Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam
Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam
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DOI：
10.1016/s0009-9236(99)70051-2
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发表时间：
1999-07-01
影响因子：
6.7
通讯作者：
Olkkola, KT
中科院分区：
文献类型：
--
作者：
Palkama, VJ;Ahonen, J;Olkkola, KT
目的：目的：评价人类免疫缺陷病毒蛋白酶抑制剂沙奎那韦对口服和静脉注射咪达唑仑的药代动力学和药效学的影响。（六男六女;年龄范围，21至32岁）接受口服剂量1200 mg沙奎那韦（Fortovase软胶囊制剂）或安慰剂，每日三次，持续5天。第3天，6例受试者接受7.5 mg口服咪达唑仑，其他6例受试者接受0.05 mg/kg静脉咪达唑仑。第5天，第3天接受口服咪达唑仑的受试者接受静脉咪达唑仑，反之亦然。在咪达唑仑给药后18小时测定咪达唑仑、α-羟基咪达唑仑和沙奎那韦的血浆浓度，并通过6项精神病学测试测量咪达唑仑效应长达7小时。沙奎那韦使口服咪达唑仑的生物利用度从41%提高到90%咪达唑仑血药浓度峰值为对照组的2倍以上，血药浓度-时间曲线下面积为对照组的5倍以上（P < .001）。在沙奎那韦治疗期间，6项精神病学测试中有5项显示摄入咪达唑仑后技能受损和镇静作用增加（P <0.05）。沙奎那韦使静脉咪达唑仑的清除率降低56%（P <0.001），消除半衰期从4.1小时增加到9.5小时（P <0.01）。结论：口服咪达唑仑时应尽量减少或避免使用沙奎那韦，但静脉推注咪达唑仑可能是安全的。在长期咪达唑仑输注期间，建议将初始剂量减少50%，然后仔细滴定，以抵消沙奎那韦引起的清除率降低。
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.