Washington Carla B, Flexner Charles, Sheiner Lewis B, Rosenkranz Susan L, Segal Yoninah, Aberg Judith A, Blaschke Terrence F
Department of Medicine, Stanford University Medical Center, Stanford, CA 94305-5130, USA.
Clin Pharmacol Ther. 2003 May;73(5):406-16. doi: 10.1016/s0009-9236(03)00006-7.
The aim of this study was to determine whether pharmacokinetic interactions between the protease inhibitors saquinavir soft gel, nelfinavir, and ritonavir are affected by the timing of administration.
We used an open-label, 6-period, incomplete Latin square crossover study in 18 human immunodeficiency virus-negative subjects. Each received single oral doses of 2 of the 3 protease inhibitors during each of 6 periods. Single doses were given either simultaneously or separated by 4 hours. The order of the periods was balanced, and periods were separated by 2 days. We measured protease inhibitor concentrations over a 24-hour period by HPLC and estimated pharmacokinetic parameters by noncompartmental methods.
Median saquinavir area under the curve (AUC) increased by 62-fold when ritonavir was coadministered, by 50-fold when ritonavir was given 4 hours earlier, and by 16-fold when saquinavir preceded ritonavir by 4 hours. Saquinavir AUC increased by 7-fold when nelfinavir was coadministered. Nelfinavir AUC increased by 2.5-fold with coadministration of ritonavir and by 1.8- and 2.1-fold when ritonavir was administered before nelfinavir and after nelfinavir, respectively. Ritonavir AUCs were unaffected by coadministration of the other drugs. The effect of ritonavir on the kinetics of saquinavir persisted for at least 48 hours after a single dose of ritonavir, suggesting the possibility of metabolic intermediates that form inhibitory complexes.
Except for saquinavir followed by ritonavir, there is little difference in protease inhibitor exposure for simultaneous or staggered doses. The persistent effect of ritonavir suggests the possibility that lower doses and longer dosing intervals might be effective when ritonavir is used to boost concentrations of other protease inhibitors.
本研究旨在确定蛋白酶抑制剂沙奎那韦软胶囊、奈非那韦和利托那韦之间的药代动力学相互作用是否受给药时间的影响。
我们在18名人类免疫缺陷病毒阴性受试者中进行了一项开放标签、6周期、不完全拉丁方交叉研究。在6个周期中的每个周期，每位受试者接受3种蛋白酶抑制剂中2种的单次口服剂量。单次剂量同时给药或间隔4小时给药。周期顺序是平衡的，且周期间隔为2天。我们通过高效液相色谱法在24小时内测量蛋白酶抑制剂浓度，并通过非房室方法估算药代动力学参数。
与利托那韦合用时，沙奎那韦曲线下面积（AUC）中位数增加62倍；利托那韦提前4小时给药时，沙奎那韦AUC增加50倍；沙奎那韦比利托那韦提前4小时给药时，沙奎那韦AUC增加16倍。与奈非那韦合用时，沙奎那韦AUC增加7倍。与利托那韦合用时，奈非那韦AUC增加2.5倍；利托那韦在奈非那韦之前和之后给药时，奈非那韦AUC分别增加1.8倍和2.1倍。利托那韦的AUC不受其他药物合用的影响。单剂量利托那韦给药后，利托那韦对沙奎那韦动力学的影响持续至少48小时，提示可能存在形成抑制性复合物的代谢中间体。
除沙奎那韦在利托那韦之后给药外，同时给药或错开给药时蛋白酶抑制剂的暴露量差异不大。利托那韦的持续作用提示，当利托那韦用于提高其他蛋白酶抑制剂的浓度时，较低剂量和较长给药间隔可能有效。
