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


METHODS
Prospective, open-label, one-sequence, two-period crossover study.


METHODS
Clinical pharmacology unit in the United Kingdom.


METHODS
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.


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.


CONCLUSIONS
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.
Departments of Clinical Pharmacology, F. Hoffmann-La Roche, Ltd., Basel, Switzerland. Christophe.schmitt@roche.com
Christophe
C
Schmitt
Carsten
C
Hofmann
Myriam
M
Riek
Arpna
A
Patel
Elke
E
Zwanziger
D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects* / Q000378:metabolism; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008874:Midazolam / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D011446:Prospective Studies; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D019258:Saquinavir / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*
D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D006993:Hypnotics and Sedatives; C040081:1-hydroxymethylmidazolam; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D019258:Saquinavir; D019438:Ritonavir; D008874:Midazolam