Grazoprevir/Ruzasvir/Uprifosbuvir versus Midazolam
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Study Design
This was an open-label, two-period, fixed-sequence pharmacokinetic (PK) drug interaction study in fourteen healthy male and female subjects. On Study Day 1 (Period 1), a single oral dose of 2 mg midazolam was administered. On Study Days 2 to 8 (Period 2), multiple once daily oral doses of two (2) fixed dose combination (FDC) MK-3682B tablets, consisting of 100 mg grazoprevir (GZR), 60 mg rusasvir (RZR), and 450 mg uprifosbuvir (UPR) and one (1) GZR 100 mg tablet were administered for seven (7) days, with coadministration of 2 mg midazolam on Study Day 8. Plasma was collected prior to midazolam administration and at specified time points up to 24 hours after midazolam administration for measurement of midazolam and midazolam 1- OH concentrations. PK parameter values were calculated for both analytes by noncompartmental analysis. Geometric mean ratios (GMR) and 90% confidence intervals (CI) were calculated from the log transformed AUC0-inf and Cmax using linear mixed effect modelling. Safety and tolerability were monitored.
Study Results
Co-administration of MK-3682B with midazolam did not meaningfully affect the PK parameters of midazolam. The GMR and 90% CIs [midazolam co-administered with GZR, RZR, and UPR / midazolam alone] of AUC0-inf and Cmax for midazolam were 1.09 (0.98, 1.20) and 1.00 (0.89, 1.13), respectively, and for midazolam 1-OH were 0.87 (0.80, 0.96) and 0.77 (0.69, 0.87), respectively. Multiple doses of GZR, RZR, and UPR when co-administered with single-dose midazolam were generally well tolerated.
Study Conclusions
The author’s concluded that the steady state co-administration of GZR, RZR, and UPR had no meaningful impact on the PK of the CYP3A substrate midazolam. This data support the co-administration of MK-3682B with other CYP3A substrates without the need for dose adjustment.
References
Kim N, Gao W, Arrington L, Glasgow X, Garrett G, Rizk M. Mk-3682b is not a clinically significant cyp3a inhibiter or inducer . International Workshop On Clinical Pharmacology Of Antiviral Therapy . Chicago, IL, USA. 18; June 2017.
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