Development of weight and age-based dosing of daily primaquine for radical cure of vivax malaria

Abstract

Background: In many endemic areas, Plasmodium vivax malaria is predominantly a disease of young adults and children. International recommendations for radical cure recommend fixed target doses of 0.25 or 0.5 mg/kg/day of primaquine for 14 days in glucose-6-phosphate dehydrogenase normal patients of all ages. However, for many anti-malarial drugs, including primaquine, there is evidence that children have lower exposures than adults for the same weight-adjusted dose. The aim of the study was to develop 14-day weight-based and age-based primaquine regimens against high-frequency relapsing tropical P. vivax.

Methods: The recommended adult target dose of 0.5 mg/kg/day (30 mg in a 60 kg patient) is highly efficacious against tropical P. vivax and was assumed to produce optimal drug exposure. Primaquine doses were calculated using allometric scaling to derive a weight-based primaquine regimen over a weight range from 5 to 100 kg. Growth curves were constructed from an anthropometric database of 53,467 individuals from the Greater Mekong Subregion (GMS) to define weight-for-age relationships. The median age associated with each weight was used to derive an age-based dosing regimen from the weight-based regimen.

Results: The proposed weight-based regimen has 5 dosing bands: (i) 5-7 kg, 5 mg, resulting in 0.71-1.0 mg/kg/day; (ii) 8-16 kg, 7.5 mg, 0.47-0.94 mg/kg/day; (iii) 17-40 kg, 15 mg, 0.38-0.88 mg/kg/day; (iv) 41-80 kg, 30 mg, 0.37-0.73 mg/kg/day; and (v) 81-100 kg, 45 mg, 0.45-0.56 mg/kg/day. The corresponding age-based regimen had 4 dosing bands: 6-11 months, 5 mg, 0.43-1.0 mg/kg/day; (ii) 1-5 years, 7.5 mg, 0.35-1.25 mg/kg/day; (iii) 6-14 years, 15 mg, 0.30-1.36 mg/kg/day; and (iv) ≥ 15 years, 30 mg, 0.35-1.07 mg/kg/day.

Conclusion: The proposed weight-based regimen showed less variability around the primaquine dose within each dosing band compared to the age-based regimen and is preferred. Increased dose accuracy could be achieved by additional dosing bands for both regimens. The age-based regimen might not be applicable to regions outside the GMS, which must be based on local anthropometric data. Pharmacokinetic data in small children are needed urgently to inform the proposed regimens.

Keywords: Age-based dosing; Allometric scaling; Plasmodium vivax; Primaquine; Weight-based dosing.

Fig. 1

Distribution of the individual anthropometric weight-for-age data in the Greater Mekong Subregion for both sexes combined. The blue line represents the median when applying a three-parameter Box-Cox power exponential distribution and cubic spline smoothing, while the red and orange lines represent the 1st and 99th percentiles, respectively, of the model. The pink markers show outliers outside the 98% prediction interval of the model (n = 1193), and the green markers represent the observed data retained in the final model (n = 53,467)

Fig. 2

Simulated primaquine exposures, relative to the median exposure following administration of 30 mg primaquine base in a 60 kg patient (i.e. target exposure) for the developed weight-based and age-based dosing regimens. The shaded areas represent the 2.5th and 97.5th percentiles of the simulated exposures

Fig. 3

Relative variability in simulated exposure after different dosing regimens. Markers illustrate the relative difference between the simulated 2.5th and 97.5th percentiles of primaquine exposure, stratified on bodyweight. Variability associated with bodyweight-based dosing is shown as black triangles and variability associated with age-based dosing is shown as red circles