Sambol Nancy C, Tappero Jordan W, Arinaitwe Emmanuel, Parikh Sunil
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.
Centers for Global Health, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, United States of America.
PLoS One. 2016 May 16;11(5):e0154623. doi: 10.1371/journal.pone.0154623. eCollection 2016.
The combination of short-acting dihydroartemisinin and long-acting piperaquine (DP) is among the first-line therapies for the treatment of uncomplicated Plasmodium falciparum malaria. Population pharmacokinetic models of piperaquine (PQ) based on data from acute treatment of young children can be used to predict exposure profiles of piperaquine under different DP chemoprevention regimens. The purpose of our study was to make such predictions in young children.
Based on a prior population pharmacokinetic model of PQ in young Ugandan children, we simulated capillary plasma concentration-time profiles (including their variability) of candidate chemoprevention regimens for a reference population of 1-2 year olds weighing at least 11 kg. Candidate regimens that were tested included monthly administration of standard therapeutic doses, bimonthly dosing, and weekly dosing (with and without a loading dose).
Once daily doses of 320 mg for three days (960 mg total) at the beginning of each month are predicted to achieve an average steady-state trough capillary piperaquine concentration of 35 ng/mL, with 60% achieving a level of 30 ng/mL or higher. In contrast, weekly dosing of 320 mg (i.e., 33% higher amount per month) is predicted to approximately double the average steady-state trough concentration, increase the percent of children predicted to achieve 30 ng/mL or higher (94%), while at the same time lowering peak concentrations. Exposure at steady-state, reached at approximately 3 months of multiple dosing, is expected to be approximately 2-fold higher than exposure following initial dosing, due to accumulation. A loading dose improves early exposure, thereby reducing the risk of breakthrough infections at the initiation of chemoprevention.
Once weekly chemoprevention of DP predicts favourable exposures with respect to both trough and peak concentrations. These predictions need to be verified, as well as safety evaluated, in field-based clinical studies of young children. Simulations based on prior knowledge provide a systematic information-driven approach to evaluate candidate DP chemopreventive regimens for future trial designs.
短疗程双氢青蒿素与长疗程哌喹（DP）联合用药是治疗非复杂性恶性疟原虫疟疾的一线疗法之一。基于幼儿急性治疗数据建立的哌喹（PQ）群体药代动力学模型可用于预测不同DP化学预防方案下哌喹的暴露情况。我们研究的目的是对幼儿进行此类预测。
基于乌干达幼儿先前的PQ群体药代动力学模型，我们模拟了体重至少11千克的1至2岁参考人群候选化学预防方案的毛细血管血浆浓度-时间曲线（包括其变异性）。测试的候选方案包括每月给予标准治疗剂量、每两个月给药一次以及每周给药（有或无负荷剂量）。
预计每月初连续三天每日一次给予320毫克剂量（总计960毫克）可使哌喹的平均稳态谷毛细血管浓度达到35纳克/毫升，60%的人达到30纳克/毫升或更高水平。相比之下，每周给予320毫克剂量（即每月剂量高33%）预计可使平均稳态谷浓度增加约一倍，使预计达到30纳克/毫升或更高水平的儿童百分比增加（94%），同时降低峰值浓度。多次给药约3个月后达到的稳态暴露预计比初次给药后的暴露高约2倍，这是由于药物蓄积所致。负荷剂量可改善早期暴露，从而降低化学预防开始时突破性感染的风险。
DP每周一次的化学预防在谷浓度和峰值浓度方面均预测有良好的暴露情况。这些预测需要在幼儿的现场临床研究中进行验证，并评估安全性。基于先前知识的模拟为评估未来试验设计的候选DP化学预防方案提供了一种系统的信息驱动方法。
