title: Effect of telaprevir on the pharmacokinetics of midazolam and digoxin.
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 (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-∞)). Coadministration of telaprevir with oral midazolam resulted in approximately 3-fold decrease in the mean AUC(0-∞) 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.
authors.affiliation: Vertex Pharmaceuticals Incorporated, Cambridge, MA 02139-4242, USA. varun_garg@vrtx.com
authors.forename: Varun
authors.initials: V
authors.lastname: Garg
authors.forename: Gurudatt
authors.initials: G
authors.lastname: Chandorkar
authors.forename: H Frank
authors.initials: HF
authors.lastname: Farmer
authors.forename: Frances
authors.initials: F
authors.lastname: Smith
authors.forename: Katia
authors.initials: K
authors.lastname: Alves
authors.forename: Rolf P G
authors.initials: RP
authors.lastname: van Heeswijk
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004077:Digoxin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D011480:Protease Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000998:Antiviral Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D009842:Oligopeptides; D011480:Protease Inhibitors; C486464:telaprevir; D004077:Digoxin; C040081:1-hydroxymethylmidazolam; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam