Rattanapunya Siwalee, Cressey Tim R, Rueangweerayut Ronnatrai, Tawon Yardpiroon, Kongjam Panida, Na-Bangchang Kesara
Faculty of Science and Technology, Chiang Mai Rajabhat University, Chaing Mai, Thailand; Program for HIV Prevention and Treatment, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand; Harvard School of Public Health, Boston, Massachusetts; Mae Sot General Hospital, Tak Province, Thailand; Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Thammasat University, Pathumthani, Thailand; Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Pathumthani, Thailand.
Faculty of Science and Technology, Chiang Mai Rajabhat University, Chaing Mai, Thailand; Program for HIV Prevention and Treatment, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand; Harvard School of Public Health, Boston, Massachusetts; Mae Sot General Hospital, Tak Province, Thailand; Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Thammasat University, Pathumthani, Thailand; Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Pathumthani, Thailand
Am J Trop Med Hyg. 2015 Dec;93(6):1383-90. doi: 10.4269/ajtmh.15-0453. Epub 2015 Sep 28.
This study aimed to investigate the pharmacokinetic interactions between quinine and lopinavir boosted with ritonavir (LPV/r) in healthy Thai adults (8 males and 12 females). Period 1 (day 1): subjects received a single oral dose of 600 mg quinine sulfate. Period 2: subjects received LPV/r (400/100 mg) twice daily. Period 3: subjects received a single quinine sulfate dose plus LPV/r twice a day. Intensive blood sampling was performed during each phase. Quinine AUC0-48h (area under the plasma concentration-time curve from time 0 to 48 hours), AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity), and Cmax (maximum concentration over the time-span specified), were 56%, 57%, and 47% lower, respectively, in the presence of LPV/r. 3-Hydroxyquinine AUC0-48h, AUC0-∞, and Cmax were significantly lower and the metabolite-to-parent ratio was significantly reduced. Lopinavir and ritonavir exposures were not significantly reduced with quinine coadministration, but Cmax of both drugs were significantly lower. The geometric mean ratio (GMR) and 90% CI of AUC0-48h, AUC0-∞, and Cmax for quinine, 3-hydroxyquinine, lopinavir, and ritonavir lay outside the bioequivalent range of 0.8-1.25. Drug treatments during all periods were generally well tolerated. The reduction in systemic exposure of quinine and 3-hydroxyquinine with concomitant LPV/r use raises concerns of suboptimal exposure. Studies in HIV/malaria coinfection patients are needed to determine the clinical impact to decide if any change to the quinine dose is warranted.
本研究旨在调查奎宁与洛匹那韦利托那韦（LPV/r）在健康泰国成年人（8名男性和12名女性）中的药代动力学相互作用。第1阶段（第1天）：受试者口服单次剂量600毫克硫酸奎宁。第2阶段：受试者每日两次接受LPV/r（400/100毫克）。第3阶段：受试者每日接受单次硫酸奎宁剂量加两次LPV/r。在每个阶段进行密集血样采集。在LPV/r存在的情况下，奎宁的AUC0 - 48h（血浆浓度 - 时间曲线从0至48小时的面积）、AUC0 - ∞（血浆浓度 - 时间曲线从0至无穷大的面积）和Cmax（指定时间段内的最大浓度）分别降低了56%、57%和47%。3 - 羟基奎宁的AUC0 - 48h、AUC0 - ∞和Cmax显著降低，且代谢物与母体的比例显著降低。同时服用奎宁时，洛匹那韦和利托那韦的暴露量没有显著降低，但两种药物的Cmax显著降低。奎宁、3 - 羟基奎宁、洛匹那韦和利托那韦的AUC0 - 48h、AUC0 - ∞和Cmax的几何平均比值（GMR）及90%置信区间超出了生物等效范围（即0.8 - 1.25）。所有阶段的药物治疗总体耐受性良好。同时使用LPV/r导致奎宁和3 - 羟基奎宁的全身暴露量降低，这引发了对暴露不足的担忧。需要对HIV/疟疾合并感染患者进行研究，以确定临床影响，从而决定是否需要调整奎宁剂量。
