title: Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Anesthesia, University of Helsinki, Finland.
authors.forename: V J
authors.initials: VJ
authors.lastname: Palkama
authors.forename: J
authors.initials: J
authors.lastname: Ahonen
authors.forename: P J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: K T
authors.initials: KT
authors.lastname: Olkkola
mesh_terms: D000284:Administration, Oral; D000328:Adult; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019380:Anti-HIV Agents / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D008874:Midazolam / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D012016:Reference Values; D019258:Saquinavir / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D014151:Anti-Anxiety Agents; D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D006993:Hypnotics and Sedatives; D019258:Saquinavir; D008874:Midazolam