Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA.
Antimicrob Agents Chemother. 2020 Nov 17;64(12). doi: 10.1128/AAC.01013-20.
Dihydroartemisinin-piperaquine (DHA-PQ) provides highly effective therapy and chemoprevention for malaria in pregnant African women. PQ concentrations of >10.3 ng/ml have been associated with reduced maternal parasitemia, placental malaria, and improved birth outcomes. We characterized the population pharmacokinetics (PK) of PQ in a analysis of human immunodeficiency virus (HIV)-infected and -uninfected pregnant women receiving DHA-PQ as chemoprevention every 4 or 8 weeks. The effects of covariates such as pregnancy, nutritional status (body mass index [BMI]), and efavirenz (EFV)-based antiretroviral therapy were investigated. PQ concentrations from two chemoprevention trials were pooled to create a population PK database from 274 women and 2,218 PK observations. A three-compartment model with an absorption lag best fit the data. Consistent with our prior intensive PK evaluation, pregnancy and EFV use resulted in a 72% and 61% increased PQ clearance, compared to postpartum and HIV-uninfected pregnant women, respectively. Low BMI at 28 weeks of gestation was associated with increased clearance (2% increase per unit decrease in BMI). Low-BMI women given DHA-PQ every 8 weeks had a higher prevalence of parasitemia, malaria infection, and placental malaria compared to women with higher BMIs. The reduced piperaquine exposure in women with low BMI as well as during EFV coadministration, compared to pregnant women with higher BMIs and not taking EFV, suggests that these populations could benefit from weekly instead of monthly dosing for prevention of malaria parasitemia. Simulations indicated that because of the BMI-clearance relationship, weight-based regimens would not improve protection compared to a 2,880 mg fixed-dose regimen when provided monthly. (The clinical trials described in this paper have been registered at ClinicalTrials.gov under identifiers NCT02163447 and NCT02282293.).
双氢青蒿素-哌喹（DHA-PQ）为妊娠非洲妇女疟疾提供了高效的治疗和化学预防。 PQ 浓度> 10.3ng/ml 与减少母体寄生虫血症、胎盘疟疾和改善出生结局相关。我们分析了接受 DHA-PQ 化学预防的 HIV 感染和未感染的孕妇的 PQ 人群药代动力学（PK），并对每 4 或 8 周接受一次 DHA-PQ 化学预防的孕妇进行了分析。研究了妊娠、营养状况（体重指数[BMI]）和基于依非韦伦（EFV）的抗逆转录病毒治疗等协变量的影响。来自两项化学预防试验的 PQ 浓度被汇集在一起，为 274 名妇女和 2218 次 PK 观察创建了一个人群 PK 数据库。一个具有吸收滞后的三房室模型最适合数据。与我们之前的密集 PK 评估一致，与产后和未感染 HIV 的孕妇相比，妊娠和 EFV 使用导致 PQ 清除率分别增加 72%和 61%。妊娠 28 周时 BMI 低与清除率增加相关（BMI 每降低一个单位，清除率增加 2%）。与 BMI 较高的妇女相比，每 8 周给予 DHA-PQ 的低 BMI 妇女的寄生虫血症、疟疾感染和胎盘疟疾的患病率较高。与 BMI 较高且未服用 EFV 的孕妇相比，BMI 较低的妇女中的哌喹暴露减少以及 EFV 联合用药时，表明这些人群可能受益于每周而不是每月一次的剂量来预防疟疾寄生虫血症。模拟表明，由于 BMI 清除率的关系，与每月提供的 2880mg 固定剂量方案相比，基于体重的方案不会改善保护作用。（本文所述临床试验已在 ClinicalTrials.gov 注册，标识符为 NCT02163447 和 NCT02282293。）
