Interactions between invirase(saquinavir) and Midazolam (midazolam)
midazolam and saquinavir (Major Drug-Drug)
CONTRAINDICATED: Coadministration with protease inhibitors (PIs) may significantly increase the plasma concentrations and pharmacologic effects of midazolam and triazolam. The mechanism is PI inhibition of intestinal and hepatic CYP450 3A4, the isoenzyme that metabolizes these benzodiazepines. Within the class, ritonavir is considered the most potent 3A4 inhibitor and saquinavir the weakest. In six healthy volunteers, ritonavir (200 mg twice a day for 2 days) nearly doubled the peak plasma concentration (Cmax) of triazolam (0.125 mg single dose) and increased its area under the concentration-time curve (AUC) and elimination half-life by 20- and 14-fold, respectively, compared to placebo. Ritonavir also decreased triazolam clearance to less than 4% of control values. In 12 healthy volunteers, the Cmax and AUC of oral midazolam (7.5 mg single dose) increased by more than 2- and 5-fold, respectively, during coadministration with saquinavir (soft gelatin capsule 1200 mg three times a day for 5 days) relative to placebo, while oral bioavailability increased from 41% to 90%. The AUC of intravenous midazolam (0.05 mg/kg single dose) increased 2.4-fold, and mean plasma clearance decreased by 56%. In both studies, the pharmacokinetic changes were accompanied by increased sedation and impairment of psychomotor performance.
MANAGEMENT: Given the potential for prolonged and/or increased sedation and respiratory depression associated with excessive benzodiazepine blood levels, concomitant use of midazolam or triazolam with protease inhibitors is considered contraindicated.
