Evaluation of universal versus genotype-guided efavirenz dose reduction in pregnant women using population pharmacokinetic modelling



Olagunju, Adeniyi ORCID: 0000-0002-6588-5749, Schipani, Alessandro, Bolaji, Oluseye, Khoo, Saye ORCID: 0000-0002-2769-0967 and Owen, Andrew ORCID: 0000-0002-9819-7651
(2018) Evaluation of universal versus genotype-guided efavirenz dose reduction in pregnant women using population pharmacokinetic modelling. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 73 (1). pp. 165-172.

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Abstract

<h4>Objectives</h4>Lack of data on the pharmacokinetics of efavirenz in pregnant women at the 400 mg reduced dose currently prevents universal roll-out. Population pharmacokinetic modelling was used to explore pharmacokinetic endpoints at 200, 400 and 600 mg daily doses in pregnant women stratified by CYP2B6 metabolic status.<h4>Methods</h4>The analysis was based on 252 plasma efavirenz concentrations from 77 pregnant women (77 sparse, 175 intensive) who received antiretroviral regimens containing 600 mg of efavirenz. The model was developed using NONMEM®. The effect of genetics was investigated and concentration-time courses at steady-state were simulated for individuals (n = 1000 each) classified as CYP2B6 slow, intermediate and fast metabolizers at 200, 400 and 600 mg daily doses.<h4>Results</h4>At a 400 mg reduced dose, predicted mean (90% CI) mid-dose efavirenz concentration (C12) was 2.24 μg/mL (0.89-4.18) in pregnant women classified as slow metabolizers, compared with 0.87 μg/mL (0.34-1.64) in intermediate metabolizers and 0.78 μg/mL (0.30-1.47) in fast metabolizers. C12 was below the 0.47 μg/mL threshold determined within the ENCORE 1 trial in 10% at 400 mg, 4.6% at 600 mg and 3.4% with genotype-guided dosing. The 4.0 μg/mL toxicity threshold was exceeded in 4.6% at 400 mg, 13.5% at 600 mg and 5.2% with genotype-guided dosing.<h4>Conclusions</h4>These data provide context for the ongoing debate about reduction in efavirenz dose to 400 mg during pregnancy and should be interpreted alongside the lower toxicity expected with the lower dose. Additional research is required to investigate genotype-guided dose reduction in pregnant women.

Item Type: Article
Uncontrolled Keywords: Humans, HIV Infections, Alkynes, Cyclopropanes, Benzoxazines, Anti-HIV Agents, Pregnancy, Adolescent, Adult, Nigeria, Female, Infectious Disease Transmission, Vertical, Young Adult, Cytochrome P-450 CYP2B6, Cytochrome P-450 CYP2B6 Inducers, Black People
Depositing User: Symplectic Admin
Date Deposited: 13 Nov 2017 11:04
Last Modified: 13 Feb 2023 23:27
DOI: 10.1093/jac/dkx334
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3012059