Concomitant use of MK-3682 and MK-5172/MK-8408 may result in slightly increased PK parameters of both MK-3682 and MK 5172 and no change in PK parameters of MK-8408. The investigators concluded that the magnitude of these changes are not deemed clinically meaningful and no dose adjustment is required when co-administering these drugs. However, close monitoring is warranted since the PKs of MK-5172 were variably affected when coadministered with MK-3682.
Mk-3682 vs grazoprevir/mk-8408
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Study Design
In a 3-period, fixed sequence, open-label, phase I study, healthy subjects (n=18) were given MK-5172 200 mg together with MK-8408 60 mg daily for 7 days (Days 1-7; period 1). After a 7-day washout (Days 8-14), subjects received MK-3682 300 mg daily for 7 days (Days 15-21; period 2), followed by concomitant administration of MK-3682 300 mg daily, MK-5172 200 mg daily, and MK-8408 60 mg daily for 7 days (Days 22-29; period 3).
Study Results
1. Coadministration of MK-3682 300 mg daily with MK-5172 200 mg daily plus MK-8408 60 mg daily for 7 days resulted in slightly increased MK-3682 pharmacokinetic (PK) parameters, whereas slightly decreased PK parameters of IDX20664, a nucleoside metabolite of MK-3682. The investigators indicated that the magnitude of these changes are not clinically meaningful. The geometric mean ratios (GMRs; MK-3682 + MK-5172/MK-8408 / MK-3682) [90% CIs] of MK-3682 were: 1.21 [1.03, 1.42] for Cmax and 1.26 [1.15, 1.37] for AUCGMRs (MK-3682 + MK-5172/MK-8408 / MK-3682) [90% CIs] of IDX20664 were: 0.85 [0.81, 0.89] for AUC, 0.75 [0.72, 0.79] for Cmax, and 0.93 [0.89, 0.98] for Cmin.2. MK-5172/MK-8408 did not affect PKs of IDX23267, a cleavage metabolite of MK-3682; GMRs (MK-3682 + MK-5172/MK-8408 / MK-3682) [90% CIs] of AUC and Cmax for IDX23267 were 1.02 [0.93, 1.11] and 0.97 [0.87, 1.09], respectively.3. Co-administration of MK-3682 slightly increased MK-5172 PK parameters, whereas no effect on MK-8408 PK parameters. GMRs (MK-3682 + MK-5172/MK-8408 / MK-5172/MK-8408) [90% CIs] of MK-5172 were: 1.56 [1.19, 2.03] for Cmax and 1.36 [1.11, 1.66] for AUC; the magnitude of these increase in MK-5172 PK parameters is within a therapeutic range that has been considered safe and well tolerated.GMRs (MK-3682 + MK-5172/MK-8408 / MK-5172/MK-8408) [90% CIs] of MK-8408 were: 1.02 [0.93, 1.11] for Cmax and 0.99 [0.92, 1.06] for AUC
Study Conclusions
1. Concomitant use of MK-3682 and GZR/MK-8408 may result in slightly increased PK parameters of both MK-3682 and GZR and no change in PK parameters of MK-8408. The investigators concluded that the magnitude of these changes are not clinically meaningful and no dose adjustment is required when co-administering these drugs. However, close monitoring is warranted since the PKs of GZR were variably affected when coadministered with MK-3682.
2. An 8-week regimen of GZR (100 mg)/ MK-3862 (450 mg)/ MK-8408 (60 mg) was highly effective; more than 90% of treatment-naïve, non-cirrhotic patients with HCV genotype 1,2, and 3 infection achieved an SVR 12 (Table 2).2 Based on the results of this trial, Merck has initiated further study of GZR (100mg)/MK-3682 (450mg)/MK-8408 (60mg) in the second phase (Part B) of the C-CREST Phase 2 clinical development program.
References
Zhou XJ, E Sicard, J Chen, et al. A phase 1 study to evaluate the interaction of hcv ns5b inhibitor mk-3682 with hcv ns3/4a protease inhibitor mk-5172 and hcv ns5a inhibitor mk-8408 in healthy subjects. 50th Annual Meeting Of The European Association For The Study Of The Liver (easl). Austria. ; 2015.
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