Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
Louvain Centre for Toxicology and Applied Pharmacology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.
Clin Pharmacokinet. 2021 Feb;60(2):177-189. doi: 10.1007/s40262-020-00920-z.
Protease inhibitors such as darunavir are an important therapeutic option in the anti-human immunodeficiency virus arsenal. Current dosage guidelines recommend using cobicistat- or ritonavir-boosted darunavir 800 mg every 24 h (q24h) in protease inhibitor-naïve patients, or ritonavir-boosted darunavir 600 mg q12h in experienced patients. However, darunavir displays a large, poorly characterized, inter-individual pharmacokinetic variability. The objectives of this study were to investigate the pharmacokinetics of darunavir and to elucidate the sources of its inter-individual variability using population pharmacokinetic modeling. Then, to determine the appropriateness of current treatment guidelines and the feasibility of alternative dosing regimens in a representative cohort of adult patients using simulations.
Sparse pharmacokinetic samples were collected in 127 patients with human immunodeficiency virus type 1 infection, then supplemented with rich sampling data from a subset of 12 individuals. Data were analyzed using the nonlinear mixed-effects modeling software NONMEM. The effect of reduced doses (600 mg q24h and 400 mg q24h) or reduced frequency of administration (800 mg q24h for 5 days followed by 2 days of treatment interruption) was simulated.
Our model adequately described the pharmacokinetics of darunavir. Predictors of individual exposure were CYP3A5*3 and SLCO3A1 rs8027174 genotypes, sex, and alpha-1 acid glycoprotein level. No relationship was apparent between darunavir area under the curve and treatment efficacy or safety. For reduced dose regimens, darunavir concentrations remained above the protein binding-corrected EC in the majority of subjects. More stringent pharmacokinetic targets were not reached in a significant proportion of patients.
These results add to the growing body of evidence that darunavir-based therapy could be simplified to reduce costs and toxicity, as well as to improve patient compliance. However, the heterogeneity in pharmacokinetic response should be considered when assessing whether individual patients could benefit from a particular regimen, for instance through the use of population pharmacokinetic models.
ClinicalTrials.gov identifier: NCT03101644, date of registration: 5 April, 2017.
蛋白酶抑制剂如达芦那韦是抗人类免疫缺陷病毒武器库中的一个重要治疗选择。目前的剂量指南建议在未接受蛋白酶抑制剂治疗的患者中使用考比司他或利托那韦增强的达芦那韦 800mg 每 24 小时（q24h），或在有经验的患者中使用利托那韦增强的达芦那韦 600mg 每 12 小时（q12h）。然而，达芦那韦表现出较大的、特征较差的个体间药代动力学变异性。本研究的目的是使用群体药代动力学模型研究达芦那韦的药代动力学，并阐明其个体间变异性的来源。然后，通过模拟确定当前治疗指南的适当性以及在代表性成人患者队列中替代剂量方案的可行性。
127 例人类免疫缺陷病毒 1 型感染患者采集了稀疏的药代动力学样本，然后通过 12 名个体中的一部分进行了丰富采样数据的补充。使用 NONMEM 非线性混合效应模型软件进行数据分析。模拟了减少剂量（600mg q24h 和 400mg q24h）或减少给药频率（800mg q24h 治疗 5 天，然后中断治疗 2 天）的效果。
我们的模型充分描述了达芦那韦的药代动力学。个体暴露的预测因子为 CYP3A5*3 和 SLCO3A1 rs8027174 基因型、性别和α-1 酸性糖蛋白水平。达芦那韦 AUC 与治疗效果或安全性之间没有明显关系。对于减少剂量方案，大多数受试者的达芦那韦浓度仍保持在蛋白结合校正 EC 以上。在很大一部分患者中，未能达到更严格的药代动力学目标。
这些结果增加了越来越多的证据，表明基于达芦那韦的治疗可以简化，以降低成本和毒性，并提高患者的依从性。然而，在评估个体患者是否可以从特定方案中获益时，应考虑药代动力学反应的异质性，例如通过使用群体药代动力学模型。
ClinicalTrials.gov 标识符：NCT03101644，注册日期：2017 年 4 月 5 日。
