Pharmacokinetics and Drug-Drug Interactions of Isoniazid and Efavirenz in Pregnant Women Living With HIV in High TB Incidence Settings: Importance of Genotyping

Abstract

The World Health Organization guidelines recommend that individuals living with HIV receive ≥ 6 months of isoniazid preventive therapy, including pregnant women. Yet, plasma isoniazid exposure during pregnancy, in the antiretroviral therapy era, has not been well-described. We investigated pregnancy-induced and pharmacogenetic-associated pharmacokinetic changes and drug-drug interactions between isoniazid and efavirenz in pregnant women. Eight hundred forty-seven women received isoniazid for 28 weeks, either during pregnancy or at 12 weeks postpartum, and 786 women received efavirenz. After adjusting for NAT2 and CYP2B6 genotype and weight, pregnancy increased isoniazid and efavirenz clearance by 26% and 15%, respectively. Isoniazid decreased efavirenz clearance by 7% in CYP2B6 normal metabolizers and 13% in slow and intermediate metabolizers. Overall, both isoniazid and efavirenz exposures were reduced during pregnancy, but the main determinants of drug concentration were NAT2 and CYP2B6 genotypes, which resulted in a five-fold difference for both drugs between rapid and slow metabolizers.

Figure 1

Distribution of the enzyme metabolizer genotypes for NAT2, CYP2B6, and CYP2A6 in the participants across the eight countries involved in the study. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 2

Schematic representation of the pharmacokinetic model of both efavirenz and isoniazid. The absorption is described with a series of transit‐compartment to capture the delay in absorption, and a rate constant K _a. The hepatic extraction (Eh) is responsible for both first‐pass metabolism and the systemic elimination with first‐order kinetics. V _c represents the volume of distribution in the central compartment. Drug transfer between the central and peripheral compartment is defined by intercompartmental clearance Q/F, were F represents the oral bioavailability. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 3

Isoniazid exposures stratified by NAT2 genotype and pregnancy. The box plot (with box representing median and interquartile range and whiskers the 5th‐95th interval) summarizes isoniazid maximum concentration (C_max) on the right and 0–24‐hour area under the concentration‐time curve (AUC_0–24) on the left for the three genotypes (slow, intermediate, and rapid acetylator) for both the antepartum (red solid line) and postpartum (blue dashed lines) visit. AUC_0–24 was calculated by integrating between the 0 and 24 hours after dosing time points. The inset panel shows the same values on the log‐scale. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 4

Efavirenz exposures stratified by CYP2B6 genotype, pregnancy and isoniazid co‐administration. (a, b) Displays box plot (with box representing median and interquartile range and whiskers the 5th‐95th interval) summarizing 0–24‐hour area under the concentration‐time curve (AUC_0–24) and concentrations at 12 hours postdosing (C₁₂), respectively, for the three genotypes (slow, intermediate, and normal metabolizer) stratified by pregnancy (solid line) and postpartum (dashed lines) visit. (c, d) Stratify AUC_0‐24 and C₁₂, respectively, using INH co‐administration. [Colour figure can be viewed at wileyonlinelibrary.com]