Document Detail


Pegylated interferon fractal pharmacokinetics: individualized dosing for hepatitis C virus infection.
MedLine Citation:
PMID:  23183434     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Despite recent advances in hepatitis C virus (HCV) therapeutics, the combination of pegylated interferon and ribavirin (PEGIFN/RBV) remains the cornerstone of treatment. Optimization and individualization of PEGIFN dosing could improve outcomes. Week one PEGIFN serum concentrations in 42 HCV genotype 1-infected patients treated with conventional PEGIFN/RBV were analyzed using multicompartmental pharmacokinetic models. For each patient, pharmacokinetic parameter estimates, weight, age, interleukin-28B (IL-28B) single-nucleotide polymorphism, CD4 count, baseline HCV RNA, gender, race, and HIV status were examined using classification and regression tree analysis to identify factors predictive of sustained viral response (SVR). Survival analysis was performed to compare the time to undetectable viral load in patients with and without the highest scoring predictor. PEGIFN concentrations varied at least 87-fold. Pharmacokinetics were best described by a two-compartment model with an 8.4-h absorption lag. Patient weight correlated with PEGIFN systemic clearance based on fractal geometry relationships. SVR was achieved in 36% of patients; a PEGIFN cumulative 1-week area under the curve (AUC) of ≤0.79 mg · h/liter scored highest in predicting poor response, followed by a weight of ≥93.7 kg. Patients with a PEGIFN AUC of >0.79 mg · h/liter achieved undetectable viral load more rapidly than those with a lower AUC (hazard ratio, 1.63; 95% confidence interval, 1.21 to 2.04). PEGIFN exhibits wide pharmacokinetic variability, mainly driven by patient weight, so that the standard dose may not reach levels needed to achieve SVR. Optimizing dose to patient weight and PEGIFN AUC in the first week offers a solution to improve SVR and to potentially shorten duration of therapy.
Authors:
Mamta K Jain; Jotam G Pasipanodya; Lara Alder; William M Lee; Tawanda Gumbo
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-11-26
Journal Detail:
Title:  Antimicrobial agents and chemotherapy     Volume:  57     ISSN:  1098-6596     ISO Abbreviation:  Antimicrob. Agents Chemother.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-15     Completed Date:  2013-07-30     Revised Date:  2013-09-03    
Medline Journal Info:
Nlm Unique ID:  0315061     Medline TA:  Antimicrob Agents Chemother     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1115-20     Citation Subset:  IM    
Affiliation:
UT Southwestern Medical Center, Department of Internal Medicine, Dallas, TX, USA. mamta.jain@utsouthwestern.edu
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT00703560
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Age Factors
Aged
Antiviral Agents / pharmacokinetics*,  pharmacology,  therapeutic use
Area Under Curve
Drug Administration Schedule
Drug Dosage Calculations
Drug Therapy, Combination
Female
Fractals
Hepacivirus / drug effects*,  growth & development
Hepatitis C / drug therapy*,  virology
Humans
Individualized Medicine*
Interferon-alpha / pharmacokinetics*,  pharmacology,  therapeutic use
Interleukins / genetics
Male
Middle Aged
Polyethylene Glycols / pharmacokinetics*,  pharmacology,  therapeutic use
Polymorphism, Single Nucleotide
Recombinant Proteins / pharmacokinetics,  pharmacology,  therapeutic use
Regression Analysis
Ribavirin / pharmacokinetics*,  pharmacology,  therapeutic use
Treatment Outcome
Viral Load / drug effects
Grant Support
ID/Acronym/Agency:
DP2 OD001886/OD/NIH HHS; K23-AI-065630/AI/NIAID NIH HHS; R01AI079497/AI/NIAID NIH HHS; UL1 RR024982/RR/NCRR NIH HHS; UL1-RR-024982/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Antiviral Agents; 0/IL28B protein, human; 0/Interferon-alpha; 0/Interleukins; 0/Polyethylene Glycols; 0/Recombinant Proteins; 0/peginterferon alfa-2a; 36791-04-5/Ribavirin
Comments/Corrections

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