Effect of saquinavir-ritonavir on cytochrome P450 3A4 activity in healthy volunteers using midazolam as a probe.

Article Details

Citation

Copy to clipboard

Schmitt C, Hofmann C, Riek M, Patel A, Zwanziger E

Effect of saquinavir-ritonavir on cytochrome P450 3A4 activity in healthy volunteers using midazolam as a probe.

Pharmacotherapy. 2009 Oct;29(10):1175-81. doi: 10.1592/phco.29.10.1175.

PubMed ID

19792991 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Saquinavir	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate Inhibitor	Details