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

Abstract

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 International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s study, we assessed the PK of rifampin, isoniazid, ethambutol, and pyrazinamide during pregnancy and postpartum (PP) in women on efavirenz-based antiretroviral therapy (ART). Results were compared to a previously published non-HIV group and described minimum targets. World Health Organization-recommended daily doses of antituberculosis and ART medications were administered, followed by PK sampling of all antituberculosis drugs over 24 h during the second trimester (2T), third trimester (3T), and 2-8 weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made among stages of pregnancy and between groups using geometric mean ratios with 90% confidence intervals. Twenty-two participants were enrolled, and 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 area-under-the-plasma-concentration-time-curve up to 24 h post-dose (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.

Keywords: antiretroviral therapy; drug-susceptible tuberculosis; efavirenz; ethambutol; isoniazid; pharmacokinetics; pregnancy; pyrazinamide; rifampin.

Fig 1

Median plasma concentration-time profiles of (A) RIF, (B) INH, (C) EMB, and (D) PZA during 2T, 3T, and PP (error bars indicate the interquartile range [IQR]). The minimum target C_max of each drug is represented by the horizontal dashed lines.

Fig 2

Box and whisker plots comparing plasma AUC_0–24 of (A) RIF, (B) INH, (C) EMB, and (D) PZA and C_max of (E) RIF, (F) INH, (G) EMB, and (H) PZA, respectively, during 2T, 3T, and PP (median, IQR, and range). The minimum targets are represented by the horizontal dashed lines.

Fig 3

Box and whisker plots showing plasma INH (A) AUC_0–24 and (B) C_max for the total group and per metabolizer type during the 2T and 3T and PP (median, IQR, and range). The minimum target AUC_0–24 and C_max are represented by the dashed lines.