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.