Overbeek Joanneke K, van Erp Nielka P, Burger David M, den Broeder Alfons A, Koolen Stijn L W, Huitema Alwin D R, Ter Heine Rob
Department of Pharmacy, Radboud University Medical Center, PO Box 9101, 6500HB, Nijmegen, The Netherlands.
Department of Rheumatology, Sint Maartenskliniek, Nijmegen, The Netherlands.
Clin Pharmacokinet. 2025 Mar;64(3):425-435. doi: 10.1007/s40262-025-01480-w. Epub 2025 Feb 5.
Pharmacokinetic (PK) boosting is the intentional use of strong inhibitors of metabolic enzymes or transporters to boost the systemic exposure of a therapeutic drug. PK boosting is expanding to therapeutic areas outside human immunodeficiency virus (HIV) therapy. Data on the PK of the booster cobicistat and its effect on CYP3A-substrates outside of HIV therapy are lacking. This study aimed to describe the PK of once- and twice-daily cobicistat regimens in healthy volunteers and patients with rheumatoid arthritis, cancer, or HIV infection and to investigate the interplay between cobicistat and the anticancer drug olaparib.
Cobicistat levels from 683 samples from 66 subjects in four clinical trials were included in the analysis. For olaparib, 261 samples from 12 subjects from one trial were included. Population PK analysis was performed by nonlinear mixed-effects modelling.
Both cobicistat and olaparib PK were adequately described by a well-stirred liver model with one central compartment and Erlang type absorption. Cobicistat PK was similar across patient populations and dosing regimens. Cobicistat increased olaparib prehepatic bioavailability 1.65-fold (RSE 6%) and decreased intrinsic clearance 0.34-fold (RSE 6.5%). A correlation between olaparib PK and cobicistat exposure could not be identified. The interindividual variability in olaparib clearance was lower with cobicistat than without cobicistat.
The developed pharmacokinetic models adequately described cobicistat and olaparib plasma concentrations. PK boosting with cobicistat at 150 mg twice daily led to an increase in olaparib bioavailability and decrease in clearance. This effect was not correlated with cobicistat exposure, which may reflect saturation of the boosting effect of cobicistat at this dose.
TRIAL REGISTRATION NUMBERS (DATE OF REGISTRATION): NCT02565888 (30-09-2015), NCT00825929 (19-01-2009), Netherlands Trial Register NL7766 (18-12-2018), NCT05078671 (22-09-2021).
药代动力学（PK）增强是指有意使用代谢酶或转运体的强效抑制剂来提高治疗药物的全身暴露量。PK增强正扩展到人类免疫缺陷病毒（HIV）治疗以外的治疗领域。目前缺乏关于增强剂考比司他的PK及其在HIV治疗以外对CYP3A底物影响的数据。本研究旨在描述健康志愿者以及类风湿性关节炎、癌症或HIV感染患者每日一次和每日两次考比司他给药方案的PK，并研究考比司他与抗癌药物奥拉帕利之间的相互作用。
分析纳入了来自四项临床试验中66名受试者的683份样本中的考比司他水平。对于奥拉帕利，纳入了来自一项试验中12名受试者的261份样本。采用非线性混合效应模型进行群体PK分析。
考比司他和奥拉帕利的PK均通过具有一个中央室和Erlang型吸收的充分搅拌肝脏模型得到了充分描述。考比司他的PK在不同患者群体和给药方案中相似。考比司他使奥拉帕利肝前生物利用度提高了1.65倍（相对标准误6%），并使内在清除率降低了0.34倍（相对标准误6.5%）。未发现奥拉帕利PK与考比司他暴露之间存在相关性。与无考比司他时相比，考比司他存在时奥拉帕利清除率的个体间变异性更低。
所建立的药代动力学模型充分描述了考比司他和奥拉帕利的血浆浓度。每日两次150 mg考比司他的PK增强导致奥拉帕利生物利用度增加和清除率降低。这种效应与考比司他暴露无关，这可能反映了该剂量下考比司他增强效应的饱和。
试验注册号（注册日期）：NCT02565888（2015年9月30日）、NCT00825929（2009年1月19日）、荷兰试验注册编号NL7766（2018年12月18日）、NCT05078671（2021年9月22日）。
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