which meet the criteria for assuming bioequivalence as defined by Health Canada: MPH extended-release (ER-C) and osmotic controlled-release oral-delivery-system (OROS-MPH). Methods: In vitro dissolution tests were performed using 54-mg OROS-MPH, 54-mg MPH ER-C, and 20-mg MPH sustained-release (SR) tablets. In vivo pharmacokinetics of single oral doses of 54 mg OROS-MPH, 54 mg MPH ER-C, and 60 mg MPH-SR were evaluated in an open-label, randomized, crossover study in healthy subjects. Plasma samples were collected up to 24 hours after administration of the drug. Results: In vitro dose-corrected release profiles of MPH ER-C and MPH-SR tablets were similar (<10% difference), whereas OROS-MPH exhibited a profile distinct from that of the other formulations. Twenty-four subjects completed the pharmacokinetic study and were included in the analyses. Analysis of Cmax and AUC of MPH showed that OROS-MPH and MPH ER-C met the criteria for assumed bioequivalence according to Health Canada guidelines. However, partial AUCs exhibited significant differences between the two formulations, which were supported by ratios of MPH concentrations over time. Comparison of MPH ER-C with MPH-SR (dose corrected) also satisfied bioequivalence criteria. Conclusions: The pharmacokinetic data suggest that in vitro and in vivo profiles of OROS-MPH and MPH ER-C are distinct. However, using traditional criteria for bioequivalence, MPH ER-C would be assumed bioequivalent to both OROS-MPH and MPH-SR. Inclusion of partial AUCs as additional criteria could aid in ensuring therapeutic equivalence. ClinicalTrials.gov identifier: NCT01118702.

Effects of Ketoconazole and Rifampicin on the Pharmacokinetics of Gemigliptin, a Dipeptidyl Peptidase-IV Inhibitor: A Crossover Drug–Drug Interaction Study in Healthy Male Korean Volunteers

2012-04-26

Abstract: Background: Gemigliptin (LC15-0444) is a newly developed selective and competitive inhibitor of dipeptidyl peptidase (DPP)-4 and has potential for the treatment of type 2 diabetes mellitus. Gemigliptin is metabolized by the cytochrome P450 (CYP) 3A4 isozyme to yield the active major metabolite LC15-0636. Objective: The effects of multiple oral doses of ketoconazole (a potent CYP3A4 inhibitor) and multiple oral doses of rifampicin (a potent CYP3A4 inducer) on the pharmacokinetic properties of a single oral dose of gemigliptin were evaluated in fasting healthy male Korean volunteers. Methods: In this open-label, 2-part, 3-treatment, 1-sequence, 2-period crossover drug–drug interaction study, 1 group of subjects received a single 50-mg oral dose of gemigliptin on 2 separate occasions—once as monotherapy and again after pretreatment with 400 mg of oral ketoconazole once daily for 7 days. The other group of subjects received a single 50-mg oral dose of gemigliptin on 2 separate occasions—once without pretreatment and again after pretreatment with 600 mg of oral rifampicin once daily for 10 days. Blood samples were obtained at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, and 72 hours after gemigliptin dosing. Plasma concentrations were determined using LC-MS/MS. Pharmacokinetic parameters were estimated via noncompartmental methods. Tolerability was assessed using measurements of vital signs, clinical chemistry tests, and interviews. Results: Twenty-four subjects were enrolled (12 per group). Concurrent administration of ketoconazole was associated with increased total gemigliptin plasma exposure (AUC0–∞; 2.36-fold [90% CI, 2.19–2.54]) and decreased metabolism of gemigliptin until negligible concentrations of LC15-0636 were detected. Pretreatment with rifampicin was associated with decreased AUC0–∞ of gemigliptin (by 80% [90% CI, 78%–82%]) and a 2.9-fold increase (mean [SD], 0.18 [0.08] to 0.52 [0.10]) in the metabolic ratio of gemigliptin to LC15-0636. The treatments were well-tolerated, with no severe adverse events reported. Six of the 24 subjects (25%) experienced AEs during the first period of gemigliptin monotherapy administration. Six of 12 subjects (50%) each experienced AEs during concurrent administration with ketoconazole and rifampicin. Conclusions: In this select group of healthy male Korean volunteers, concurrent administration of gemigliptin with ketoconazole or rifampicin was associated with significantly increased or decreased systemic exposure to gemigliptin, respectively. These findings suggest that gemigliptin may require a dose adjustment when concurrently administered with drugs that alter CYP3A4 activity. Concurrent administration of gemigliptin with ketoconazole or rifampicin was well tolerated. ClinicalTrials.gov identifier: NCT01426906.

