Nitroimidazole Intermediates

Pretomanid, an oral nitroimidazooxazine antimycobacterial agent administered as part of the BPaL (bedaquiline, pretomanid and linezolid) and BPaMZ (bedaquiline, pretomanid, moxifloxacin and pyrazinamide) regimens, has been developed by the Global Alliance for TB Drug Development (TB Alliance) under license from Novartis, for the treatment for tuberculosis (TB). TB Alliance has licensed Mylan to manufacture and commercialize pretomanid for use as part of the BPaMZ and BPaL regimens. The license is non-exclusive in low- and middle-income countries and exclusive in high-income markets. 

Pretomanid pharmacokinetics after oral, single-dose administration were approximately dose proportional over a dose range of 50–200 mg and less than dose proportional over a dose range > 200–1000 mg. Administration of pretomanid with a high-fat, high calorie meal increased expo-sure to pretomanid (mean Cmax increased by 76% and mean AUC ∞ by 88%); the drug should be taken with food. After a single 200 mg dose of pretomanid administered with food to healthy adults, the mean Cmax of 2.0 μg/mL was achieved in a median 5.0 h and the mean AUC ∞ was 53.0 μg h/mL. Pretomanid is ≈ 86.4% bound to plasma protein and the estimated mean apparent volume of distribution is 97 L. Steady state was achieved ≈ 4–6 days after repeated administration of pretomanid 200 mg once daily under fasted conditions in the same population. The accumulation ratio was ≈ 2 under fasted conditions; the steady state mean Cmax (1.7 μg/mL) was achieved in a median 4.5 h and the mean AUC 24 was 30.2 μg.h/mL.

Pretomanid is metabolized by multiple reductive and oxidative pathways, with no single pathway dominating. In vitro studies, CYP3A4 accounted for up to ≈ 20% of pretomanid metabolism. Pretomanid is excreted in urine (53% of a dose) and faeces (38%), predominantly as metabolites ≈ 1% of a dose is excreted in urine as the unchanged drug. The estimated mean apparent oral clearance of pretomanid after a single 200 mg dose under fed conditions in healthy adults is 3.9 h and the estimated mean half-life is 17.4 h. Bodyweight, sex, race, HIV status and pulmonary TB status (XDR, treatment intolerant or non-responsive MDR) has no clinically significant effect on pretomanid pharma-cokine tics. The impact of patient age (≥ 65 vs < 65 years) and renal or hepatic impairment on pretomanid pharmacokinetics is not known. Co-administration of pretomanid with the CYP3A4 inducers efavirenz and rifampicin reduced pretomanid plasma concentrations; consequently, coadministration of BPaL with efavirenz and rifampicin or other moderate or strong CYP3A4 inducers should be avoided.

Pretomanid significantly inhibited the OAT3 drug transporter in vitro, which suggests that concentrations of OAT3 substrate drugs (e.g., methotrexate) could be increased at clinically relevant pretomanid concentrations. If coadministration is required, monitoring for OAT3 substrate drug-related adverse events is recommended and dosage reduction of OAT3 substrate drugs may be required. The features and properties of Pretomanid was summarized in Figure 3.