Dickinson Laura, Winston Alan, Boffito Marta, Khoo Saye, Back David, Siccardi Marco
Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK The Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK
Faculty of Medicine, Imperial College, London, UK Department of HIV & GU Medicine, Imperial College Healthcare NHS Trust, St Mary's Hospital, London, UK.
J Antimicrob Chemother. 2016 Apr;71(4):1041-5. doi: 10.1093/jac/dkv439. Epub 2015 Dec 27.
Treatment of HIV/TB coinfection is challenging due to potent drug-drug interactions between antiretrovirals and rifampicin. The effect of rifampicin on darunavir/ritonavir has not been studied. Population pharmacokinetic modelling was applied to investigate the interaction and generate alternative doses to inform clinical trial design.
Darunavir/ritonavir concentrations were modelled simultaneously, including data from three studies in HIV patients (n = 51, 7 female). The darunavir/ritonavir-rifampicin interaction was assumed to mimic that previously observed with lopinavir/ritonavir. Daily darunavir/ritonavir 800/100 mg was simulated as a reference (n = 1000; -rifampicin). Simulations with apparent oral clearance increased by 71% and 36% and relative bioavailability decreased by 20% and 45% for darunavir and ritonavir, respectively, were performed for +rifampicin, 600 mg once daily (n = 1000). Darunavir/ritonavir 1200/200 mg once daily, 1600/200 mg once daily, 800/100 mg twice daily and 1200/150 mg twice daily +rifampicin were simulated. Darunavir parameters for each dose +rifampicin were compared with -rifampicin by geometric mean ratio (90% CI).
A maximum effect model, with ritonavir inhibiting darunavir clearance, best described the relationship between the drugs. Compared with -rifampicin, simulated darunavir AUC0-24 was 57%, 26%, 1% and 16% lower for 800/100 mg once daily, 1200/200 mg once daily, 1600/200 mg once daily and 800/100 mg twice daily +rifampicin, respectively; but 39% higher with 1200/150 mg twice daily +rifampicin.
Darunavir/ritonavir 1600/200 mg once daily, 800/100 mg twice daily and 1200/150 mg twice daily could potentially overcome reduced darunavir concentrations with rifampicin. In the absence of clinical data, modelling and simulation may be useful to predict drug-drug interactions and aid optimal dose selection.
由于抗逆转录病毒药物与利福平之间存在强效药物相互作用，治疗HIV/TB合并感染具有挑战性。利福平对达芦那韦/利托那韦的影响尚未得到研究。应用群体药代动力学模型来研究这种相互作用，并生成替代剂量以指导临床试验设计。
同时对达芦那韦/利托那韦浓度进行建模，纳入来自三项HIV患者研究的数据（n = 51，7名女性）。假设达芦那韦/利托那韦与利福平的相互作用类似于先前观察到的洛匹那韦/利托那韦的相互作用。模拟每日一次服用达芦那韦/利托那韦800/100 mg作为对照（n = 1000；-利福平）。对于+利福平（每日一次600 mg，n = 1000），分别进行模拟，使达芦那韦和利托那韦的表观口服清除率增加71%和36%，相对生物利用度分别降低20%和45%。模拟了每日一次服用达芦那韦/利托那韦1200/200 mg、每日一次服用达芦那韦/利托那韦1600/200 mg、每日两次服用达芦那韦/利托那韦800/100 mg以及每日两次服用达芦那韦/利托那韦1200/150 mg +利福平的情况。通过几何平均比值（90%CI）比较每种剂量+利福平与-利福平的达芦那韦参数。
一个利托那韦抑制达芦那韦清除的最大效应模型最能描述药物之间的关系。与-利福平相比，每日一次服用达芦那韦/利托那韦800/100 mg、每日一次服用达芦那韦/利托那韦1200/200 mg、每日一次服用达芦那韦/利托那韦1600/200 mg以及每日两次服用达芦那韦/利托那韦800/100 mg +利福平的模拟达芦那韦AUC0 - 24分别降低57%、26%、1%和16%；但每日两次服用达芦那韦/利托那韦1200/150 mg +利福平则升高39%。
每日一次服用达芦那韦/利托那韦1600/200 mg、每日两次服用达芦那韦/利托那韦800/100 mg以及每日两次服用达芦那韦/利托那韦1200/150 mg可能克服利福平导致的达芦那韦浓度降低。在缺乏临床数据的情况下，建模与模拟可能有助于预测药物相互作用并辅助优化剂量选择。
