Department of Medicine, University of Udine, Udine, Italy.
Institute of Clinical Pharmacology, Santa Maria della Misericordia University Hospital of Udine, ASUFC, P.le S. Maria della Misericordia 3, 33100, Udine, Italy.
Clin Pharmacokinet. 2020 Oct;59(10):1251-1260. doi: 10.1007/s40262-020-00933-8.
Darunavir is an anti-HIV protease inhibitor repurposed for SARS-CoV-2 treatment.
The aim of this study was to assess the population pharmacokinetics of darunavir in SARS-CoV-2 patients compared with HIV patients.
Two separate models were created by means of a nonlinear mixed-effect approach. The influence of clinical covariates on each basic model was tested and the association of significant covariates with darunavir parameters was assessed at multivariate regression and classification and regression tree (CART) analyses. Monte Carlo simulation assessed the influence of covariates on the darunavir concentration versus time profile.
A one-compartment model well-described darunavir concentrations in both groups. In SARS-CoV-2 patients (n = 30), interleukin (IL)-6 and body surface area were covariates associated with darunavir oral clearance (CL/F) and volume of distribution (V), respectively; no covariates were identified in HIV patients (n = 25). Darunavir CL/F was significantly lower in SARS-CoV-2 patients compared with HIV patients (4.1 vs. 10.3 L/h; p < 0.001). CART analysis found that an IL-6 level of 18 pg/mL may split the SARS-CoV-2 population in patients with low versus high darunavir CL/F (mean ± standard deviation 3.47 ± 1.90 vs. 8.03 ± 3.24 L/h; proportion of reduction in error = 0.46). Median (interquartile range) darunavir CL/F was significantly lower in SARS-CoV-2 patients with IL-6 levels ≥ 18 pg/mL than in SARS-CoV-2 patients with IL-6 levels < 18 pg/mL or HIV patients (2.78 [2.16-4.47] vs. 7.24 [5.88-10.38] vs. 9.75 [8.45-13.79] L/h, respectively; p < 0.0001). Increasing IL-6 levels affected darunavir concentration versus time simulated profiles. We hypothesized that increases in IL-6 levels associated with severe SARS-CoV-2 disease may downregulate the cytochrome P450 (CYP) 3A4-mediated metabolism of darunavir.
This is a proof-of-concept of SARS-CoV-2 disease-drug interactions, and may support the need for optimal dose selection of sensitive CYP3A4 substrates in severe SARS-CoV-2 patients.
达芦那韦是一种抗 HIV 蛋白酶抑制剂，现被重新用于 SARS-CoV-2 的治疗。
本研究旨在评估 SARS-CoV-2 患者与 HIV 患者相比，达芦那韦的群体药代动力学特征。
采用非线性混合效应模型分别建立了两个模型。通过多变量回归和分类回归树（CART）分析，对每个基本模型中临床协变量的影响进行了测试，并对与达芦那韦参数相关的显著协变量进行了评估。蒙特卡罗模拟评估了协变量对达芦那韦浓度-时间曲线的影响。
一个一室模型很好地描述了两组患者的达芦那韦浓度。在 SARS-CoV-2 患者（n=30）中，白细胞介素（IL）-6 和体表面积分别是与达芦那韦口服清除率（CL/F）和分布容积（V）相关的协变量；在 HIV 患者（n=25）中未发现有意义的协变量。与 HIV 患者相比，SARS-CoV-2 患者的达芦那韦 CL/F 显著降低（4.1 比 10.3 L/h；p<0.001）。CART 分析发现，IL-6 水平为 18 pg/mL 时，可能会将 SARS-CoV-2 患者分为达芦那韦 CL/F 低与高的两组（平均±标准差 3.47±1.90 比 8.03±3.24 L/h；误差减少比例 0.46）。IL-6 水平≥18 pg/mL 的 SARS-CoV-2 患者的达芦那韦 CL/F 中位数（四分位间距）显著低于 IL-6 水平<18 pg/mL 的 SARS-CoV-2 患者或 HIV 患者（2.78 [2.16-4.47] 比 7.24 [5.88-10.38] 比 9.75 [8.45-13.79] L/h；p<0.0001）。IL-6 水平的升高影响了达芦那韦浓度-时间模拟曲线。我们假设，与严重 SARS-CoV-2 疾病相关的 IL-6 水平升高可能会下调达芦那韦的细胞色素 P450（CYP）3A4 介导的代谢。
这是 SARS-CoV-2 疾病-药物相互作用的概念验证，可能支持在严重 SARS-CoV-2 患者中，对敏感 CYP3A4 底物进行最佳剂量选择的需求。
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