利匹韦林在感染HIV的孕妇中的药代动力学
Pharmacokinetics of Rilpivirine in HIV-Infected Pregnant Women.
作者信息
Tran Anna H, Best Brookie M, Stek Alice, Wang Jiajia, Capparelli Edmund V, Burchett Sandra K, Kreitchmann Regis, Rungruengthanakit Kittipong, George Kathleen, Cressey Tim R, Chakhtoura Nahida, Smith Elizabeth, Shapiro David E, Mirochnick Mark
机构信息
*Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA; †Skaggs School of Pharmacy and Pharmaceutical Sciences, Pediatrics Department-Rady Children's Hospital, University of California, San Diego, CA; ‡Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA; §Department of Biostatistics, Harvard School of Public Health, Boston, MA; ‖Department of Medicine, Children's Hospital Boston, Boston, MA; ¶Irmandade da Santa Casa de Misericordia de Porto Alegre, HIV/AIDS Research Department, Porto Alegre, Brazil; #Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand; **FHI 360, IMPAACT Operations Office, Durham, NC; ††Program for HIV Prevention and Treatment, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand; ‡‡Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health, DHHS, Bethesda, MD; §§National Institute of Allergy and Infectious Diseases, Bethesda, MD; and ‖‖Department of Pediatrics, Boston University School of Medicine, Boston, MA.
出版信息
J Acquir Immune Defic Syndr. 2016 Jul 1;72(3):289-96. doi: 10.1097/QAI.0000000000000968.
BACKGROUND
Rilpivirine pharmacokinetics is defined by its absorption, distribution, metabolism, and excretion. Pregnancy can affect these factors by changes in cardiac output, protein binding, volume of distribution, and cytochrome P450 (CYP) 3A4 activity. Rilpivirine is metabolized by CYP3A4. The impact of pregnancy on rilpivirine pharmacokinetics is largely unknown.
METHODS
International Maternal Pediatric Adolescent AIDS Clinical Trials P1026s is a multicenter, nonblinded, prospective study evaluating antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving rilpivirine 25 mg once daily as part of their combination antiretrovirals for clinical care. Thirty-two women were enrolled in this study. Intensive pharmacokinetic sampling was performed at steady state during the second trimester, the third trimester, and postpartum. Maternal and umbilical cord blood samples were obtained at delivery. Plasma rilpivirine concentration was measured using liquid chromatography-mass spectrometry; lower limit of quantitation was 10 ng/mL.
RESULTS
Median (range) AUC0-24 were 1969 (867-4987, n = 15), 1669 (556-4312, n = 28), and 2387 (188-6736, n = 28) ng·h/mL in the second trimester, the third trimester, and postpartum, respectively (P < 0.05 for either trimester vs postpartum). Median (range) C24 were 63 (37-225, n = 17), 56 (<10-181, n = 30), and 81 (<10-299, n = 28) ng/mL (P < 0.05 for either trimester vs postpartum). High variability in pharmacokinetic parameters was observed between subjects. Median (range) cord blood/maternal concentration ratio was 0.55 (0.3-0.8, n = 21). Delivery HIV-1 RNA was ≤50 copies per milliliter in 70% and ≤400 copies per milliliter in 90% of women. Cmin were significantly lower at 15 visits with detectable HIV-1 RNA compared with 61 visits with undetectable HIV-1 RNA, 29 (<10-93) vs 63 (15-200) ng/mL (P = 0.0001). Cmin was below the protein binding-adjusted EC90 concentration (12.2 ng/mL) at 4 visits in 3 of 31 women (10%).
CONCLUSIONS
Rilpivirine exposure is lower during pregnancy compared with postpartum and highly variable. Ninety percent of women had minimum concentrations above the protein binding-adjusted EC90 for rilpivirine.
背景
利匹韦林的药代动力学由其吸收、分布、代谢和排泄决定。妊娠可通过心输出量、蛋白结合、分布容积和细胞色素P450（CYP）3A4活性的变化影响这些因素。利匹韦林由CYP3A4代谢。妊娠对利匹韦林药代动力学的影响很大程度上未知。
方法
国际母婴儿科青少年艾滋病临床试验P1026s是一项多中心、非盲、前瞻性研究，评估HIV感染孕妇的抗逆转录病毒药代动力学，其中一个队列接受每日一次25mg利匹韦林，作为其联合抗逆转录病毒治疗临床护理的一部分。32名女性纳入本研究。在孕中期、孕晚期和产后稳态时进行强化药代动力学采样。分娩时采集母体和脐带血样本。采用液相色谱-质谱法测定血浆利匹韦林浓度；定量下限为10ng/mL。
结果
孕中期、孕晚期和产后的AUC0-24中位数（范围）分别为1969（867-4987，n = 15）、1669（556-4312，n = 28）和2387（188-6736，n = 28）ng·h/mL（任一孕晚期与产后相比，P < 0.05）。C24中位数（范围）分别为63（37-225，n = 17）、56（<10-181，n = 30）和81（<10-299，n = 28）ng/mL（任一孕晚期与产后相比，P < （此处原文疑似有误，应补充完整比较内容））。观察到受试者之间药代动力学参数存在高度变异性。脐带血/母体浓度中位数（范围）为0.55（0.3-0.8，n = 21）。70%的女性分娩时HIV-1 RNA≤50拷贝/毫升，90%的女性≤400拷贝/毫升。与61次HIV-1 RNA检测不到的访视相比，15次HIV-1 RNA可检测到的访视时Cmin显著更低，分别为29（<10-93）与63（15-200）ng/mL（P = 0.0001）。31名女性中有3名（10%）在4次访视时Cmin低于蛋白结合调整后的EC90浓度（12.2 ng/mL）。
结论
与产后相比，妊娠期间利匹韦林的暴露量较低且高度可变。90%的女性最低浓度高于利匹韦林蛋白结合调整后的EC90。
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