Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Ilorin, Ilorin, Nigeria.
Federal Medical Centre, Makurdi, Nigeria.
Clin Pharmacol Ther. 2024 Oct;116(4):1062-1070. doi: 10.1002/cpt.3343. Epub 2024 Jun 10.
In this study, we investigated the combined influence of pregnancy and genetic polymorphisms on efavirenz pharmacokinetics in cervicovaginal fluid (CVF) of women receiving antiretroviral therapy. Women receiving efavirenz-containing antiretroviral therapy were recruited from two hospitals in Nigeria during 2017-2020. Sparse CVF and plasma samples were obtained during pregnancy to assess the possible association between drug concentration and CYP2B6 polymorphisms (stage I). Participants were stratified into three CYP2B6 516G>T (rs3745274) genotype groups and re-enrolled for intensive pharmacokinetic sampling (stage II). Overall, 159 women (142 pregnant and 12 postpartum) contributed samples in stage I (88 CVF, 81 plasma and 73 paired). CYP2B6 516G>T (rs3745274) remained independently associated with log efavirenz CVF concentration during pregnancy after adjusting for plasma concentration, with β (Log efavirenz concentration, 95%CI) of 0.204 (0.027, 0.382), P = 0.025). Median (IQR) efavirenz C in CVF during pregnancy (n = 12) vs. postpartum (n = 12) was 243 ng/mL (168-402) vs. 447 ng/mL (159-974), C was 1,031 ng/mL (595-1,771) vs. 1,618 ng/mL (675-2,695), and AUC was 16,465 ng.h/mL (9,356-30,417) vs. 30,715 ng.h/mL (10,980-43,714). CVF-to-plasma AUC ratio was 0.36 during pregnancy and 0.46 postpartum. Upon stratification, efavirenz clearance during pregnancy was 57.9% higher than postpartum in patients with the CYP2B6 516GT genotype; the AUC and C were 33.8% and 8.6% lower, respectively. Efavirenz C in CVF exceeded the protein binding-adjusted IC (PBIC) of 126 ng/mL during pregnancy and postpartum. Efavirenz is well distributed into the CVF; both pregnancy and CYP2B6 polymorphisms affect the extent of exposure.
在这项研究中，我们调查了妊娠和基因多态性对接受抗逆转录病毒治疗的女性宫颈阴道液（CVF）中依非韦伦药代动力学的联合影响。在 2017 年至 2020 年期间，从尼日利亚的两家医院招募了接受包含依非韦伦的抗逆转录病毒治疗的女性。在妊娠期间获得稀疏的 CVF 和血浆样本，以评估药物浓度与 CYP2B6 多态性之间的可能关联（第 I 阶段）。将参与者分为三组 CYP2B6 516G>T（rs3745274）基因型组，并重新招募进行强化药代动力学采样（第 II 阶段）。总体而言，159 名女性（142 名孕妇和 12 名产后）在第 I 阶段（88 份 CVF、81 份血浆和 73 份配对）提供了样本。调整血浆浓度后，CYP2B6 516G>T（rs3745274）仍然与妊娠期间依非韦伦 CVF 浓度的对数呈独立相关，β（依非韦伦浓度的对数，95%CI）为 0.204（0.027，0.382），P=0.025）。妊娠期间（n=12）与产后（n=12）相比，依非韦伦 CVF 中的中位（IQR）C 分别为 243ng/mL（168-402）与 447ng/mL（159-974），C 分别为 1031ng/mL（595-1771）与 1618ng/mL（675-2695），AUC 分别为 16465ng.h/mL（9.356-30417）与 30715ng.h/mL（10980-43714）。妊娠期间 CVF 与血浆 AUC 比值为 0.36，产后为 0.46。分层后，CYP2B6 516GT 基因型患者妊娠期间依非韦伦清除率比产后高 57.9%；AUC 和 C 分别低 33.8%和 8.6%。妊娠和产后期间，依非韦伦 CVF 中的 C 均超过了蛋白结合调整的 IC（PBIC）126ng/mL。依非韦伦很好地分布在 CVF 中；妊娠和 CYP2B6 多态性均会影响暴露程度。
