Population pharmacokinetics and pharmacogenetics of ritonavir-boosted darunavir in the presence of raltegravir or tenofovir disoproxil fumarate/emtricitabine in HIV-infected adults and the relationship with virological response: a sub-study of the NEAT001/ANRS143 randomized trial
Population pharmacokinetics and pharmacogenetics of ritonavir-boosted darunavir in the presence of raltegravir or tenofovir disoproxil fumarate/emtricitabine in HIV-infected adults and the relationship with virological response: a sub-study of the NEAT001/ANRS143 randomized trial
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DOI：
10.1093/jac/dkz479
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发表时间：
2020-03-01
影响因子：
5.2
通讯作者：
Boffito, Marta
中科院分区：
文献类型：
--
作者：
Dickinson, Laura;Gurjar, Rohan;Boffito, Marta
目的：NEAT 001/ANRS 143证明了在初治患者中，地瑞那韦/利托那韦每日一次（800/100 mg）+雷特格韦每日两次（400 mg）与地瑞那韦/利托那韦+富马酸替诺福韦酯/恩曲他滨（245/200 mg每日一次）相比的非劣效性。我们研究了地瑞那韦、利托那韦、替诺福韦和恩曲他滨的群体药代动力学以及与人口统计学、遗传多态性和病毒学失败的关系。非线性混合效应模型（NONMEM v.7.3）用于确定药代动力学参数并评估人口统计学协变量和与SNP的关系（SLCO 3A 1、SLCO 1B 1、NR 1 I2、NR 1 I3、CYP 3A 5 *3、CYP 3A 4 *22、ABCC 2、ABCC 10、ABCG 2和SCL 47 A1）。模型预测的地瑞那韦AUC（0-24）和C-24与病毒学失败时间之间的关系进行了评估，通过考克斯regression.Results：在805名入选者中，分别有716，720，347和361名被纳入地瑞那韦，利托那韦，替诺福韦和恩曲他滨模型（11%女性，83%白人）。未观察到患者人口统计学或SNP对地瑞那韦或替诺福韦表观口服清除率（CL/F）的显著影响;同时给予雷特格韦不影响地瑞那韦或利托那韦的CL/F。利托那韦CL/F降低23%，恩曲他滨CL/F与肌酐清除率呈线性相关（P
Objectives: NEAT001/ANRS143 demonstrated non-inferiority of once-daily darunavir/ritonavir (800/100 mg)+twice-daily raltegravir (400 mg) versus darunavir/ritonavir+tenofovir disoproxil fumarate/emtricitabine (245/200 mg once daily) in treatment-naive patients. We investigated the population pharmacokinetics of darunavir, ritonavir, tenofovir and emtricitabine and relationships with demographics, genetic polymorphisms and virological failure.Methods: Non-linear mixed-effects models (NONMEM v. 7.3) were applied to determine pharmacokinetic parameters and assess demographic covariates and relationships with SNPs (SLCO3A1, SLCO1B1, NR1I2, NR1I3, CYP3A5*3, CYP3A4*22, ABCC2, ABCC10, ABCG2 and SCL47A1). The relationship between model-predicted darunavir AUC(0-24) and C-24 with time to virological failure was evaluated by Cox regression.Results: Of 805 enrolled, 716, 720, 347 and 361 were included in the darunavir, ritonavir, tenofovir and emtricitabine models, respectively (11% female, 83% Caucasian). No significant effect of patient demographics or SNPs was observed for darunavir or tenofovir apparent oral clearance (CL/F); coadministration of raltegravir did not influence darunavir or ritonavir CL/F. Ritonavir CL/F decreased by 23% in NR1I2 63396C>T carriers and emtricitabine CL/F was linearly associated with creatinine clearance (P