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 post hoc 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.)

中文翻译：

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乌干达妇女的哌拉喹暴露会因怀孕，HIV和营养状况而改变

二氢青蒿素-哌喹（DHA-PQ）为非洲孕妇提供了有效的疟疾治疗和化学预防方法。PQ浓度> 10.3 ng / ml与降低母亲寄生虫病，胎盘疟疾和改善出生结局有关。我们在事后对PQ的群体药代动力学（PK）进行了表征每4或8周接受DHA-PQ进行化学预防的人类免疫缺陷病毒（HIV）感染和未感染孕妇的分析。研究了协变量的影响，如妊娠，营养状况（体重指数[BMI]）和基于依非韦伦（EFV）的抗逆转录病毒疗法。将来自两个化学预防试验的PQ浓度合并起来，以创建来自274名女性和2218例PK观察值的人群PK数据库。具有吸收滞后的三室模型最适合该数据。与我们之前的大量PK评估一致，与产后和未感染HIV的孕妇相比，怀孕和EFV的使用分别使PQ清除率提高了72％和61％。妊娠28周时的BMI较低与清除率增加有关（BMI每降低1％，增加2％）。与具有较高BMI的女性相比，每8周接受DHA-PQ的低BMI女性的寄生虫病，疟疾感染和胎盘疟疾患病率更高。与具有较高BMI且未服用EFV的孕妇相比，具有较低BMI的妇女以及在EFV共同给药期间减少的哌喹喹暴露表明，这些人群可从每周而不是每月的剂量中受益，以预防疟疾寄生虫病。模拟表明，由于BMI清除关系，与每月提供2880 mg固定剂量方案相比，基于体重的方案不能改善保护效果。（本文中描述的临床试验已在ClinicalTrials.gov上注册，标识为NCT02163447和NCT02282293。）和BMI较高的女性相比，胎盘疟疾。与具有较高BMI且未服用EFV的孕妇相比，具有较低BMI的妇女以及在EFV共同给药期间减少的哌喹喹暴露表明，这些人群可从每周而不是每月的剂量中受益，以预防疟疾寄生虫病。模拟表明，由于BMI清除关系，与每月提供2880 mg固定剂量方案相比，基于体重的方案不能改善保护效果。（本文中描述的临床试验已在ClinicalTrials.gov上注册，标识为NCT02163447和NCT02282293。）和BMI较高的女性相比，胎盘疟疾。与具有较高BMI且未服用EFV的孕妇相比，具有较低BMI的妇女以及在EFV共同给药期间减少的哌喹喹暴露表明，这些人群可从每周而不是每月的剂量中受益，以预防疟疾寄生虫病。模拟表明，由于BMI清除关系，与每月提供2880 mg固定剂量方案相比，基于体重的方案不能改善保护效果。（本文中描述的临床试验已在ClinicalTrials.gov上注册，标识为NCT02163447和NCT02282293。）这表明这些人群可以从每周一次而不是每月一次的剂量中受益，以预防疟疾寄生虫病。模拟表明，由于BMI清除关系，与每月提供2880 mg固定剂量方案相比，基于体重的方案不能改善保护效果。（本文中描述的临床试验已在ClinicalTrials.gov上注册，标识为NCT02163447和NCT02282293。）这表明这些人群可以从每周一次而不是每月一次的剂量中受益，以预防疟疾寄生虫病。模拟表明，由于BMI清除关系，与每月提供2880 mg固定剂量方案相比，基于体重的方案不能改善保护效果。（本文中描述的临床试验已在ClinicalTrials.gov上注册，标识为NCT02163447和NCT02282293。）