Mean steady state AUC 0-T, Cmax and C24h of GZR are unchanged when daily doses of 200 mg GZR are co-administered with daily doses of 60 mg of DCV when compared to 200 mg GZR administered alone. Mean steady state AUC 0-T of daclatasvir is unchanged when 60 mg of DCV is given with 200 mg GZR compared with 60 mg of DCV given alone. Mean steady state Cmax of DCV decreased approximately 20% and mean C24h increased approximately 23%. Co-administration of 60 mg DCV and 200 mg GZR did not result in a clinically significant pharmacokinetic drug interaction. Concomitant use of these agents appeared safe and well tolerated in this study. However, given the limited sample size and use in healthy volunteers, further data is required before definitive conclusions can be drawn.
Daclatasvir vs grazoprevir
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Study Design
Yeh, et al conducted a single-center, open-label, fixed-sequence, multiple-dose study in 14 HCV-negative adult male and female volunteers, ages 21-49 years.Because grazoprevir (GZR; formerly known as MK-5172) in HCV-infected patients demonstrates ~2-fold higher exposure compared with healthy subjects, a 200 mg dose of GZR in healthy subjects was used in this study to match the exposure of a 100 mg dose (the intended clinical dose) in HCV-infected patients. 60mg dosing of daclatasvir (DCV) is expected to be utilized clinically pending FDA approval of this agent.In Period 1, subjects received oral doses of 60 mg DCV once daily on Days 1 to 7. Following a 4-day washout, subjects received oral doses of 200 mg GZR once daily on Days 1 to 7 in Period 2. In Period 3, which commenced immediately after Period 2, subjects were co-administered once daily oral doses of 200 mg GZR and 60 mg DCV on Days 1 to 8. Plasma pharmacokinetic samples were obtained for daclatasvir on Day 7 in Period 1 and Day 8 in Period 3, as well as for GZR on Day 7 in Period 2 and Day 8 in Period 3. Safety assessments included electrocardiograms, vital signs, clinical laboratory tests, physical examination, and adverse event monitoring.
Study Results
Co-administration of GZR with daclatasvir was safe and well tolerated. Multiple oral doses of GZR did not meaningfully change the steady-state AUC0-t, Cmax, or C24h of DCV, with GZR+DCV/DCV geometric mean ratios (GMRs) [90% confidence intervals (CIs)] of 1.02 [0.93, 1.11], 0.80 [0.74, 0.86], and 1.23 [1.09, 1.38], respectively. Multiple oral doses of daclatasvir did not meaningfully change the steady-state AUC0-t, Cmax, or C24h of GZR, with GZR+DCV/GZR GMRs [90% CIs] of 1.12 [0.87, 1.44], 1.11 [0.77, 1.60], and 1.04 [0.97, 1.12], respectively.
References
Yeh WW, Fraser IP, M Bifano, L Caro, J Talaty, Z Guo, et al. Lack of pharmacokinetic interaction between hcv protease inhibitor mk-5172 and hcv ns5a inhibitor daclatasvir in healthy volunteers. 64th Annual Meeting Of The American Association For The Study Of Liver Diseases. Washington DC. ; 2013.
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