Single low dose primaquine to block the transmission of Plasmodium falciparum-proposed stand-alone and ACT-adapted regimens.

IF 8.3 1区 医学 Q1 MEDICINE, GENERAL & INTERNAL
Walter R J Taylor, Peter Olupot-Olupot, Marie A Onyamboko, Natenapa Chimjinda, Chiraporn Taya, Julie Nguyen Ngoc Pouplin, Thomas N Williams, Kathryn Maitland, Caterina A Fanello, Nicholas P J Day, Joel Tarning, Nicholas J White, Mavuto Mukaka
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引用次数: 0

Abstract

Background: Despite the 2012 WHO recommendation to add single low dose primaquine (SLDPQ, 0.25 mg/kg body weight) to artemisinin-based combination treatments (ACTs) for blocking the transmission of artemisinin-resistant Plasmodium falciparum, there are currently no weight-based regimens founded on robust evidence.

Methods: Applying published safety, transmission blocking and pharmacokinetic data, and exploring pharmacokinetic-pharmacodynamic relationships of age-based dosing of SLDPQ in African children with acute, uncomplicated Plasmodium falciparum, we derived weight-based, stand-alone, ACT-, triple ACT-, and vivax-matched regimens by following allometric dosing principles and simulating PQ exposure (area under the concentration time curve). The ACTs were dihydroartemisinin piperaquine (DHAPP), artesunate pyronaridine (ASPYR), artesunate amodiaquine (ASAQ), artesunate mefloquine (ASMQ), artemether lumefantrine (AL), and ALAQ. Tablet strengths were predefined: 2.5, 3.75, 5, 7.5, and 15 mg, and no tablet fractions were allowed. The maximum mg/kg dose was set at 0.5, and, primarily for ease of ACT co-blistering, 1 tablet = 1 dose. We assessed different mg/kg doses and selected the dosing associated with a predicted median exposure closest to 1200 ng*h/mL, the exposure predicted for a 60 kg individual given 15 mg of PQ.

Results: The designed 8 regimens had 4-8 dosing bands. The stand-alone, DHAPP, and ASPYR regimens contain the full line of PQ tablets and all other regimens, except AL (2.5, 7.5, 15 mg) and ALAQ (2.5, 5, 7.5, 15 mg), use 3.75 mg. The 2.5 mg tablet resulted in a maximum dose of 0.56 mg/kg for ASAQ, as this regimen starts at 4.5 kg body weight, whilst all other regimens start at 5 kg and resulted in 0.5 mg/kg. Substituting 3.75 mg with 5 mg results in maximum doses of 0.56 mg/kg (ASAQ, ASMQ) and 0.63 mg/kg (other regimens), risking greater toxicity. Across all dosing bands, 0.17 - 0.56 mg/kg doses predict exposures of ~ 500 - 2000 ng*mL/h. Regimens with more dosing bands had less variations in exposure.

Conclusions: These regimens offer flexibility for malaria control programmes and guidance for drug manufacturers wishing to co-blister SLDPQ with ACTs. The WHO should reinstate the 3.75 mg tablet for prequalification and determine which regimens should be incorporated into their treatment guidelines to advance malaria elimination.

Trial registration: The trial is registered at ISRCTN, number 11594437.

单一低剂量伯氨喹阻断恶性疟原虫传播——建议的独立方案和适应act的方案。
背景:尽管2012年世卫组织建议在以青蒿素为基础的联合治疗(ACTs)中添加单次低剂量伯氨喹(SLDPQ, 0.25 mg/kg体重)以阻断耐青蒿素恶性疟原虫的传播,但目前尚无基于有力证据的基于体重的方案。方法:应用已发表的安全性、传播阻断和药代动力学数据,探索非洲急性、无并发症恶性疟原虫儿童SLDPQ基于年龄给药的药代动力学-药效学关系,遵循异速给药原则,模拟PQ暴露(浓度时间曲线下面积),推导出基于体重、独立、ACT-、三联ACT-和间日匹配的方案。ACTs分别为双氢青蒿素哌喹(dapp)、青蒿素吡啶(ASPYR)、青蒿素阿莫地喹(ASAQ)、青蒿素甲氟喹(ASMQ)、蒿甲醚甲芳碱(AL)和ALAQ。片剂强度为2.5、3.75、5、7.5和15mg,不允许有片剂组分。最大剂量设定为0.5 mg/kg,主要是为了方便ACT共泡,1片= 1剂量。我们评估了不同的mg/kg剂量,并选择了与预测中位暴露量最接近1200 ng*h/mL的剂量,这是给予15 mg PQ的60 kg个体的预测暴露量。结果:设计的8个方案有4-8个给药频带。单药、dapp和ASPYR方案包含全系列PQ片,所有其他方案,除了AL(2.5、7.5、15毫克)和ALAQ(2.5、5、7.5、15毫克),使用3.75毫克。2.5 mg片剂导致ASAQ的最大剂量为0.56 mg/kg,因为该方案从4.5 kg体重开始,而所有其他方案从5 kg开始,导致0.5 mg/kg。用5mg代替3.75 mg的最大剂量为0.56 mg/kg (ASAQ、ASMQ)和0.63 mg/kg(其他方案),有更大的毒性风险。在所有剂量带中,0.17 - 0.56 mg/kg剂量预测暴露量为~ 500 - 2000 ng*mL/h。剂量频带较多的治疗方案暴露变化较小。结论:这些方案为疟疾控制规划提供了灵活性,并为希望将SLDPQ与ACTs联合使用的药品制造商提供了指导。世卫组织应恢复3.75毫克片剂进行资格预审,并确定应将哪些方案纳入其治疗指南,以推进消除疟疾。试验注册:该试验在ISRCTN注册,编号11594437。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
BMC Medicine
BMC Medicine 医学-医学:内科
CiteScore
13.10
自引率
1.10%
发文量
435
审稿时长
4-8 weeks
期刊介绍: BMC Medicine is an open access, transparent peer-reviewed general medical journal. It is the flagship journal of the BMC series and publishes outstanding and influential research in various areas including clinical practice, translational medicine, medical and health advances, public health, global health, policy, and general topics of interest to the biomedical and sociomedical professional communities. In addition to research articles, the journal also publishes stimulating debates, reviews, unique forum articles, and concise tutorials. All articles published in BMC Medicine are included in various databases such as Biological Abstracts, BIOSIS, CAS, Citebase, Current contents, DOAJ, Embase, MEDLINE, PubMed, Science Citation Index Expanded, OAIster, SCImago, Scopus, SOCOLAR, and Zetoc.
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