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Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam
Author(s) -
Palkama Vilja J.,
Ahonen Jouni,
Neuvonen Pertti J.,
Olkkola Klaus T.
Publication year - 1999
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(99)70051-2
Subject(s) - midazolam , saquinavir , pharmacokinetics , medicine , anesthesia , crossover study , oral administration , pharmacology , placebo , sedation , viral load , antiretroviral therapy , alternative medicine , family medicine , pathology , human immunodeficiency virus (hiv)
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, α‐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. Clinical Pharmacology & Therapeutics (1999) 66 , 33–39;