A Randomized, Double-Blind, Parallel, Single-Site Pilot Trial to Compare Two Different Starting Doses of Methotrexate in Methotrexate-Naïve Adult Patients with Rheumatoid Arthritis

2012-04-20

Abstract: Background: Methotrexate (MTX) is a cornerstone in the treatment of rheumatoid arthritis. Despite its widespread use, expert opinions differ about the optimal MTX starting dosage to achieve rapid onset of action while averting increased occurrence of adverse effects. Plasma concentrations have not been assessed in previous studies that monitored clinical efficacy. Objective: This study was performed to compare the pharmacokinetic parameters and clinical response of a standard (15 mg) and an accelerated (25 mg) dosing regimen, each administered orally once a week. Methods: This randomized, controlled, double-blind, parallel, single-site study included 19 MTX-naïve patients older than 18 years with rheumatoid arthritis. Patients participated for 16 weeks. Disease activity was assessed using the Disease Activity Score in 28 joints (DAS-28) as the primary outcome parameter. Plasma MTX concentrations were measured using HPLC at weeks 1, 5, 10, and 16. Tolerability was assessed via routine blood analysis (hematology and clinical chemistry) and a patient questionnaire to monitor adverse events. Reported or observed adverse events were recorded along with information about their severity and causal relationship to the study medication. Results: Nineteen white patients (13 women and 6 men; mean age, 56 years; and mean weight, 74 kg) participated. At study entry, mean (SD) DAS-28-4v (erythrocyte sedimentation rate) was 4.73 (1.02). Health Assessment Questionnaire scores were 1.45 (0.85); for C-reactive protein, 11.45 (10.04) mg/dL; for alkaline phosphatase, 73.58 (19.91) U/L; for aspartate aminotransferase, 23.32 (7.13) U/L; and for creatinine, 0.87 (0.22) mg/dL. Although pharmacokinetic parameters such as AUC and Cmax were significantly higher after the accelerated dosing regimen, clinical activity scores (DAS-28) and inflammation parameters (C-reactive protein) did not indicate a significant benefit of an accelerated starting regimen. Considering toxicity, no elevation in liver function enzymes and no decrease in renal function were observed using the accelerated dosing (statistical significance set at P ≤ 0.05). No serious adverse events were noted. All observed adverse events were classified as study related. Overall, adverse events were noted in 58% of patients. Comparison of the two doses revealed that 60% of patients receiving the standard dosing regimen and 56% of patients receiving the accelerated dosing regimen reported adverse events, the most frequent being gastrointestinal. These events were generally self-limiting. Conclusions: Differences in clinical response between these two small selected patient groups who received an initial oral dose of either 15 or 25 mg MTX per week did not reach the level of statistical significance. The overall incidence of adverse effects, all classified as study related, was 58%, with 60% of patients receiving the standard dosage and 56% of patients receiving the accelerated dosing regimen reporting adverse effects. However, because of the small sample size, this study was not powered to detect differences in the incidence of adverse events between the two dosing groups. ClinicalTrials.gov identifier: NCT00695188.

Fraud or flawed ? At the end of the day it may be the patient who pays the bill !

Peter Kranke, Jan Wallenborn, Norbert Roewer, Leopold H.J. Eberhart — 2012-04-27

We read with interest the systematic review published recently in Clinical Therapeutics that concluded that “with respect to PONV prophylaxis, granisetron was significantly better than ondansetron and dolasetron;…” We would like to express concerns about the overall conclusion based on the applied inclusion and exclusion criteria and the inclusion of data, which may have led to skewed results.

The authors respond

Derek H. Tang, Daniel C. Malone — 2012-04-27

Thank you and Dr. Kranke and colleagues for the opportunity to further clarify the scope, objective, and limitations of our study, recently published in Clinical Therapeutics, associated with postoperative nausea and vomiting (PONV), hereafter referred to as the study.