Leading Program, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Department of Clinical Product Development, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.
Clin Pharmacol Ther. 2020 May;107(5):1209-1220. doi: 10.1002/cpt.1721. Epub 2020 Jan 12.
The coformulated lopinavir/ritonavir significantly reduces quinine concentration in healthy volunteers due to potential drug-drug interactions (DDIs). However, DDI information in malaria and HIV coinfected patients are lacking. The objective of the study was to apply physiologically-based pharmacokinetic (PBPK) modeling to predict optimal dosage regimens of quinine when coadministered with lopinavir/ritonavir in malaria and HIV coinfected patients with different conditions. The developed model was validated against literature. Model verification was evaluated using the accepted method. The verified PBPK models successfully predicted unbound quinine disposition when coadministered with lopinavir/ritonavir in coinfected patients with different conditions. Suitable dose adjustments to counteract with the DDIs have identified in patients with various situations (i.e., a 7-day course at 1,800 mg t.i.d. in patients with malaria with HIV infection, 648 mg b.i.d. in chronic renal failure, 648 mg t.i.d. in hepatic insufficiency except for severe hepatic insufficiency (324 mg b.i.d.), and 648 mg t.i.d. in CYP3A4 polymorphism).
洛匹那韦利托那韦复方制剂由于潜在的药物相互作用（DDI），可显著降低健康志愿者体内奎宁的浓度。然而，疟疾和 HIV 合并感染患者的 DDI 信息却缺乏。本研究的目的是应用基于生理学的药代动力学（PBPK）模型来预测当奎宁与洛匹那韦利托那韦联合用于不同情况下的疟疾和 HIV 合并感染患者时的最佳剂量方案。所开发的模型经过文献验证。模型验证采用公认的方法进行评估。验证后的 PBPK 模型成功预测了在不同情况下合并感染患者中与洛匹那韦利托那韦联合使用时的游离奎宁处置情况。已在各种情况下确定了适当的剂量调整以对抗 DDI（即，HIV 感染性疟疾患者 7 天疗程，每日 3 次，每次 1800mg；慢性肾功能衰竭患者每日 2 次，每次 648mg；除严重肝功能不全（每日 2 次，每次 324mg）外的肝功能不全患者每日 3 次，每次 648mg；CYP3A4 多态性患者每日 3 次，每次 648mg）。
