Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California.
Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina.
AIDS. 2022 Mar 15;36(4):525-532. doi: 10.1097/QAD.0000000000003141.
Dosing efavirenz (EFV) in children less than 3 years of age is challenging due to large variability in drug levels. This study evaluated differences in pharmacokinetics with tuberculosis (TB) therapy, formulation, age, and CYP2B6 genotype.
Pharmacokinetic data from three IMPAACT/PACTG studies (P382, P1021, and P1070) for children initiating therapy less than 40 months of age were evaluated.
Pharmacokinetic data were combined in a population pharmacokinetic model. Exposure from the 2-week pharmacokinetic visit was compared with changes in viral RNA between the Week 0 and Week 4 visits.
The model included 103 participants (19 on TB therapy). CYP2B6 516 genotype information was available for 82 participants (TT: 15, GT: 28, GG: 39). Median age at the first pharmacokinetic visit was 17.0 months (range: 2.0-39.0 months). Liquid formulation led to a 42% decrease in bioavailability compared with opened capsules. TB therapy (isoniazid and rifampin) led to a 29% decreased clearance, however Monte Carlo simulations demonstrated the majority of participants on TB therapy receiving standard EFV dosing to be in the target area under the curve range. Clearance was 5.3-fold higher for GG than TT genotype and 3.3-fold higher for GT than TT genotype. Age did not have a significant effect on clearance in the final model. Initial viral RNA decay was lower for patients in the lowest quartile of exposures (area under the curves) than for higher quartiles (P = 0.013).
EFV dosing should account for CYP2B6 516 genotype and formulation, but does not require adjustment for concurrent TB therapy.
由于药物水平的个体差异较大，因此为 3 岁以下的儿童开处方依非韦伦（EFV）剂量颇具挑战。本研究旨在评估结核（TB）治疗、剂型、年龄和 CYP2B6 基因型对药代动力学的影响。
评估了三个 IMPAACT/PACTG 研究（P382、P1021 和 P1070）中开始治疗时年龄小于 40 个月的儿童的药代动力学数据。
将药代动力学数据合并到群体药代动力学模型中。在第 2 周的药代动力学检查中评估暴露情况，并将第 0 周和第 4 周的病毒 RNA 变化进行比较。
该模型纳入了 103 名参与者（19 名接受 TB 治疗）。82 名参与者（TT：15，GT：28，GG：39）的 CYP2B6 516 基因型信息可用。首次药代动力学检查时的中位年龄为 17.0 个月（范围：2.0-39.0 个月）。与打开胶囊相比，液体剂型导致生物利用度降低了 42%。TB 治疗（异烟肼和利福平）导致清除率降低了 29%，但蒙特卡罗模拟显示，大多数接受 TB 治疗的参与者接受标准 EFV 剂量治疗后，其 AUC 均处于目标范围内。与 TT 基因型相比，GG 基因型的清除率高 5.3 倍，GT 基因型的清除率高 3.3 倍。最终模型中年龄对清除率无显著影响。在最低暴露（AUC）四分位的患者初始病毒 RNA 衰减率低于较高四分位（P=0.013）。
EFV 剂量应考虑 CYP2B6 516 基因型和剂型，但无需根据同时进行的 TB 治疗进行调整。
