Bolton Moore Carolyn, Capparelli Edmund V, Samson Pearl, Bwakura-Dangarembizi Mutsa, Jean-Philippe Patrick, Worrell Carol, Heckman Barbara, Purdue Lynette, Spector Stephen A, Benns Alex, Borkowsky William, Loftis Amy, Hawkins Elizabeth, Wallis Carole, Chadwick Ellen G
aCentre for Infectious Disease Research in Zambia, Lusaka, Zambia bUniversity of Alabama at Birmingham, Birmingham, Alabama cUniversity of California San Diego, La Jolla dRady Children's Hospital, San Diego, California eHarvard T.H. Chan School of Public Health, Boston, Massachusetts, USA fUniversity of Zimbabwe, Harare, Zimbabwe gNational Institutes of Allergy and Infectious Diseases hEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland iFrontier Science and Technology Research Foundation, Amherst jNew York University's School of Medicine, New York, New York kUNC Global Health and Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina lSocial and Scientific Systems Inc, Silver Springs, Maryland, USA mBARC-SA and Lancet Laboratories, Johannesburg, South Africa nNorthwestern University's Feinberg School of Medicine, Chicago, Illinois, USA.
AIDS. 2017 May 15;31(8):1129-1136. doi: 10.1097/QAD.0000000000001463.
To determine safety-specific, efficacy-specific and genotypic-specific dose requirements of efavirenz (EFV) in children aged 3 to less than 36 months with HIV infection.
IMPAACT P1070 was a 24-week prospective cohort trial of EFV (as open capsules) and two nucleoside reverse transcriptase inhibitors in children with HIV infection 3 to less than 36 months without tuberculosis (Cohort 1).
CYP2B6 G516T genotype was determined, and intensive pharmacokinetics was performed at week 2. EFV dose was adjusted if outside the target area under the curve (AUC) 35-180 μg*h/ml. Pharmacokinetic and CYP2B6 G516T genotype data were used to model EFV exposures based on Food and Drug Administration (FDA)-approved doses.
Forty-seven participants, median age 19 months, initiated the study regimen with 24 weeks median follow-up; 38 516GG/GT and 9 516TT genotypes. Initially, median EFV AUC was higher in 516TT vs. 516GG/GT (median 490 vs. 107 μg*h/ml; P = 0.0001) with all 516TT above AUC target. Following an amendment that reduced the 516TT EFV dose by 75%, pharmacokinetic modeling predicted that 83% of participants met the AUC target (31/38 516GG/GT, 8/9 516TT). In contrast, modeling using P1070 data predicted that FDA-approved doses would produce subtherapeutic AUCs in almost one-third of participants with 516GG/GT and excessive AUCs in more than 50% with 516TT genotypes.
CYP2B6 G516T genotype strongly influences EFV exposures in this age group. Genotype-directed dosing yields therapeutic EFV concentrations and appears to outperform other dosing approaches.
确定依法韦仑（EFV）在3至未满36个月的HIV感染儿童中的安全性特定、疗效特定和基因型特定的剂量要求。
IMPAACT P1070是一项为期24周的前瞻性队列试验，研究对象为3至未满36个月无结核病的HIV感染儿童，给予EFV（以开放胶囊形式）和两种核苷类逆转录酶抑制剂（队列1）。
测定CYP2B6 G516T基因型，并在第2周进行强化药代动力学研究。如果曲线下面积（AUC）不在35 - 180μg*h/ml的目标范围内，则调整EFV剂量。药代动力学和CYP2B6 G516T基因型数据用于根据美国食品药品监督管理局（FDA）批准的剂量对EFV暴露进行建模。
47名参与者，中位年龄19个月，开始研究方案，中位随访24周；38名516GG/GT基因型和9名516TT基因型。最初，516TT基因型者的中位EFV AUC高于516GG/GT基因型者（中位值分别为490和107μg*h/ml；P = 0.0001），所有516TT基因型者的AUC均高于目标值。在一项将516TT基因型的EFV剂量降低75%的修正案之后，药代动力学建模预测83%的参与者达到了AUC目标（31/38名516GG/GT基因型者，8/9名516TT基因型者）。相比之下，使用P1070数据进行的建模预测，FDA批准的剂量在近三分之一的516GG/GT基因型参与者中会产生低于治疗水平的AUC，而在超过50%的516TT基因型参与者中会产生过高的AUC。
CYP2B6 G516T基因型强烈影响该年龄组的EFV暴露。基于基因型的给药可产生治疗性的EFV浓度，且似乎优于其他给药方法。
