Pretomanid + Rifampin = Prohibited

Study Design

In phase 1, open-label, 3-period study, 16 healthy subjects with age of 18-65 years old were randomized to one of the two treatment sequences.Subjects randomized to sequence 1 received PA-824 200 mg once daily for 7 days (Days 1-7). After a 14-day washout (Days 8-21), subjects received efavirenz (EFV) 600mg once daily for 14 days (Days 22-35), followed by coadministration of PA-824 200 mg plus EFV 600mg once daily for 7 days (Days 36-42). Intensive PK sampling for PA-824 and/or EFV was performed at Day 7, 35, and 42.Subjects randomized to sequence 2 received EFV 600mg once daily for 14 days (Days 1-14), followed by coadministration of PA-824 200 mg plus EFV 600mg once daily for 7 days (Days 15-21). After a 14-day washout (Days 22-35), subjects received PA-824 200 mg once daily for 7 days (Days 36-42). Intensive PK sampling for PA-824 and/or EFV was performed at Day 14, 21, and 42.

Study Results

Coadministration of PA-824 and RIF resulted in significant decrease of AUC, Cmax, and Cmin for PA-824; AUC, Cmax, and Cmin with geometric mean ratios (GMRs; RIF+ PA-824 / PA-824) [90% CI] were 0.34 [0.27, 0.42], 0.47 [0.39,0.56], and 0.15 [0.11, 0.21], respectively.

Study Conclusions

References

Kelly E Dooley, Anne F Luetkemeyer, Jeong-Gun Park, Reena Allen, Yoninah Cramer, Stephen Murray, Deborah Sutherland, et al. Phase i safety, pharmacokinetics, and pharmacogenetics study of the antituberculosis drug pa-824 with concomitant lopinavir-ritonavir, efavirenz, or rifampin. Antimicrobial Agents And Chemotherapy. 2014; 9: 5245-5252.