Pretomanid + Lopinavir/Ritonavir = Precautionary

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

PK of PA-824 was not significantly impacted when coadministered with LPV/r. GMRs (PA-824+LPV/r / PA-824) [90% CIs] of AUC, Cmax, and Cmin for PA-824 were 0.83 [0.71, 0.98], 0.87 [0.75, 1.0], and 0.79 [0.66, 0.93], respectively.Similarly, PK of LPV/r was only modestly impacted when coadministered with PA-824. GMRs (PA-824+LPV/r / LPV/r) [90% CIs] of AUC, Cmax, and Cmin for LPV/r were 0.86 [0.77, 0.96], 0.83 [0.76, 0.92], and 1.03 [0.60, 1.80], respectively.The investigators concluded that PA-824 and LPV/r can be coadministered without dose adjustment as LPV/r only modestly reduced PA-824 exposure.

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.