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.
Schmitt
Christophe
C
Departments of Clinical Pharmacology, F. Hoffmann-La Roche, Ltd., Basel, Switzerland. Christophe.schmitt@roche.com
Hofmann
Carsten
C
Riek
Myriam
M
Patel
Arpna
A
Zwanziger
Elke
E
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