Beclabuvir + Midazolam = Precautionary

Study Design

This was a phase 1, open-label, sequential, ascending multiple dose study in 16 healthy Japanese and Caucasian adults. In the first dosing panel, investigational drug BMS-791325 75mg BID was given on days 1-14, with a single (AM) dose given on day 15. This was followed by the second dosing panel, where subjects were given BMS-791325 150mg BID on days 2-15, plus a single AM dose on day 16, with midazolam (MDZ) 5mg QD which was administered in the morning of day 1 and 15 in the fasted state. In the third panel, subjects received BMS-791325 300mg BID on days 2-15, plus a single AM dose on day 16, with MDZ 5mg QD which was administered in the morning of day 1 and 15 in the fasted state.Dose escalation did not occur until data from the preceding panel were reviewed. Pharmacokinetic (PK) samples were obtained (pre-dose to 24 hours post dose) on day 1 (MDZ alone) and day 15 (MDZ + steady-state BMS-791325 150mg or 300mg BID).

Study Results

MDZ plasma concentrations in both Japanese (n=8) and Caucasian (n=8) subjects were reduced when co-administered with BMS-791325 150mg BID (AUC 0.50, 90%CI; 0.44-0.56), and to a slightly greater extent with BMS-791325 300mg BID (AUC 0.44, 90%CI; 0.40-0.48), compared to MDZ alone. As expected, MDZ metabolite 1-hydroxy-midazolam plasma concentrations were increased after co-administration of MDZ and BMS-791325 150mg BID and 300mg BID (AUC 1.10, 90%CI; 0.97-1.25 and AUC 1.22; 1.11-1.35, respectively). These results are consistent with weak-to-moderate CYP3A4 induction by BMS-791325. Co-administration was generally well-tolerated.

Study Conclusions

References

M AbuTarif, B He, Y Ding, et al. The effect of steady-state bms-791325, a non-nucleoside hcv ns5b polymerase inhibitor, on the pharmacokinetics of midazolam in healthy japanese and caucasian males. 15th International Workshop On Clinical Pharmacology Of Hiv And Hepatitis. Washington, DC. ; 2014.