Safety evaluation of pretomanid, an anti-tuberculosis drug, for the treatment of pregnant and lactating women

Safe and effective treatment options for tuberculosis (TB) are urgently needed for pregnant and lactating women due to the adverse maternal and neonatal outcomes associated with TB disease. Pretomanid is recommended by the World Health Organization for treatment of multidrug-resistant pulmonary TB in combination with bedaquiline and linezolid. However, this regimen is not recommended during pregnancy or breastfeeding due to the absence of clinical safety and efficacy data of pretomanid in these populations. This manuscript presents the nonclinical developmental and reproductive toxicology profile of pretomanid and clinical outcomes of pregnancies in women known to have been exposed to pretomanid. In nonclinical studies, pretomanid did not have a direct effect on fertility and reproductive function in female rats, and no adverse maternal or developmental effects were seen in rats or rabbits up to two times the clinical exposure during organogenesis. Additionally, no adverse developmental effects were observed in pups of pregnant rats orally dosed throughout gestation and lactation at approximately 1.5-fold clinical exposure. In the rat pre- and postnatal development study at 4.4-fold clinical exposure, there was maternal toxicity, lower pup body weights, and a delay in attaining the righting reflex, but no effects on fertility were seen in the male or female rat offspring. Clinically, 11 women became pregnant during pretomanid treatment: 5 had healthy babies, 5 had elective abortions, and 1 had a spontaneous abortion. The weight of evidence from preclinical studies and limited clinical outcomes supports further evaluation of pretomanid use in pregnant or lactating women. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT03086486.