ritonavir and 1-hydroxymethylmidazolam

This study aimed to demonstrate that the dose of a CYP3A substrate (simvastatin) can be adapted individually on the basis of CYP3A activity as assessed by midazolam metabolic clearance. In 18 healthy participants individual CYP3A activity was quantified using midazolam metabolic clearance both alone and during CYP3A inhibition with 40 mg ritonavir. Thereafter, simvastatin acid exposure was determined after a simvastatin standard dose (40 mg) and doses adapted to individual CYP3A activity at baseline and during CYP3A inhibition. Interindividual variability of CYP3A activity and simvastatin acid AUC0-24 was large and both correlated (r(2)  = 0.745, P < .001). The adapted simvastatin doses ranged from 25 to 80 mg and their administration reduced simvastatin variability fivefold. Despite the low adapted simvastatin dose of 12 mg during CYP3A inhibition with ritonavir, exposure increased (point estimate of 4.2 [90% CI: 3.15-5.61]) probably caused by additional OATP1B1 inhibition. CYP3A activity-based dose adaptation can be used to reduce interindividual variability in simvastatin exposure.

Topics: Adult; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Enzyme Inhibitors; Female; Humans; Male; Midazolam; Middle Aged; Ritonavir; Simvastatin

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.. Prospective, open-label, one-sequence, two-period crossover study.. Clinical pharmacology unit in the United Kingdom.. 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.. 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.. 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.

Topics: Adult; Area Under Curve; Cross-Over Studies; Cytochrome P-450 CYP3A; Drug Combinations; Drug Interactions; Female; Half-Life; HIV Protease Inhibitors; Humans; Hypnotics and Sedatives; Male; Midazolam; Prospective Studies; Ritonavir; Saquinavir