Tremoulet Adriana H, Capparelli Edmund V, Patel Parul, Acosta Edward P, Luzuriaga Katherine, Bryson Yvonne, Wara Diane, Zorrilla Carmen, Holland Diane, Mirochnick Mark
Division of Pharmacology and Drug Discovery, Pediatric Pharmacology Research Unit, University of California San Diego, MC 8214, San Diego, CA 92103-8214, USA.
Antimicrob Agents Chemother. 2007 Dec;51(12):4297-302. doi: 10.1128/AAC.00332-07. Epub 2007 Sep 24.
This study aimed to determine lamivudine disposition in infants and to construct an appropriate dose adjustment for age, given the widespread use of lamivudine for both the prevention of mother-to-child transmission of human immunodeficiency virus (HIV) and the treatment of HIV-infected infants. Using a pooled-population approach, the pharmacokinetics of lamivudine in HIV-exposed or -infected infants from four Pediatric AIDS Clinical Trials Group studies were assessed. Ninety-nine infants provided 559 plasma samples for measurement of lamivudine concentrations. All infants received combination antiretroviral therapy including lamivudine dosed at 2 mg/kg of body weight every 12 h (q12h) for the first 4 to 6 weeks of life and at 4 mg/kg q12h thereafter. Lamivudine's apparent clearance was 0.25 liter/h/kg at birth, doubling by 28 days. In the final model, age and weight were the only significant covariates for lamivudine clearance. While lamivudine is predominantly renally eliminated, the serum creatinine level was not an independent covariate in the final model, possibly because it was confounded by age. Inclusion of interoccasion variability for bioavailability improved the individual subject clearance prediction over the age range studies. Simulations based on the final model predicted that by the age of 4 weeks, 90% of infant lamivudine concentrations with the standard 2 mg/kg dose of lamivudine fell below the adult median concentration. This population pharmacokinetic analysis affirms that adjusting the dose of lamivudine from 2 mg/kg to 4 mg/kg q12 h at the age of 4 weeks for infants with normal maturation of renal function will provide optimal lamivudine exposure, potentially contributing to more successful therapy.
鉴于拉米夫定广泛用于预防人类免疫缺陷病毒（HIV）母婴传播及治疗HIV感染婴儿，本研究旨在确定婴儿体内拉米夫定的处置情况，并构建适合不同年龄的剂量调整方案。采用合并人群分析方法，评估了四项儿科艾滋病临床试验组研究中HIV暴露或感染婴儿体内拉米夫定的药代动力学。99名婴儿提供了559份血浆样本用于测定拉米夫定浓度。所有婴儿均接受联合抗逆转录病毒治疗，其中拉米夫定在出生后头4至6周按2mg/kg体重每12小时（q12h）给药，之后按4mg/kg q12h给药。拉米夫定的表观清除率在出生时为0.25升/小时/千克，到28天时翻倍。在最终模型中，年龄和体重是拉米夫定清除率仅有的显著协变量。虽然拉米夫定主要经肾脏清除，但血清肌酐水平在最终模型中并非独立协变量，可能是因为它与年龄存在混杂。纳入生物利用度的个体间变异性改善了研究年龄范围内个体受试者清除率预测。基于最终模型的模拟预测，到4周龄时，标准2mg/kg剂量拉米夫定的婴儿体内，90%的拉米夫定浓度低于成人中位数浓度。这项群体药代动力学分析证实，对于肾功能正常成熟的婴儿，在4周龄时将拉米夫定剂量从2mg/kg调整为4mg/kg q12h，将提供最佳的拉米夫定暴露，可能有助于治疗更成功。
