Effect of Telaprevir on the Pharmacokinetics of Midazolam and Digoxin

被引:42
作者
Garg, Varun [1 ]
Chandorkar, Gurudatt [1 ,2 ]
Farmer, H. Frank [3 ]
Smith, Frances [1 ]
Alves, Katia [1 ]
van Heeswijk, Rolf P. G. [4 ]
机构
[1] Vertex Pharmaceut Inc, Cambridge, MA 02139 USA
[2] Cubist Pharmaceut Inc, Lexington, MA USA
[3] Covance Res Unit, Daytona Beach, FL USA
[4] Tibotec BVBA, Beerse, Belgium
关键词
Midazolam; digoxin; telaprevir; drug interaction; HCV; PEGINTERFERON; RIBAVIRIN;
D O I
10.1177/0091270011419850
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 (C-max) and 3.40 (3.04, 3.79) for area under the curve from 0 to 24 hours (AUC(0-24h)); for oral midazolam 2.86 (2.52, 3.25) for C-max and 8.96 (7.75, 10.35) for AUC(0-24h); and for oral digoxin 1.50 (1.36, 1.65) for C-max and 1.85 (1.70, 2.00) for area under the curve from 0 to infinity (AUC(0-infinity)). Coadministration of telaprevir with oral midazolam resulted in approximately 3-fold decrease in the mean AUC(0-infinity) 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.
引用
收藏
页码:1566 / 1573
页数:8
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