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01.12.2017 | Research article | Ausgabe 1/2017 Open Access

BMC Infectious Diseases 1/2017

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

Zeitschrift:
BMC Infectious Diseases > Ausgabe 1/2017
Autoren:
Daniel Joseph Hayes, Clifford George Banda, Alexandra Chipasula-Teleka, Dianne Janette Terlouw
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s12879-017-2378-9) contains supplementary material, which is available to authorized users.

Abstract

Background

Low-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.

Methods

Optimised 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.

Results

Dose 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.

Conclusion

Optimised 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.
Zusatzmaterial
Additional file 1: Table S1. Modelled regimen characteristics. Summary of the regimen characteristics used in the models. (DOCX 11 kb)
12879_2017_2378_MOESM1_ESM.docx
Additional file 2: Figure S1. Comparison of dosing accuracy for different therapeutic dose ranges in Asia. Population under (red), over (blue) and correctly (white) dosed by age for Africa using three dose ranges (0.1–0.4, 0.125–0.375 and 0.15–0.35 mg/kg). PQ = Primaquine, TDR = Therapeutic dose range, tab = tablet strength. (TIFF 117 kb)
12879_2017_2378_MOESM2_ESM.tif
Additional file 3: Figure S2. Comparison of accuracy for different therapeutic dose ranges in Latin America. Population under (red), over (blue) and correctly (white) dosed by age for Africa using three dose ranges (0.1–0.4, 0.125–0.375 and 0.15–0.35 mg/kg). PQ = Primaquine, TDR = Therapeutic dose range, tab = tablet strength. (TIFF 130 kb)
12879_2017_2378_MOESM3_ESM.tif
Additional file 4: Figure S3. Predicted dose intake for selected body weight centiles by age for Africa, Asia and Latin America. Proportion of the population in the three regions predicted to receive doses between 0.1–0.4 mg/kg (plane dotted line) and 0.125–0.375 mg/kg (bold dotted line) by age for Primaquine, black triangle indicates regimen cut-offs on the horizontal which for the 0.1–0.4 mg/kg range translated to the following regimen cut offs: Africa = 6 months (mo) -4, 5–11, 12–16 and 17+ years; Asia =6mo-4, 5–12, 13–19 and 20+ years; Latin America = 6mo-3, 4–9, 10–14 and 15+ years. A similar illustration for the 0.125–0.375 mg/kg resulted in the following regimen cut-offs: Africa = 6 months (mo) -3, 4–10, 11–16 and 17+ years; Asia =6mo-4, 5–12, 13–16 and 17+ years; Latin America = 6mo-3, 4–8, 9–13 and 14+ years. (TIFF 120 kb)
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