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应用药代动力学/药效动力学模型描述人免疫缺陷病毒感染者中瑞舒伐他汀的降脂作用。

Pharmacokinetic/Pharmacodynamic Modelling to Describe the Cholesterol Lowering Effect of Rosuvastatin in People Living with HIV.

机构信息

Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

Centre for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Rue du Bugnon 17, 1005, 1011, Lausanne, Switzerland.

出版信息

Clin Pharmacokinet. 2021 Mar;60(3):379-390. doi: 10.1007/s40262-020-00946-3. Epub 2020 Oct 29.

DOI:10.1007/s40262-020-00946-3

PMID:33124006

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7932937/

Abstract

BACKGROUND

Rosuvastatin is a lipid-lowering agent widely prescribed in people living with HIV, which is actively transported into the liver, making it a potential victim of drug-drug interactions with antiretroviral agents.

OBJECTIVES

The aims of this study were to characterise the pharmacokinetic profile of rosuvastatin and to describe the relationship between rosuvastatin concentrations and non-high-density lipoprotein (HDL)-cholesterol levels in people living with HIV.

METHODS

A population pharmacokinetic model (NONMEM) was developed to quantify the influence of demographics, clinical characteristics and comedications on rosuvastatin pharmacokinetics. This model was combined with an indirect effect model to describe non-HDL-cholesterol measurements.

RESULTS

A two-compartment model with sequential zero- and first-order absorption best fitted the 154 rosuvastatin concentrations provided by 65 people living with HIV. None of the tested covariates significantly influenced rosuvastatin pharmacokinetics. A total of 403 non-HDL cholesterol values were available for pharmacokinetic-pharmacodynamic modelling. Baseline non-HDL cholesterol decreased by 14% and increased by 12% with etravirine and antiretroviral drugs with a known impact on the lipid profile (i.e. protease inhibitors, efavirenz, cobicistat), respectively. The baseline value was surprisingly 43% lower in people living with HIV aged 80 years compared with those aged 40 years. Simulations based on the covariate-free model predicted that, under standard rosuvastatin dosages of 5 mg and 20 mg once daily, 31% and 64% of people living with HIV would achieve non-HDL-cholesterol targets, respectively.

CONCLUSIONS

The high between-subject variability that characterises both rosuvastatin pharmacokinetic and pharmacodynamic profiles remained unexplained after the inclusion of usual covariates. Considering its limited potential for drug-drug interactions with antiretroviral agents and its potent lipid-lowering effect, rosuvastatin prescription appears safe and effective in people living with HIV with hypercholesterolaemia.

CLINICAL TRIAL REGISTRATION NO

NCT03515772.

摘要

背景

瑞舒伐他汀是一种降脂药物，广泛用于 HIV 感染者，它被主动转运到肝脏，因此成为与抗逆转录病毒药物发生药物相互作用的潜在受害者。

目的

本研究旨在描述 HIV 感染者中瑞舒伐他汀的药代动力学特征，并描述瑞舒伐他汀浓度与非高密度脂蛋白（HDL）-胆固醇水平之间的关系。

方法

采用 NONMEM 群体药代动力学模型定量描述人口统计学、临床特征和合并用药对瑞舒伐他汀药代动力学的影响。该模型与间接效应模型相结合，以描述非 HDL-胆固醇的测量值。

结果

154 例 HIV 感染者的 154 个瑞舒伐他汀浓度数据，采用两室模型加序贯零级和一级吸收的拟合效果最佳。未发现测试的协变量对瑞舒伐他汀药代动力学有显著影响。共获得 403 个非 HDL 胆固醇值进行药代动力学-药效学建模。依非韦伦和具有已知脂质谱影响的抗逆转录病毒药物（即蛋白酶抑制剂、依非韦伦、考比司他）使基线非 HDL 胆固醇分别降低 14%和增加 12%。令人惊讶的是，80 岁的 HIV 感染者的基线非 HDL 胆固醇比 40 岁的 HIV 感染者低 43%。基于无协变量模型的模拟预测，在标准剂量瑞舒伐他汀 5mg 和 20mg 每日一次的情况下，分别有 31%和 64%的 HIV 感染者将达到非 HDL-胆固醇目标。