| Title | Effect of saquinavir-ritonavir on cytochrome P450 3A4 activity in healthy volunteers using midazolam as a probe. | | Author(s) | Schmitt C, Hofmann C, Riek M, Patel A, Zwanziger E | | Institution | Departments of Clinical Pharmacology, F. Hoffmann-La Roche, Ltd., Basel, Switzerland. Christophe.schmitt@roche.com | | Source | Pharmacotherapy 2009 Oct; 29(10):1175-81. | | Abstract | STUDY OBJECTIVE: To investigate the inhibitory potential of multiple doses of ritonavir-boosted saquinavir on the pharmacokinetics of oral midazolam, a cytochrome P450 (CYP) 3A4 model substrate.
DESIGN: Prospective, open-label, one-sequence, two-period crossover study.
SETTING: Clinical pharmacology unit in the United Kingdom.
PARTICIPANTS: Eighteen healthy adult male and female volunteers (median age 37.5 yrs). Intervention. A single oral dose of midazolam 7.5 mg was administered on day 1. A second dose was administered on day 16, after 14 days of oral saquinavir 1000 mg-ritonavir 100 mg twice/day.
MEASUREMENTS AND MAIN RESULTS: Serial blood samples were taken for measurement of plasma concentrations of midazolam and its metabolite, 1'-hydroxymidazolam. Pharmacokinetic parameters of midazolam and 1'-hydroxymidazolam were determined when midazolam was given alone (day 1) and after coadministration with saquinavir-ritonavir for 14 days (day 16). Two weeks of treatment with saquinavir-ritonavir resulted in a 4.3-fold increase in maximum plasma concentration (C(max)) and a 12.4-fold increase in the area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC(0-infinity)) for midazolam. Midazolam's half-life increased from 4.7 to 14.9 hours. Concomitant reductions for 1'-hydroxymidazolam were approximately 7-fold for C(max) and 2-fold for AUC(0-infinity). The 1'-hydroxymidazolam AUC(0-infinity):midazolam AUC(0-infinity) ratio was only 1% during coadministration of midazolam with saquinavir-ritonavir compared with 33% for midazolam alone. Adverse-event reports indicated that the combination of saquinavir, ritonavir, and midazolam was well tolerated but resulted in prolonged sedation.
CONCLUSION: Administration of ritonavir-boosted saquinavir markedly increased the exposure of midazolam by inhibiting its metabolism, confirming that the combination of saquinavir and ritonavir at steady state strongly inhibits CYP3A4 activity. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, Non-U.S. Gov't
| | PubMed ID | 19792991 |
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