Effect of albumin and CYP2B6 polymorphisms on exposure of efavirenz: A population pharmacokinetic analysis in Chinese HIV-infected adults.

Abstract

BACKGROUND:

Efavirenz is a vital component used to treat HIV-1 infection. Nevertheless, it shows large between-subject variability, which affects both its therapeutic response and adverse effects.

OBJECTIVE:

To investigate the impact of gene polymorphisms and non-genetic factors on the variability of efavirenz pharmacokinetics and to propose the optimal dose regimens.

METHODS:

A total of 769 plasma samples from 376 HIV-infected Han Chinese outpatients were collected to develop a population pharmacokinetic model using NONMEM software. The impact of patient demographics, laboratory tests, concomitant medication, and genetic polymorphisms of CYP2B6 and ABCB1 on efavirenz pharmacokinetics were explored. According to the final model, the model-informed dose optimization was conducted.

RESULTS:

The pharmacokinetics of efavirenz was characterized by a one-compartment model with first-order absorption and elimination. The typical values of the estimated apparent oral clearance, volume of distribution, and absorption rate constant in the final model were 9.44 L/h, 200 L, and 0.727 h - 1, respectively. Efavirenz clearance was significantly influenced by CYP2B6 variants, including rs2099361, rs3745274, and rs2279343, along with albumin and weight. The volume of distribution was affected by albumin and weight. Based on the CYP2B6 polymorphisms of patients, the recommended daily doses of efavirenz were 100 mg for CYP2B6 slow metabolizers, 400 or 600 mg for intermediate metabolizers, and 800 or 1000 mg for extensive metabolizers.

CONCLUSIONS:

Polymorphisms of CYP2B6, along with albumin and weight, resulted as the predictors of efavirenz pharmacokinetic variability, which could be used in prescribing optimal efavirenz doses.

• Authors: Xian-Min Meng, Zi-Ran Li, Xin-Yin Zheng, Yi-Xi Liu, Wan-Jie Niu, Xiao-Yan Qiu, Hong-Zhou Lu
• Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (Eur J Pharm Sci) Vol. 167 Pg. 105986 (Dec 01 2021) ISSN: 1879-0720 [Electronic] Netherlands
• PMID: 34474119 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Albumins
• Alkynes
• Anti-HIV Agents
• Benzoxazines
• Cyclopropanes
• CYP2B6 protein, human
• Cytochrome P-450 CYP2B6
• efavirenz

Topics

• Adult
• Albumins
• Alkynes (therapeutic use)
• Anti-HIV Agents (therapeutic use)
• Benzoxazines
• China
• Cyclopropanes
• Cytochrome P-450 CYP2B6 (genetics)
• HIV Infections (drug therapy, genetics)
• Humans
• Polymorphism, Genetic