Pharmacogenetic Analysis of the Model-Based Pharmacokinetics of Five Anti-HIV Drugs: How Does This Influence the Effect of Aging?
Pharmacogenetic Analysis of the Model-Based Pharmacokinetics of Five Anti-HIV Drugs: How Does This Influence the Effect of Aging?
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DOI：
10.1111/cts.12525
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发表时间：
2018-03-01
影响因子：
3.9
通讯作者：
Dumond, Julie B.
中科院分区：
文献类型：
--
作者：
Chen, Jingxian;Akhtari, Farida S.;Dumond, Julie B.
抗逆转录病毒药代动力学（PK）的衰老和药物遗传学（PGx）分析可以为老年人类HIV感染患者提供精确剂量。74名接受阿扎那韦/利托那韦（ATV/RTV）或依法韦仑（EFV）与替诺福韦/恩曲他滨（TFV/FTC）的受试者提供了PK和PGx信息。使用单因素方差分析（ANOVA）、多元线性回归和随机森林集成方法进行老化-PGx-PK关联和相互作用分析。我们的分析将未结合的ATV处置与多药耐药蛋白（MRP）4、RTV与P-糖蛋白（P-gp）以及EFV与细胞色素P450（CYP）2B 6和MRP 4遗传变异相关联。TFV的清除率和细胞分布与P-gp、MRP 2和浓缩核苷转运蛋白（CNT）相关，FTC参数与有机阳离子转运蛋白（OCT）和MRP 2遗传变异相关。值得注意的是，p16（INK 4a）表达，细胞衰老标志物，预测EFV和FTC PK时，遗传因素进行了调整。年龄和p16（INK 4a）表达与PGx对ATV和TFV处置的相互作用，这意味着基于年龄的潜在剂量调整可能取决于遗传背景。
Analysis of aging and pharmacogenetics (PGx) on antiretroviral pharmacokinetics (PKs) could inform precision dosing for older human HIV-infected patients. Seventy-four participants receiving either atazanavir/ritonavir (ATV/RTV) or efavirenz (EFV) with tenofovir/emtricitabine (TFV/FTC) provided PK and PGx information. Aging-PGx-PK association and interaction analyses were conducted using one-way analysis of variance (ANOVA), multiple linear regression, and Random Forest ensemble methods. Our analyses associated unbound ATV disposition with multidrug resistance protein (MRP)4, RTV with P-glycoprotein (P-gp), and EFV with cytochrome P450 (CYP)2B6 and MRP4 genetic variants. The clearance and cellular distribution of TFV were associated with P-gp, MRP2, and concentrative nucleoside transporters (CNTs), and FTC parameters were associated with organic cation transporters (OCTs) and MRP2 genetic variants. Notably, p16(INK4a) expression, a cellular aging marker, predicted EFV and FTC PK when genetic factors were adjusted. Both age and p16(INK4a) expression interacted with PGx on ATV and TFV disposition, implying potential dose adjustment based on aging may depend on genetic background.