From the Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA.
Department of Pharmacometrics, Pfizer Global Research and Development, Sandwich, United Kingdom.
Pediatr Infect Dis J. 2022 Nov 1;41(11):885-890. doi: 10.1097/INF.0000000000003665. Epub 2022 Aug 9.
Treatment and prophylaxis options for neonatal HIV are limited. This study aimed to develop a population pharmacokinetic model to characterize the disposition of maraviroc in neonates to inform dosing regimens and expand available options.
Using maraviroc concentrations from neonates who received either a single dose or multiple doses of 8 mg/kg of maraviroc in the first 6 weeks of life, a population pharmacokinetic model was developed to determine the effects of age, sex, maternal efavirenz exposure and concomitant ARV therapy on maraviroc disposition. The final model was used in Monte Carlo simulations to generate expected exposures with recommended dosing regimens.
A total of 396 maraviroc concentrations, collected in the first 4 days of life, at 1 week, at 4 weeks and at 6 weeks, from 44 neonates were included in the analysis. After allometrically scaling for weight, age less than 4 days was associated with a 44% decreased apparent clearance compared with participants 7 days to 6 weeks of life. There were no differences identified in apparent clearance or volume of distribution from ages 7 days to 6 weeks, sex, maternal efavirenz exposure or concomitant nevirapine therapy. Monte Carlo simulations with FDA-approved weight band dosing resulted in the majority of simulated patients (84.3%) achieving an average concentration of ≥75 ng/mL.
While maraviroc apparent clearance is decreased in the first few days of life, the current FDA-approved maraviroc weight band dosing provides maraviroc exposures for neonates in the first 6 weeks of life, which were consistent with adult maraviroc exposure range. Maraviroc provides another antiretroviral treatment option for very young infants.
目前针对新生儿 HIV 的治疗和预防选择有限。本研究旨在建立群体药代动力学模型，以描述马拉维若在新生儿中的药物处置情况，为制定给药方案提供信息，并拓展现有选择。
使用在生命最初 6 周内接受 8mg/kg 马拉维若单剂量或多剂量的新生儿的马拉维若浓度，建立群体药代动力学模型，以确定年龄、性别、母亲依非韦伦暴露和同时进行的抗逆转录病毒治疗对马拉维若处置的影响。最终模型用于蒙特卡罗模拟，以生成推荐给药方案的预期暴露量。
纳入分析的共有 44 名新生儿的 396 个马拉维若浓度数据，采集时间分别为出生后第 1 天、第 1 周、第 4 周和第 6 周。对体重进行体表面积归一化后，小于 4 天的年龄与 7 天至 6 周的参与者相比，表观清除率降低了 44%。在 7 天至 6 周的年龄、性别、母亲依非韦伦暴露或同时使用奈韦拉平治疗中，未发现表观清除率或分布容积的差异。采用 FDA 批准的体重区间剂量进行的蒙特卡罗模拟结果显示，大多数模拟患者（84.3%）的平均浓度达到了≥75ng/mL。
虽然马拉维若的表观清除率在生命的最初几天会降低，但目前 FDA 批准的马拉维若体重区间剂量为新生儿在生命最初 6 周内提供了马拉维若的暴露量，与成人马拉维若的暴露范围一致。马拉维若为非常年幼的婴儿提供了另一种抗逆转录病毒治疗选择。
