Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria.
Department of Molecular and Clinical Pharmacology, University of Liverpool, 70 Pembroke Place, Liverpool L693GF, UK.
J Antimicrob Chemother. 2018 Jan 1;73(1):165-172. doi: 10.1093/jac/dkx334.
Lack of data on the pharmacokinetics of efavirenz in pregnant women at the 400 mg reduced dose currently prevents universal roll-out. Population pharmacokinetic modelling was used to explore pharmacokinetic endpoints at 200, 400 and 600 mg daily doses in pregnant women stratified by CYP2B6 metabolic status.
The analysis was based on 252 plasma efavirenz concentrations from 77 pregnant women (77 sparse, 175 intensive) who received antiretroviral regimens containing 600 mg of efavirenz. The model was developed using NONMEM®. The effect of genetics was investigated and concentration-time courses at steady-state were simulated for individuals (n = 1000 each) classified as CYP2B6 slow, intermediate and fast metabolizers at 200, 400 and 600 mg daily doses.
At a 400 mg reduced dose, predicted mean (90% CI) mid-dose efavirenz concentration (C12) was 2.24 μg/mL (0.89-4.18) in pregnant women classified as slow metabolizers, compared with 0.87 μg/mL (0.34-1.64) in intermediate metabolizers and 0.78 μg/mL (0.30-1.47) in fast metabolizers. C12 was below the 0.47 μg/mL threshold determined within the ENCORE 1 trial in 10% at 400 mg, 4.6% at 600 mg and 3.4% with genotype-guided dosing. The 4.0 μg/mL toxicity threshold was exceeded in 4.6% at 400 mg, 13.5% at 600 mg and 5.2% with genotype-guided dosing.
These data provide context for the ongoing debate about reduction in efavirenz dose to 400 mg during pregnancy and should be interpreted alongside the lower toxicity expected with the lower dose. Additional research is required to investigate genotype-guided dose reduction in pregnant women.
由于缺乏有关孕妇中依非韦伦（efavirenz）400mg 减少剂量的药代动力学数据，目前无法普遍推广。本研究采用群体药代动力学模型，对依非韦伦 200、400 和 600mg 日剂量在按 CYP2B6 代谢状态分层的孕妇中的药代动力学终点进行了探索。
该分析基于 77 名接受包含 600mg 依非韦伦的抗逆转录病毒方案的孕妇（77 名稀疏采集，175 名密集采集）的 252 个血浆依非韦伦浓度。使用 NONMEM® 进行模型开发。研究了遗传因素的影响，并对 200、400 和 600mg 日剂量下被分类为 CYP2B6 慢代谢、中速代谢和快代谢个体的稳态浓度时间曲线进行了模拟（n=1000 个个体）。
在 400mg 减少剂量下，被分类为慢代谢者的孕妇的中位剂量依非韦伦浓度（C12）预测均值（90%CI）为 2.24μg/mL（0.89-4.18），而中速代谢者为 0.87μg/mL（0.34-1.64），快代谢者为 0.78μg/mL（0.30-1.47）。在 400mg 时，10%的患者 C12 低于 ENCORE 1 试验中确定的 0.47μg/mL 阈值，600mg 时为 4.6%，而基因型指导剂量时为 3.4%。在 400mg 时，4.6%的患者 C12 超过 4.0μg/mL 的毒性阈值，600mg 时为 13.5%，而基因型指导剂量时为 5.2%。
这些数据为正在进行的关于孕妇中依非韦伦剂量减少至 400mg 的争论提供了背景信息，应结合较低剂量下预期的毒性降低进行解释。需要进一步研究以调查孕妇中基因型指导剂量减少。
