No relationship between drug transporter genetic variants and tenofovir plasma concentrations or changes in glomerular filtration rate in HIV-infected adults.
No relationship between drug transporter genetic variants and tenofovir plasma concentrations or changes in glomerular filtration rate in HIV-infected adults.
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HIV 感染成人的药物转运蛋白遗传变异与替诺福韦血浆浓度或肾小球滤过率变化之间没有关系。
DOI：
10.1097/qai.0000000000000504
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Cressey,Ti
中科院分区：
文献类型：
--
作者：
Sirirungsi,Wasna;Urien,Saik;Harrison,Linda;Kamkon,Jiraporn;Tawon,Yardpiroon;Luekamlung,Nuananong;Thongpaen,Suchart;Nilmanat,Ampaipith;Jourdain,Gonzague;Lallemant,Marc;LeCoeur,Sophie;Ngo-Giang-Huong,Nicole;Owen,Andrew;Cressey,Ti
Plasma TFV concentrations were measured using a validated reversedphase high-performance liquid chromatography assay. 6 This assay was internally validated, and the average accuracy was 99%-102% and precision (inter-assay/intra-assay) was, 5% of the coefficient of variation. Population means and variances of TFV pharmacokinetic parameters were estimated using non-linear mixed-effects regression (Monolix v4. 2, http://www. lixoft. eu). 7 Individual patient characteristics including weight, sex, age, body mass index, serum creatinine, and CrCL were evaluated for their inclusion in the model using a stepwise forward inclusion and backward elimination procedure. Validity of the model was evaluated using a visual predictive check. Post hoc subject-specific pharmacokinetic parameters were used to estimate individual TFV trough concentrations (C24) and area under the concentrationtime curve (AUC0-24h). With; 240 subjects, we had 90% power to detect a difference in TFV C24 of 0.02 mg/mL between combined variants (homozygous and heterozygous), and homozygosity of the common allele provided at least 6%(; 14 subjects) were in the combined variant group (using a 2-sided test, with a standard deviation of 0.02 mg/mL). Differences in TFV C24 between variants (homozygous and heterozygous) and homozygosity of the common allele were assessed by Wilcoxon rank-sum tests (due to nonnormal C24 distribution). To control the false discovery rate, q values were determined. 8 CrCL was assumed to be normally distributed, so t-tests were used to compare differences in change in CrCL between variants and homozygosity of the common allele (adjusted for baseline CrCL level). All statistical tests performed were 2-sided using STATA (v11. 1).Two hundred thirty-eight HIV-infected adults (58% female) were included. At treatment initiation, the median (interquartile range) age was 36 (31-42) years, weight 52 (48-59) kg, serum creatinine (SCr) 0.8 (0.7-0.9) mg/dL, creatinine clearance (CrCL) 89 (74-105) mL/min, HIV-1 RNA viral load 4.8 (4.3-5.2) log10 copies per milliliter, and CD4 count 144 (91-208) cells per cubic millimeter. Antiretroviral regimens were either TDF/emtricitabine/efavirenz (n= 191, 80%) or TDF/emtricitabine/nevirapine (n= 47, 20%). One thousand one hundred twenty-three plasma samples from 238 patients were included. Median (range) number of samples per patient was 5 (1-6), and median time after dose was 13 (0.17-26.75) hours. TFV plasma concentrations were best described by a 2-compartment model, with the absorption and the distribution rate constants equal. Residual variability was described using a proportional error model. For the
