PDF(Pubmed)
Abstract：
In adults requiring protease inhibitor (PI)-based antiretroviral therapy (ART), replacing rifampicin with rifabutin is a preferred option, but there is lack of evidence to guide rifabutin dosing in children, especially with PIs. We aimed to characterize the population pharmacokinetics of rifabutin and 25-O-desacetyl rifabutin (des-rifabutin) in children and optimize its dose. We included children from three age cohorts: (i) <1-year-old cohort and (ii) 1- to 3-year-old cohort, who were ART naïve and received 15- to 20-mg/kg/day rifabutin for 2 weeks followed by lopinavir/ritonavir (LPV/r)-based ART with 5.0- or 2.5 mg/kg/day rifabutin, respectively, while the (iii) >3-year-old cohort was ART-experienced and received 2.5-mg/kg/day rifabutin with LPV/r-based ART. Non-linear mixed-effects modeling was used to interpret the data. Monte Carlo simulations were performed to evaluate the study doses and optimize dosing using harmonized weight bands. Twenty-eight children were included, with a median age of 10 (range 0.67-15.0) years, a median weight of 11 (range 4.5-45) kg, and a median weight-for-age z score of -3.33 (range -5.15 to -1.32). A two-compartment disposition model, scaled allometrically by weight, was developed for rifabutin and des-rifabutin. LPV/r increased rifabutin bioavailability by 158% (95% confidence interval: 93.2%-246.0%) and reduced des-rifabutin clearance by 76.6% (74.4%-78.3%). Severely underweight children showed 26% (17.9%-33.7%) lower bioavailability. Compared to adult exposures, simulations resulted in higher median steady-state rifabutin and des-rifabutin exposures in 6-20 kg during tuberculosis-only treatment with 20 mg/kg/day. During LPV/r co-treatment, the 2.5-mg/kg/day dose achieved similar exposures to adults, while the 5-mg/kg/day dose resulted in higher exposures in children >7 kg. All study doses maintained a median Cmax of <900 µg/L. The suggested weight-band dosing matches adult exposures consistently across weights and simplifies dosing.
摘要：
在需要基于蛋白酶抑制剂（PI）的抗逆转录病毒治疗（ART）的成年人中，用利福布汀代替利福平是首选，但是缺乏证据来指导儿童服用利福布汀，尤其是PI。我们旨在表征利福布汀和25-O-去乙酰利福布汀（des-rifabutin）在儿童中的群体药代动力学，并优化其剂量。我们纳入了三个年龄组的儿童：（i）<1岁的队列和（ii）1至3岁的队列，谁是未接受ART，并接受15-20-mg/kg/天的利福布汀2周，然后使用基于洛匹那韦/利托那韦（LPV/r）的基于5.0-或2.5mg/kg/天的利福布汀，分别,而（iii）>3岁的队列接受了ART，并接受了2.5mg/kg/天的利福布汀和基于LPV/r的ART。非线性混合效应建模用于解释数据。进行蒙特卡罗模拟以评估研究剂量并使用协调的体重带优化给药。包括28名儿童，年龄中位数为10岁（范围为0.67-15.0），平均体重为11公斤（范围4.5-45公斤），年龄体重z评分中位数为-3.33（范围为-5.15至-1.32）。两室配置模型，按重量按比例缩放，是为rifabutin和des-rifabutin开发的。LPV/r使利福布汀的生物利用度增加了158％（95％置信区间：93.2％-246.0％），并使利福布汀的清除率降低了76.6％（74.4％-78.3％）。体重严重不足的儿童显示26％（17.9％-33.7％）的生物利用度降低。与成人暴露相比，模拟导致在仅使用20mg/kg/天的结核病治疗期间，在6-20kg中，稳态利福布汀和des-rifabutin暴露的中位数较高。在LPV/r共同治疗期间，2.5mg/kg/天的剂量对成年人的暴露量相似，而5-mg/kg/day剂量导致>7kg儿童的暴露量更高。所有研究剂量均维持中位数Cmax<900µg/L。建议的体重带给药在体重上一致地与成人暴露相匹配，并简化了给药。
