Pharmacokinetics and safety of first-line tuberculosis drugs rifampin, isoniazid, ethambutol, and pyrazinamide during pregnancy and postpartum: results from IMPAACT P1026s

Abstract

Physiological changes during pregnancy may alter the pharmacokinetics (PK) of antituberculosis drugs. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s was a multicenter, phase IV, observational, prospective PK and safety study of antiretroviral and antituberculosis drugs administered as part of clinical care in pregnant persons living with and without HIV. We assessed the effects of pregnancy on rifampin, isoniazid, ethambutol, and pyrazinamide PK in pregnant and postpartum (PP) persons without HIV treated for drug-susceptible tuberculosis disease. Daily antituberculosis treatment was prescribed following World Health Organization-recommended weight-band dosing guidelines. Steady-state 12-hour PK profiles of rifampin, isoniazid, ethambutol, and pyrazinamide were performed during second trimester (2T), third trimester (3T), and 2-8 of weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made using geometric mean ratios (GMRs) with 90% confidence intervals (CI). Twenty-seven participants were included: 11 African, 9 Asian, 3 Hispanic, and 4 mixed descent. PK data were available for 17, 21, and 14 participants in 2T, 3T, and PP, respectively. Rifampin and pyrazinamide AUC_0-24 and C _max in pregnancy were comparable to PP with the GMR between 0.80 and 1.25. Compared to PP, isoniazid AUC_0-24 was 25% lower and C _max was 23% lower in 3T. Ethambutol AUC_0-24 was 39% lower in 3T but limited by a low PP sample size. In summary, isoniazid and ethambutol concentrations were lower during pregnancy compared to PP concentrations, while rifampin and pyrazinamide concentrations were similar. However, the median AUC_0-24 for rifampin, isoniazid, and pyrazinamide met the therapeutic targets. The clinical impact of lower isoniazid and ethambutol exposure during pregnancy needs to be determined.

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

Fig 1

Median plasma concentration-time profiles of (A) rifampin, (B) isoniazid, (C) ethambutol, and (D) pyrazinamide during the second and third trimesters and postpartum (error bars indicate the IQR). The minimum target C _max of each drug is represented by the horizontal dashed lines.

Fig 2

Box and whisker plots showing plasma AUC_0-24 of (A) rifampin, (B) ethambutol, and (C) pyrazinamide during the second and third trimesters and postpartum (median, IQR, and range). The dots represent additional individual values. The minimum target AUC_0-24 of rifampin and pyrazinamide is represented by the dashed lines.

Fig 3

Box and whisker plots showing plasma isoniazid (A) AUC_0-24 and (B) C _max for the total group and per metabolizer type during the second and third trimesters and postpartum (median, IQR, and range). The dots represent additional individual values. The minimum target AUC_0-24 and C _max are represented by the dashed lines.