Pharmacokinetics and Safety of Clofazimine in Women With Rifampicin-resistant Tuberculosis During Pregnancy and the Postpartum Period: Results From IMPAACT P1026s.

BACKGROUND: There are no published data on clofazimine pharmacokinetics during pregnancy, and safety data are limited. We present data from pregnant and postpartum women receiving clofazimine for treatment of rifampicin-resistant tuberculosis (RR-TB).

METHODS: IMPAACT P1026s was an observational study to assess the pharmacokinetics of tuberculosis and/or antiretroviral drugs during pregnancy. Between 2017 and 2019, pregnant women receiving ≥2 second-line antituberculosis drugs in routine care were enrolled in the second or third trimester and had intensive pharmacokinetic sampling at least once during pregnancy, and 2-8 weeks postpartum. Pharmacokinetic parameters were estimated using noncompartmental methods and compared between the antepartum and postpartum periods using geometric mean ratios (GMR) with 90% confidence intervals (CIs) and the Wilcoxon signed rank test for paired data.

RESULTS: Eleven pregnant women from South Africa, 7 (64%) with HIV, were receiving clofazimine (100 mg daily) at enrollment, of which 82% received clofazimine for more than 8 weeks prior to pharmacokinetic evaluation. Nine (82%) women continued treatment postpartum. Peak plasma concentrations and area-under-the-concentration-time-curve over 12 hours were comparable to historical clofazimine pharmacokinetic data in nonpregnant women with RR-TB but were approximately 30% higher in the third trimester of pregnancy compared to the postpartum period. Eight women and 8 infants experienced at least one severe adverse event while on study but direct relatedness to clofazimine was considered unlikely.

CONCLUSIONS: Overall, antepartum and postpartum clofazimine exposures were comparable to those reported in nonpregnant women with RR-TB. Exposures were lower than expected in the postpartum period, particularly compared with the third trimester of pregnancy.