Nakamaru Yuta, Sako Ken-Ichi, Ide Naohito, Matsuda Yoshikazu, Yamashita Fumiyoshi, Maeda Tomoji
Department of Clinical Pharmacy, Nihon Pharmaceutical University, Saitama, Japan.
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
In Vivo. 2025 Jul-Aug;39(4):2101-2108. doi: 10.21873/invivo.14005.
BACKGROUND/AIM: Lopinavir (LPV) combined with ritonavir (LPV/r) was initially developed to treat human immunodeficiency virus (HIV) infection and was subsequently repurposed to treat coronavirus disease 2019 (COVID-19) during the COVID-19 pandemic. As the efficacy of LPV/r in COVID-19 treatment has not been confirmed in clinical trials, LPV/r is not included in the Japanese COVID-19 treatment guidelines. Furthermore, previous clinical studies have not demonstrated the benefit of LPV/r against COVID-19 when used at the same dose as that used to treat HIV infection. Therefore, the aim of this study was to determine the optimal LPV/r dose combination for COVID-19 treatment.
Based on data from healthy volunteers and patients with HIV infection, maximum-effect models were used to estimate the relationship between LPV clearance and ritonavir plasma concentration. Pharmacokinetic simulations were performed using a range of assumptions based on previously reported modeling equations.
The standard LPV/r dose combination of 400 mg/100 mg twice daily did not yield optimal blood concentrations. Based on the pharmacokinetic booster effect of ritonavir, the estimated optimal dose combination was 400 mg LPV boosted with 1,200 mg ritonavir.
These findings provide a basis to quantify the booster effect of ritonavir on LPV in COVID-19 treatment and calculate the optimal LPV and ritonavir dose combination.
背景/目的：洛匹那韦（LPV）联合利托那韦（LPV/r）最初用于治疗人类免疫缺陷病毒（HIV）感染，在2019冠状病毒病（COVID-19）大流行期间被重新用于治疗COVID-19。由于LPV/r在COVID-19治疗中的疗效尚未在临床试验中得到证实，因此LPV/r未被纳入日本COVID-19治疗指南。此外，以往的临床研究并未证明LPV/r在以治疗HIV感染的相同剂量使用时对COVID-19有益。因此，本研究的目的是确定用于COVID-19治疗的最佳LPV/r剂量组合。
基于健康志愿者和HIV感染患者的数据，使用最大效应模型来估计LPV清除率与利托那韦血浆浓度之间的关系。根据先前报道的建模方程，在一系列假设条件下进行了药代动力学模拟。
标准的LPV/r剂量组合（每日两次，每次400 mg/100 mg）未能产生最佳血药浓度。基于利托那韦的药代动力学增强作用，估计的最佳剂量组合是400 mg LPV加用1200 mg利托那韦。
这些发现为量化利托那韦在COVID-19治疗中对LPV的增强作用以及计算最佳的LPV和利托那韦剂量组合提供了依据。
