Grazoprevir (Single Agent) + Rifampin = Prohibited

Study Design

In an open-label, multiple-dose study, 12 healthy adults (ages 19-55 years) received a single intravenous (IV) dose of rifampin (RIF) 600 mg with a single oral dose of 200 mg grazoprevir (GZR), followed by a 7-day washout. Subjects then received GZR 200 mg daily for 8 days, followed by coadministration of GZR 200 mg daily with RIF 600 mg orally once daily for 14 days.

Study Results

Coadministration of GZR and a single dose of IV RIF led to AUC and Cmax of GZR with geometric mean ratios (GMRs, GZR+RIF/GZR) [90% CI] of 12.61 [10.83, 14.67] and 10.94 [8.92, 13.43], respectively.Coadministration with a single dose of oral RIF led to AUC and Cmax of GZR with GMRs (GZR+RIF/GZR) [90% CIs] of 8.35 [7.38, 9.45] and 6.52 [5.16, 8.24], respectively, presumably via P-glycoprotein (P-gp) and the organic anion transport proteins (OATP) inhibition by RIF. Steady-state AUC of GZR was not significantly affected by multiple oral doses of RIF; GMR of GZR AUC (GZR+RIF/GZR) [90% CI] was 0.93 [0.75, 1.17]. However, plasma concentration at 24 hours post-dose (C24h) of GZR was significantly reduced; 0.15 [0.11, 0.20]. This is likely due to the net effect of the OATP inhibition and CYP3A4/ Pgp induction by chronic RIF administration.

Study Conclusions

References

L Caro, Talaty JE, Z Guo, et al. Pharmacokinetic interaction between the hcv protease inhibitor mk-5172 and iv and oral rifampin in healthy volunteers [abstract 495]. 64th Annual Meeting Of The American Association For The Study Of Liver Diseases (aasld). Washington, DC. ; 2013.