Yeh Rosa F, Rezk Naser L, Kashuba Angela D M, Dumond Julie B, Tappouni Hiba L, Tien Hsiao-Chuan, Chen Ya-Chi, Vourvahis Manoli, Horton Amanda L, Fiscus Susan A, Patterson Kristine B
School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Antimicrob Agents Chemother. 2009 Jun;53(6):2367-74. doi: 10.1128/AAC.01523-08. Epub 2009 Mar 23.
The objective of the study was to measure antiretroviral exposures in four physiological compartments during pregnancy, delivery, and postpartum. This prospective, open-label, longitudinal study collected paired blood plasma (BP) and genital tract (GT) aspirates antepartum, at delivery, and up to 12 weeks postpartum. Antiretroviral cord BP and amniotic fluid concentrations were also measured. Drug concentrations were analyzed by validated high-performance liquid chromatography/UV and liquid chromatography/tandem mass spectrometry methods, with secondary compartment concentrations presented as the percentage of BP. Fourteen women taking lamivudine plus zidovudine and either lopinavir-ritonavir (n = 7), nelfinavir (n = 6), or nevirapine (n = 1) were enrolled; four also received tenofovir. GT penetration relative to BP was highest for the nucleoside reverse transcriptase inhibitors compared to the protease inhibitors and nevirapine. Only antepartum nelfinavir GT penetration was significantly higher than in the second trimester (geometric mean ratio [GMR], 179.3) or third trimester (GMR, 41.9). Compared to nonpregnant historical controls, antepartum GT penetration was significantly lower (P < 0.05) for zidovudine (GMR, 0.25) and lopinavir (GMR, 0.03); postpartum lopinavir GT penetration continued to be significantly lower (GMR, 0.27). Cord BP exposures were highest for lamivudine and tenofovir (> or = 100%), with cord BP levels of the remaining drugs ranging from 49 to 86% of that of the respective BP level. Amniotic exposures for lamivudine, zidovudine, tenofovir, and nelfinavir were > or = 100%, nevirapine exposure was 53%, and lopinavir and ritonavir exposures were < or = 6% that of BP. We conclude that GT, cord BP, and amniotic fluid exposures vary within and between antiretroviral drug classes and biologic sites. Measurement of antiretroviral exposure in maternal genital secretions, cord BP, and amniotic fluid may be needed to identify signals of subtherapeutic or supratherapeutic drug exposure.
该研究的目的是测量孕期、分娩期和产后四个生理腔室中的抗逆转录病毒药物暴露情况。这项前瞻性、开放标签的纵向研究收集了产前、分娩时及产后12周内配对的血浆（BP）和生殖道（GT）吸出物。同时还测量了抗逆转录病毒药物在脐带血血浆和羊水中的浓度。药物浓度通过经过验证的高效液相色谱/紫外法和液相色谱/串联质谱法进行分析，次要腔室的浓度以血浆浓度的百分比表示。纳入了14名服用拉米夫定加齐多夫定以及洛匹那韦-利托那韦（n = 7）、奈韦拉平（n = 6）或奈非那韦（n = 1）的女性；其中4名女性还接受了替诺福韦治疗。与蛋白酶抑制剂和奈韦拉平相比，核苷类逆转录酶抑制剂在生殖道中的穿透率相对于血浆最高。仅产前奈非那韦在生殖道中的穿透率显著高于孕中期（几何平均比值[GMR]，179.3）或孕晚期（GMR，41.9）。与非孕历史对照相比，齐多夫定（GMR，0.25）和洛匹那韦（GMR，0.03）在产前生殖道中的穿透率显著较低（P < 0.05）；产后洛匹那韦在生殖道中的穿透率仍然显著较低（GMR，0.27）。拉米夫定和替诺福韦的脐带血血浆暴露率最高（≥100%），其余药物的脐带血血浆水平为各自血浆水平的49%至86%。拉米夫定、齐多夫定、替诺福韦和奈非那韦的羊水暴露率≥100%，奈韦拉平的羊水暴露率为53%，洛匹那韦和利托那韦的羊水暴露率≤血浆暴露率的6%。我们得出结论，抗逆转录病毒药物在不同药物类别和生物部位之间以及内部，生殖道、脐带血血浆和羊水的暴露情况各不相同。可能需要测量母体生殖道分泌物、脐带血血浆和羊水中的抗逆转录病毒药物暴露情况，以识别治疗不足或治疗过度的药物暴露信号。
