Mukonzo Jackson K, Owen Joel S, Ogwal-Okeng Jasper, Kuteesa Ronald B, Nanzigu Sarah, Sewankambo Nelson, Thabane Lehana, Gustafsson Lars L, Ross Colin, Aklillu Eleni
Department of Pharmacology and Therapeutics, College of Health Sciences, Makerere University, Kampala, Uganda ; CIHR, Canadian HIV Trials Network, Vancouver, British Columbia, Canada.
School of Pharmacy, Union University, Jackson, Tennessee, United States of America.
PLoS One. 2014 Jan 31;9(1):e86919. doi: 10.1371/journal.pone.0086919. eCollection 2014.
Pharmacogenetics contributes to inter-individual variability in pharmacokinetics (PK) of efavirenz (EFV), leading to variations in both efficacy and toxicity. The purpose of this study was to assess the effect of genetic factors on EFV pharmacokinetics, treatment outcomes and genotype based EFV dose recommendations for adult HIV-1 infected Ugandans.
In total, 556 steady-state plasma EFV concentrations from 99 HIV infected patients (64 female) treated with EFV/lamivudine/zidovidine were analyzed. Patient genotypes for CYP2B6 (*6 & *11), CYP3A5 (*3,*6 & *7) and ABCB1 c.4046A>G, baseline biochemistries and CD4 and viral load change from baseline were determined. A one-compartment population PK model with first-order absorption (NONMEM) was used to estimate genotype effects on EFV pharmacokinetics. PK simulations were performed based upon population genotype frequencies. Predicted AUCs were compared between the product label and simulations for doses of 300 mg, 450 mg, and 600 mg.
EFV apparent clearance (CL/F) was 2.2 and 1.74 fold higher in CYP2B6*6 (*1/1) and CYP2B66 (*1/6) compared CYP2B66 (*6/*6) carriers, while a 22% increase in F1 was observed for carriers of ABCB1 c.4046A>G variant allele. Higher mean AUC was attained in CYP2B6 *6/*6 genotypes compared to CYP2B6 *1/*1 (p<0.0001). Simulation based AUCs for 600 mg doses were 1.25 and 2.10 times the product label mean AUC for the Ugandan population in general and CYP2B6*6/*6 genotypes respectively. Simulated exposures for EFV daily doses of 300 mg and 450 mg are comparable to the product label. Viral load fell precipitously on treatment, with only six patients having HIV RNA >40 copies/mL after 84 days of treatment. No trend with exposure was noted for these six patients.
Results of this study suggest that daily doses of 450 mg and 300 mg might meet the EFV treatment needs of HIV-1 infected Ugandans in general and individuals homozygous for CYP2B6*6 mutation, respectively.
药物遗传学导致依非韦伦（EFV）药代动力学存在个体间差异，进而导致疗效和毒性出现变化。本研究的目的是评估遗传因素对成年HIV - 1感染乌干达人的EFV药代动力学、治疗结果以及基于基因型的EFV剂量推荐的影响。
总共分析了99例接受EFV/拉米夫定/齐多夫定治疗的HIV感染患者（64例女性）的556份稳态血浆EFV浓度。确定了患者的CYP2B6（6和11）、CYP3A5（*3、6和7）以及ABCB1 c.4046A>G的基因型、基线生化指标以及CD4和病毒载量相对于基线的变化。使用具有一级吸收的单室群体药代动力学模型（NONMEM）来估计基因型对EFV药代动力学的影响。基于群体基因型频率进行药代动力学模拟。比较了产品标签和300 mg、450 mg和600 mg剂量模拟的预测AUC。
与CYP2B6*6（*6/6）携带者相比，CYP2B66（*1/1）和CYP2B66（*1/*6）的EFV表观清除率（CL/F）分别高2.2倍和1.74倍，而ABCB1 c.4046A>G变异等位基因携带者的F1增加了22%。与CYP2B6 *1/*1相比，CYP2B6 *6/*6基因型的平均AUC更高（p<0.0001）。对于600 mg剂量，基于模拟的AUC分别是乌干达总体人群和CYP2B6*6/*6基因型产品标签平均AUC的1.25倍和2.10倍。EFV每日300 mg和450 mg剂量的模拟暴露量与产品标签相当。治疗后病毒载量急剧下降，治疗84天后只有6例患者的HIV RNA>40拷贝/mL。这6例患者未发现暴露量与病毒载量之间的趋势。
本研究结果表明，每日450 mg和300 mg剂量可能分别满足一般HIV - 1感染乌干达人以及CYP2B6*6突变纯合个体的EFV治疗需求。
