Abstract
Background
Interferon (IFN)-based therapy is the recommended treatment for hepatitis C virus.
Because pegylated IFN (PEG-IFN) alfa-2a is administered subcutaneously, it is of interest
to determine the proportion of the dose that is absorbed from the subcutaneous (SC)
tissue and ultimately reaches systemic circulation.
Objective
The goal of this study was to characterize the absolute bioavailability of PEG-IFN
alfa-2a (40 kDa) after SC dosing (180 μg) and to evaluate the pharmacokinetics of
PEG-IFN alfa-2a after intravenous (IV) and SC administration.
Methods
In this parallel-group study, 18 participants were given a single IV dose of PEG-IFN
alfa-2a 90 μg and 18 participants received PEG-IFN alfa-2a 180 μg SC. Serum concentrations
of PEG-IFN alfa-2a were measured predose and serially until 312 hours after the first
dose. Pharmacokinetic parameters (CL/F, volume of distribution, Cmax, and Tmax) were estimated using noncompartmental methods. Bioavailability was calculated by
using the following formula: (AUCSC/AUCIV) · (doseIV/doseSC).
Results
Eighteen healthy males received IV PEG-IFN alfa-2a, and an additional 18 healthy males
received SC PEG-IFN alfa-2a. Subjects in each group had comparable mean weight, height,
and body mass index. After IV administration of PEG-IFN alfa-2a (90 μg), there was
a slow decline in serum concentration, the mean rate of systemic clearance was low
at 126 mL/h, and the estimated mean volume of distribution at steady state was 9 L.
After SC administration of PEG-IFN alfa-2a 180 μg, absorption was sustained, with
mean Tmax occurring 102 hours after administration. The mean absolute bioavailability was 84%.
A higher rate of influenza-like symptoms was observed after IV administration, along
with decreased neutrophil counts, compared with subjects who underwent SC dosing.
Conclusions
Approximately 84% of a SC-administered dose of PEG-IFN alfa-2a reached the systemic
circulation in these male healthy volunteers. The slow absorption, restricted distribution,
and slow elimination of PEG-IFN alfa-2a resulted in sustained serum levels throughout
the 7-day dosing interval.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Clinical TherapeuticsAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- An overview of emerging therapies for the treatment of chronic hepatitis C.Clin Liver Dis. 2011; 15: 515-536
- Boceprevir for previously treated chronic HCV genotype 1 infection.N Engl J Med. 2011; 364: 1207-1217
- Response-guided telaprevir combination treatment for hepatitis C virus infection.N Engl J Med. 2011; 365: 1014-1024
- The face of future hepatitis C antiviral drug development: recent biological and virologic advances and their translation to drug development and clinical practice.J Hepatol. 2006; 44: 411-421
- Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus.Lancet. 1998; 352: 1426-1432
- Pegylation: a novel process for modifying pharmacokinetics.Clin Pharmacokinet. 2001; 40: 539-551
- Pegylated-interferon-alpha(2a) in clinical practice: how to manage patients suffering from side effects.Expert Opin Drug Saf. 2011; 10: 429-435
- Management of adverse effects of Peg-IFN and ribavirin therapy for hepatitis C.Nat Rev Gastroenterol Hepatol. 2011; 8: 212-223
- Diagnosis, management, and treatment of hepatitis C.Hepatology. 2004; 39: 1147-1171
- International, multicenter, randomized, controlled study comparing dynamically individualized versus standard treatment in patients with chronic hepatitis C.J Hepatol. 2005; 43: 250-257
- Telaprevir for retreatment of HCV infection.N Engl J Med. 2011; 364: 2417-2428
- Boceprevir for untreated chronic HCV genotype 1 infection.N Engl J Med. 2011; 364: 1195-1206
- Telaprevir for previously untreated chronic hepatitis C virus infection.N Engl J Med. 2011; 364: 2405-2416
- Pharmacokinetics of interferon alpha–2b in healthy volunteers.J Clin Pharmacol. 1987; 27: 432-435
- The influence of food on the oral and intravenous pharmacokinetics of a high clearance drug: a study with labetalol.Br J Clin Pharmacol. 1982; 14: 73-78
- The Declaration of Helsinki and public health.Bull World Health Organ. 2008; 86: 650-652
- The International Conference on Harmonization Good Clinical Practice guideline.Qual Assur. 1998; 6: 65-74
- Viral dynamics and pharmacokinetics of peginterferon alpha-2a and peginterferon alpha-2b in naive patients with chronic hepatitis C: a randomized, controlled study.Antivir Ther. 2004; 9: 491-497
- Bioavailability of drugs with long elimination half-lives.Eur J Clin Pharmacol. 1983; 25: 689-693
- Evaluation of pharmacokinetics, user handling, and tolerability of peginterferon alfa-2a (40 kDa) delivered via a disposable autoinjector device.Patient Prefer Adherence. 2011; 5: 587-599
- A branched methoxy 40 kDa polyethylene glycol (PEG) moiety optimizes the pharmacokinetics (PK) of peginterferon alfa-2a (PEG-IFN) and may explain its enhanced efficacy in chronic hepatitis C (CHC).Hepatology. 1999; 40: 190A
- Pharmacokinetics of pegylated interferons: what is misleading?.Dig Liver Dis. 2004; 36: S334-S339
- Pharmacokinetics of peginterferons.Semin Liver Dis. 2003; 23: 23-28
- Review article: pegylated interferons: chemical and clinical differences.Aliment Pharmacol Ther. 2004; 20: 825-830
- Peginterferon pharmacokinetics in African American and Caucasian American patients with hepatitis C virus genotype 1 infection.Clin Gastroenterol Hepatol. 2008; 6: 575-583
- Peginterferon alfa-2a and ribavirin in Latino and non-Latino whites with hepatitis C.N Engl J Med. 2009; 360: 257-267
Article info
Publication history
Published online: August 03, 2012
Accepted:
July 10,
2012
Identification
Copyright
© 2012 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.
