Pharmacokinetics of First-line Tuberculosis Drugs Rifampin, Isoniazid, Ethambutol and Pyrazinamide during Pregnancy and Postpartum with and without Efavirenz-based Antiretroviral Treatment: IMPAACT P1026s study.

The pharmacokinetics (PK) of antituberculosis drugs may be altered by both pregnancy-induced physiological changes and drug interactions in individuals living with HIV who develop tuberculosis. Within the multicenter IMPAACT P1026s study, we assessed the PK of rifampin, isoniazid, ethambutol and pyrazinamide during pregnancy and postpartum in women on efavirenz-based antiretroviral treatment (ART). Results were compared to a previously published non-HIV-group and described minimum targets. WHO-recommended daily doses of antituberculosis and ART medications were administered, followed by PK sampling of all antituberculosis drugs over 24 hours during 2^nd trimester (2T), 3^rd trimester (3T) and 2–8 weeks postpartum (PP). PK parameters were characterized using noncompartmental analysis and comparisons were made among stages of pregnancy and between groups using geometric mean ratios (GMR) with 90% confidence intervals (CI). Twenty-two participants enrolled: 18 African, 2 Asian, 1 Hispanic and 1 mixed-race. PK data were available for 12, 20 and 13 participants in 2T, 3T and PP, respectively. While no significant difference in rifampin exposure between pregnancy and postpartum was detected, the median AUC_0-24 and C_max were below target during each period and were 42% and 35% lower in 3T than the non-HIV-group. No significant difference in isoniazid exposure was found between pregnancy and PP or between the groups. Ethambutol and pyrazinamide AUC_0-24 and C_max in 2T and 3T were similar between the groups. In both groups, pyrazinamide C_max was above target in all periods. The clinical relevance of lower rifampin exposure in pregnant women requiring tuberculosis treatment while on efavirenz should be determined.

DNA extraction was performed at Bio-Analytical Research Corporation SA laboratories, Johannesburg, South Africa, and 7 NAT2 SNPs were analyzed. Additionally, 4 SLCO1B1 SNPs: rs2306283 (388A>G), rs11045819 (463C>A), rs4149056 (521T>C) and rs4149032 (38664C>T) were analyzed based on previous evidence of effect on RIF exposure. The non-HIV-group showed a trend towards more (n=3) participants with SLCO1B1 c.388A>G (*1b) SNP homozygous variant (AA genotype), as the ART-group had none (P-value 0.09). In the non-HIV-group this AA genotype was associated with higher AUC_0-24 and C_max compared to the wildtype GG but had very small sample size. This is demonstrated in the Supplemental Material Figure S1 published here.