Modelling the therapeutic dose range of single low dose primaquine to reduce malaria transmission through age-based dosing

BMC Infectious Diseases

Research Article

Daniel Joseph Hayes¹  Dianne Janette Terlouw²  Alexandra Chipasula-Teleka³  Clifford George Banda³ 

[1] Department of Clinical Sciences, Liverpool School of Tropical Medicine (LSTM), Liverpool, UK;Department of Clinical Sciences, Liverpool School of Tropical Medicine (LSTM), Liverpool, UK;Malawi-Liverpool Wellcome Trust Clinical Research Programme, P.O. Box 30096, Chichiri Blantyre 3, Malawi;Malawi-Liverpool Wellcome Trust Clinical Research Programme, P.O. Box 30096, Chichiri Blantyre 3, Malawi;

关键词: Malaria;    Primaquine;    Dosing;    Disease elimination;    Transmission;    Dose response relationship;   

DOI  :  10.1186/s12879-017-2378-9

 received in 2017-03-30, accepted in 2017-04-01,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundLow-dose primaquine is a key candidate for use in malaria transmission reduction and elimination campaigns such as mass drug administration (MDA). Uncertainty about the therapeutic dose range (TDR) required for general and paediatric populations challenge the implementation of the World Health Organisation’s recommendation to add 0.25 mg/kg to current standard antimalarial treatment in such settings. Modelling work shows that for low-dose primaquine to have an impact, high efficacy and extensive population coverage are needed. In practice, age-based dose regimens, often used in MDA, could lead to safety concerns and a different effectiveness profile. We aimed to define TDRs for primaquine and to assess dosing accuracy of age-based dose regimens.MethodsOptimised regional age-based dosing regimens for low-dose primaquine were developed in steps. First, we identified potential TDR options based on suggested published efficacy and safety thresholds (i.e. 0.1–0.4, 0.125–0.375, 0.15–0.35 mg/kg). We then used our previously defined weight-for-age growth references and age-based dose optimisation tool to model predicted regimen accuracies for Africa, Asia and Latin America based on low-dose primaquine tablets (3.75 mg and 7.5 mg) currently under development by Sanofi while employing the identified dose range options and pre-specified regimen characteristics.ResultsDose regimens employing TDRs of 0.1–0.4 and 0.125–0.375 mg/kg had the highest average predicted dose accuracies in all regions with the widest dose range of 0.1–0.4 mg/kg resulting in ≥99% dose accuracy in all three regions. The narrower 0.15–0.35 mg/kg range was on average predicted to correctly dose 91.4% of the population in Africa, 93.2% in Asia and 92.6% in Latin America. This range would prescribe ≥20% of 3-year-olds doses below 0.15 mg/kg and ≥20% of 11-year-olds doses above 0.35 mg/kg. Widening the TDR from 0.15–0.35 to 0.1–0.4 mg/kg increased the dose accuracy by ≥20% in Africa, ≥15% in Asia and ≥10% in Latin America.ConclusionOptimised age-based dose regimens derived from wider TDRs are predicted to attain the dose accuracies required for effective MDA in malaria transmission reduction and elimination settings. We highlight the need for a clearly defined TDR and for safety and efficacy trials to focus on doses compatible with age-based dosing often employed in such settings.

【 授权许可】

CC BY   
© The Author(s). 2017