Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam

Clin Pharmacol Ther. 1999 Jul;66(1):33-9. doi: 10.1016/S0009-9236(99)70051-2.


Objective: To assess the effect of human immunodeficiency virus protease inhibitor saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam.

Methods: In a double-blind, randomized, two-phase crossover study, 12 healthy volunteers (six men and six women; age range, 21 to 32 years) received oral doses of either 1200 mg saquinavir (Fortovase soft-gel capsule formulation) or placebo three times a day for 5 days. On day 3, six subjects were given 7.5 mg oral midazolam and the other six subjects received 0.05 mg/kg intravenous midazolam. On day 5, the subjects who had received oral midazolam on day 3 received intravenously midazolam and vice versa. Plasma concentrations of midazolam, alpha-hydroxymidazolam, and saquinavir were determined for 18 hours after midazolam administration, and midazolam effects were measured up to 7 hours by six psychomotor tests.

Results: Saquinavir increased the bioavailability of oral midazolam from 41% to 90% (P < .005), the peak midazolam plasma concentration more than twofold, and the area under plasma concentration-time curve more than fivefold (P < .001). During saquinavir treatment, five of the six psychomotor tests revealed impaired skills and increased sedative effects after midazolam ingestion (P < .05). Saquinavir decreased the clearance of intravenous midazolam by 56% (P < .001) and increased its elimination half-life from 4.1 to 9.5 hours (P < .01). After intravenous midazolam, only the subjective feeling of drug effect was increased significantly (P < .05) by saquinavir.

Conclusion: The dose of oral midazolam should be greatly reduced or avoided with saquinavir, but bolus doses of intravenous midazolam can probably be used quite safely. During a prolonged midazolam infusion, an initial dose reduction of 50% followed by careful titration is recommended to counteract the reduced clearance caused by saquinavir.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Anti-Anxiety Agents / administration & dosage
  • Anti-Anxiety Agents / pharmacokinetics
  • Anti-HIV Agents / pharmacology*
  • Cross-Over Studies
  • Double-Blind Method
  • Female
  • HIV Protease Inhibitors / pharmacology
  • Humans
  • Hypnotics and Sedatives / administration & dosage*
  • Hypnotics and Sedatives / blood
  • Hypnotics and Sedatives / pharmacokinetics*
  • Injections, Intravenous
  • Male
  • Midazolam / administration & dosage*
  • Midazolam / blood
  • Midazolam / pharmacokinetics*
  • Reference Values
  • Saquinavir / pharmacology*
  • Time Factors


  • Anti-Anxiety Agents
  • Anti-HIV Agents
  • HIV Protease Inhibitors
  • Hypnotics and Sedatives
  • Saquinavir
  • Midazolam