Population Approach to Efavirenz Therapy

Efavirenz (EFV) is a nonnucleoside reverse transcriptase inhibitor commonly used as first-line therapy in the treatment of human immunodeficiency virus (HIV), with a narrow therapeutic range and a high between-subject variability which can lead to central nervous system toxicity or therapeutic failu...

Full description

Saved in:
Bibliographic Details
Published in:Journal of pharmaceutical sciences 2017-10, Vol.106 (10), p.3161-3166
Main Authors: Duarte, Hélder, Cruz, João Paulo, Aniceto, Natália, Ribeiro, Ana Clara, Fernandes, Ana, Paixão, Paulo, Antunes, Francisco, Morais, José
Format: Article
Language:English
Subjects:
Anti-HIV Agents - therapeutic use
Benzoxazines - therapeutic use
CYP enzymes
Dose-Response Relationship, Drug
Female
Hepacivirus - drug effects
Hepatitis C - drug therapy
Hepatitis C - genetics
HIV - drug effects
HIV Infections - drug therapy
HIV Infections - genetics
HIV/AIDS
Humans
Male
pharmacogenetics
Polymorphism, Single Nucleotide - genetics
population pharmacokinetics
Reverse Transcriptase Inhibitors - therapeutic use
therapeutic drug monitoring
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Efavirenz (EFV) is a nonnucleoside reverse transcriptase inhibitor commonly used as first-line therapy in the treatment of human immunodeficiency virus (HIV), with a narrow therapeutic range and a high between-subject variability which can lead to central nervous system toxicity or therapeutic failure. To characterize the sources of variability and better predict EFV steady-state plasma concentrations, a population pharmacokinetic model was developed from 96 HIV-positive individuals, using a nonlinear mixed-effect method with Monolix® software. A one-compartment with first-order absorption and elimination model adequately described the data. To explain between-subject variability, demographic characteristics, biochemical parameters, hepatitis C virus–HIV coinfection, and genetic polymorphisms were tested. A combination of the single-nucleotide polymorphisms rs2279343 and rs3745274, both in the CYP2B6 gene, were the only covariates influencing clearance, included in the final model. Oral clearance was estimated to be 19.6 L/h, 14.15 L/h, and 6.08 L/h for wild-type, heterozygous mutated and homozygous mutated individuals, respectively. These results are in accordance with the current knowledge of EFV metabolism and also suggest that in homozygous mutated individuals, a dose adjustment is necessary. Hepatitis C virus–HIV coinfection does not seem to be a predictive indicator of EFV pharmacokinetic disposition.
ISSN:0022-3549
1520-6017
DOI:10.1016/j.xphs.2017.06.004