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Effect of Telaprevir on the Pharmacokinetics of Midazolam and Digoxin

Authors


Address for correspondence: Varun Garg, PhD, Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, MA 02139-4242; e-mail: varun_garg@vrtx.com.

Abstract

In this open-label study, 24 healthy volunteers received a single intravenous (IV) dose of 0.5 mg of midazolam on day 1 and a single oral dose each of 2 mg of midazolam and 0.5 mg of digoxin on day 3. Telaprevir 750 mg every 8 hours was administered from day 8 through day 23, along with a single IV dose of 0.5 mg of midazolam on day 17 and single oral doses of 2 mg of midazolam and 0.5 mg of digoxin on day 19. Midazolam, 1′-hydroxymidazolam, digoxin, and telaprevir concentrations in plasma and digoxin concentrations in urine were measured and pharmacokinetic parameters calculated. On comparing administration with versus without telaprevir, the geometric least squares mean ratios (with 90% confidence limits) for IV midazolam were 1.02 (0.80, 1.31) for maximum observed concentrations (Cmax) and 3.40 (3.04, 3.79) for area under the curve from 0 to 24 hours (AUC0–24h); for oral midazolam 2.86 (2.52, 3.25) for Cmax and 8.96 (7.75, 10.35) for AUC0–24h; and for oral digoxin 1.50 (1.36, 1.65) for Cmax and 1.85 (1.70, 2.00) for area under the curve from 0 to infinity (AUC0-∞). Coadministration of telaprevir with oral midazolam resulted in approximately 3-fold decrease in the mean AUC0-∞ of 1′-hydroxymidazolam. The renal clearance of digoxin was similar with or without telaprevir. Results show that telaprevir is an inhibitor of CYP3A and P-glycoprotein.

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