St. Stephen's Centre, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, United Kingdom.
Antimicrob Agents Chemother. 2011 Sep;55(9):4218-23. doi: 10.1128/AAC.01747-10. Epub 2011 Jun 27.
The object of this study was to investigate the pharmacokinetics of darunavir-ritonavir and atazanavir-ritonavir once-daily dosing over 72 h (h) following drug intake cessation. Volunteers received darunavir-ritonavir at 800 and 100 mg, respectively, once daily for 10 days, followed by a 7-day washout period, and atazanavir-ritonavir at 300 and 100 mg, respectively, once daily for 10 days. Full pharmacokinetic profiles were assessed for each phase for the 72 h following day 10. Pharmacokinetic parameters were determined over 24 h and to the last measurable concentration by noncompartmental methods. Seventeen subjects completed the study. The geometric mean (GM) terminal elimination half-life to 72 h of darunavir was 6.48 h, which was lower than the 0- to 24-h half-life (10.70 h). The terminal elimination half-life of atazanavir was 6.74 h, which was lower than the 0- to 24-h half-life (13.72 h). All subjects but one had darunavir concentrations higher than the target of 550 ng/ml for protease-resistant HIV isolates (equivalent to 10 times the protein-binding-corrected 50% inhibitory concentration [IC(50)] for wild-type virus) at 24 h postdose, and 14 out of 17 had concentrations higher than the target at 30 h postdose (GM of 1,088 and 851 ng/ml). All subjects had atazanavir concentrations above the suggested minimum effective concentration of 150 ng/ml (equivalent to 10 times the protein-binding-corrected IC(50) for wild-type virus) at 24 and 30 h postdose (GM of 693 and 392 ng/ml). Two of 17 and 5 of 17 subjects were above target at 48 h postdose while on darunavir-ritonavir and atazanavir-ritonavir. Ritonavir half-life to 72 h was 6.84 h with darunavir and 6.07 with atazanavir. This study investigated the pharmacokinetic forgiveness of two boosted protease inhibitors. Although the rates of decline of darunavir and atazanavir slightly increased as ritonavir concentrations declined, most individuals had concentrations 6 h after the end of the ideal dosing interval of 24 h which were above the cutoff used to define therapeutic concentrations.
本研究的目的是调查达鲁那韦-利托那韦和阿扎那韦-利托那韦在停药后 72 小时（h）内每日一次给药的药代动力学。志愿者分别接受 800 和 100 mg 达鲁那韦-利托那韦，每日一次，共 10 天，然后进行 7 天的洗脱期，然后分别接受 300 和 100 mg 阿扎那韦-利托那韦，每日一次，共 10 天。在第 10 天的 72 小时后，对每个阶段的完整药代动力学特征进行了评估。通过非房室方法，在 24 小时内和最后可测量浓度处测定药代动力学参数。17 名受试者完成了研究。达鲁那韦的几何平均（GM）终末消除半衰期至 72 小时为 6.48 小时，低于 0 至 24 小时半衰期（10.70 小时）。阿扎那韦的终末消除半衰期为 6.74 小时，低于 0 至 24 小时半衰期（13.72 小时）。所有受试者除了一个，在给药后 24 小时时达鲁那韦浓度高于针对抗 HIV 耐药性病毒分离株的目标值 550ng/ml（相当于野生型病毒的蛋白结合校正 50%抑制浓度[IC(50)]的 10 倍），17 名中有 14 名在给药后 30 小时时达到目标值（GM 值为 1088 和 851ng/ml）。所有受试者在给药后 24 和 30 小时时，阿扎那韦浓度均高于建议的最低有效浓度 150ng/ml（相当于野生型病毒的蛋白结合校正 IC(50)的 10 倍）（GM 值为 693 和 392ng/ml）。在达鲁那韦-利托那韦和阿扎那韦-利托那韦治疗下，17 名受试者中有 2 名和 5 名在 48 小时时的浓度高于目标值。利托那韦的终末消除半衰期至 72 小时为 6.84 小时，与达鲁那韦合用，为 6.07 小时。本研究调查了两种强化蛋白酶抑制剂的药代动力学宽容性。尽管达鲁那韦和阿扎那韦的下降速度随着利托那韦浓度的下降而略有增加，但大多数个体在理想 24 小时给药间隔结束后 6 小时的浓度仍高于用于定义治疗浓度的截止值。
