Best B M, Burchett S, Li H, Stek A, Hu C, Wang J, Hawkins E, Byroads M, Watts D H, Smith E, Fletcher C V, Capparelli E V, Mirochnick M
School of Medicine-Rady Children's Hospital and Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, San Diego, CA, USA.
Harvard Medical School, Children's Hospital Boston, Boston, MA, USA.
HIV Med. 2015 Sep;16(8):502-11. doi: 10.1111/hiv.12252. Epub 2015 May 11.
Tenofovir disoproxil fumarate (TDF) is increasingly used in the highly active antiretroviral therapy (HAART) regimens of pregnant women, but limited data exist on the pregnancy pharmacokinetics of chronically dosed TDF. This study described tenofovir pharmacokinetics during pregnancy and postpartum.
International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) P1026s is a prospective, nonblinded pharmacokinetic study of HIV-infected pregnant women that included a cohort receiving 300 mg TDF once daily. Steady-state 24-hour pharmacokinetic profiles were measured at the second and third trimesters, postpartum, and in maternal and umbilical cord samples collected at delivery. Tenofovir was measured by liquid chromatography-mass spectrometry (LC-MS). The target area under the concentration versus time curve from time 0 to 24 h post dose (AUC) was ≥ 1.99 μg h/mL (nonpregnant historical control 10th percentile).
The median tenofovir AUC was decreased during the second (1.9 μg h/mL) and third (2.4 μg h/mL; P = 0.005) trimesters versus postpartum (3.0 μg h/mL). Tenofovir AUC exceeded the target for two of four women (50%) in the second trimester, 27 of 37 women [73%; 95% confidence interval (CI) 56%, 86%] in the third trimester, and 27 of 32 women (84%; 95% CI 67%, 95%) postpartum (P > 0.05). Median second/third-trimester troughs were lower (39/54 ng/mL) than postpartum (61 ng/mL). Median third-trimester weight was greater for subjects below the target AUC versus those above the target (97.9 versus 74.2 kg, respectively; P = 0.006). The median ratio of cord blood to maternal concentrations was 0.88. No infants were HIV infected.
This study found lower tenofovir AUC and troughs during pregnancy. Transplacental passage with chronic TDF use during pregnancy was high. Standard TDF doses appear to be appropriate for most HIV-infected pregnant women but therapeutic drug monitoring with dose adjustment should be considered in pregnant women with high weight (> 90 kg) or inadequate HIV RNA response.
富马酸替诺福韦二吡呋酯（TDF）在孕妇的高效抗逆转录病毒治疗（HAART）方案中使用得越来越多，但关于长期服用TDF的孕期药代动力学数据有限。本研究描述了孕期及产后替诺福韦的药代动力学情况。
国际母婴儿科和青少年艾滋病临床试验（IMPAACT）P1026s是一项针对感染HIV的孕妇的前瞻性、非盲法药代动力学研究，其中一组孕妇每日服用300mg TDF。在孕中期和孕晚期、产后以及分娩时采集的母体和脐带血样本中测量稳态24小时药代动力学曲线。通过液相色谱-质谱联用（LC-MS）测定替诺福韦。给药后0至24小时浓度-时间曲线下的目标面积（AUC）≥1.99μg·h/mL（非孕期历史对照的第10百分位数）。
与产后（3.0μg·h/mL）相比，孕中期（1.9μg·h/mL）和孕晚期（2.4μg·h/mL；P = 0.005）替诺福韦的AUC中位数降低。孕中期4名女性中有2名（50%）、孕晚期37名女性中有27名（73%；95%置信区间[CI] 56%，86%）以及产后32名女性中有27名（84%；95% CI 67%，95%）的替诺福韦AUC超过目标值（P > 0.05）。孕中期/孕晚期的谷浓度中位数低于产后（分别为39/54 ng/mL和61 ng/mL）。AUC低于目标值的受试者孕晚期体重中位数高于AUC高于目标值的受试者（分别为97.9 kg和74.2 kg；P = 0.006）。脐血与母体浓度的中位数比值为0.88。无婴儿感染HIV。
本研究发现孕期替诺福韦的AUC和谷浓度较低。孕期长期使用TDF时经胎盘转运率较高。标准TDF剂量似乎适用于大多数感染HIV的孕妇，但对于体重较高（>90 kg）或HIV RNA反应不佳的孕妇，应考虑进行治疗药物监测并调整剂量。
