Kaeser Benoite, Zandt Hagen, Bour Fabrice, Zwanziger Elke, Schmitt Christophe, Zhang Xiaoping
Hoffmann-La Roche, Ltd., Basel, Switzerland.
Antimicrob Agents Chemother. 2009 Feb;53(2):609-14. doi: 10.1128/AAC.00769-08. Epub 2008 Nov 17.
Saquinavir, a potent human immunodeficiency virus protease inhibitor, is extensively metabolized by CYP3A4. Saquinavir is coadministered with ritonavir, a strong CYP3A4 inhibitor, to boost its exposure. Ketoconazole is a potent CYP3A inhibitor. The objectives of this study were to investigate the effect of ketoconazole on the pharmacokinetics of saquinavir/ritonavir and vice versa using the approved dosage regimens of saquinavir/ritonavir at 1,000/100 mg twice daily and ketoconazole at 200 mg once daily. This was an open-label, randomized two-arm, one-sequence, two-period crossover study in healthy subjects. In study arm 1, 20 subjects received saquinavir/ritonavir treatment alone for 14 days, followed in combination with ketoconazole treatment for 14 days. In arm 2, 12 subjects received ketoconazole treatment for 6 days, followed in combination with saquinavir/ritonavir treatment for 14 days. The pharmacokinetics were assessed on the last day of each treatment (days 14 and 28 in arm 1 and days 6 and 20 in arm 2). The exposures C(max) and the area under the concentration-time curve from 0 to 12 h (AUC(0-12)) of saquinavir and ritonavir with or without ketoconazole were not substantially altered after 2 weeks of concomitant dosing with ketoconazole. The C(max) and AUC(0-12) of ketoconazole, dosed at 200 mg once daily, were increased by 45% (90% confidence interval = 32 to 59%) and 168% (90% confidence interval = 146 to 193%), respectively, after 2 weeks of concomitant dosing with ritonavir-boosted saquinavir (1,000 mg of saquinavir/100 mg of ritonavir given twice daily). The greater exposure to ketoconazole when given in combination with saquinavir/ritonavir was not associated with unacceptable safety or tolerability. No dose adjustment for saquinavir/ritonavir (1,000/100 mg twice daily) is required when coadministered with 200 mg of ketoconazole once daily, and high doses of ketoconazole (>200 mg/day) are not recommended.
沙奎那韦是一种强效的人类免疫缺陷病毒蛋白酶抑制剂，主要通过CYP3A4进行广泛代谢。沙奎那韦与强力CYP3A4抑制剂利托那韦联合使用，以增加其药物暴露量。酮康唑是一种强效的CYP3A抑制剂。本研究的目的是使用沙奎那韦/利托那韦批准的给药方案（每日两次，每次1000/100mg）和酮康唑（每日一次，每次200mg），研究酮康唑对沙奎那韦/利托那韦药代动力学的影响，反之亦然。这是一项针对健康受试者的开放标签、随机双臂、单序列、两阶段交叉研究。在研究组1中，20名受试者单独接受沙奎那韦/利托那韦治疗14天，随后联合酮康唑治疗14天。在研究组2中，12名受试者接受酮康唑治疗6天，随后联合沙奎那韦/利托那韦治疗14天。在每种治疗的最后一天（研究组1中的第14天和第28天，研究组2中的第6天和第20天）评估药代动力学。在与酮康唑联合给药2周后，无论是否使用酮康唑，沙奎那韦和利托那韦的药物暴露量C(max)以及浓度-时间曲线下0至12小时的面积（AUC(0-12)）均无显著变化。在与利托那韦增强的沙奎那韦（每日两次，每次1000mg沙奎那韦/100mg利托那韦）联合给药2周后，每日一次给药200mg的酮康唑的C(max)和AUC(0-12)分别增加了45%（90%置信区间 = 32%至59%）和168%（90%置信区间 = 146%至193%）。与沙奎那韦/利托那韦联合使用时酮康唑的更大暴露量与不可接受的安全性或耐受性无关。当每日一次联合使用200mg酮康唑时，无需调整沙奎那韦/利托那韦（每日两次，每次1000/100mg）的剂量，且不建议使用高剂量的酮康唑（>200mg/天）。
