Development of Weight and Age-based Dosing of Daily Primaquine for Radical Cure of Vivax Malaria
Taylor WR., Hoglund R., Peerawaranun P., Nguyen T., Hien T., Tarantola A., Seidlein LV., Tripura R., Peto T., Dondorp A., Landier J., Nosten F., Smithuis F., Phommasone K., Mayxay M., Kheang ST., Say C., Neeraj K., Leang R., Dysoley L., Kheng S., Muth S., Roca-Feltrer A., Debackere M., Fairhurst R., Song N., Buchy P., Menard D., White N., Tarning J., Mukaka M.
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. As for many antimalarial drugs there is evidence that children have lower exposures than adults for the same weight adjusted dose. We, therefore, aimed 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 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 had 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 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 regimens showed less variability around the optimal dose within each dosing band compared to the age-based regimen and is preferred. Increased dose accuracy could be achieved by additional dosing bands. Pharmacokinetic data in small children are needed urgently to inform the proposed regimen.