TY - JOUR
T1 - Development of weight and age-based dosing of daily primaquine for radical cure of vivax malaria
AU - Taylor, Walter Robert
AU - Hoglund, Richard M.
AU - Peerawaranun, Pimnara
AU - Nguyen, Thuy Nhien
AU - Hien, Tran Tinh
AU - Tarantola, Arnaud
AU - von Seidlein, Lorenz
AU - Tripura, Rupam
AU - Peto, Thomas J.
AU - Dondorp, Arjen M.
AU - Landier, Jordi
AU - H.Nosten, Francois
AU - Smithuis, Frank
AU - Phommasone, Koukeo
AU - Mayxay, Mayfong
AU - Kheang, Soy Ty
AU - Say, Chy
AU - Neeraj, Kak
AU - Rithea, Leang
AU - Dysoley, Lek
AU - Kheng, Sim
AU - Muth, Sinoun
AU - Roca-Feltrer, Arantxa
AU - Debackere, Mark
AU - Fairhurst, Rick M.
AU - Song, Ngak
AU - Buchy, Philippe
AU - Menard, Didier
AU - White, Nicholas J.
AU - Tarning, Joel
AU - Mukaka, Mavuto
N1 - Funding Information: This work was partly supported by a Wellcome Innovator award (WT-iTP-2018/001), but the Wellcome Trust was not involved in any aspect of this study. Funding Information: We are very thankful to the Demographic Health Survey of USAID for permission to download their data for Cambodia, Laos, Vietnam and Myanmar. JT is supported by the Wellcome Trust of Great Britain (220211) and RH is supported by the Bill and Melinda Gates foundation (INV-006052). Funding Information: We are very thankful to the Demographic Health Survey of USAID for permission to download their data for Cambodia, Laos, Vietnam and Myanmar. JT is supported by the Wellcome Trust of Great Britain (220211) and RH is supported by the Bill and Melinda Gates foundation (INV-006052). Publisher Copyright: © 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
KW - Age-based dosing
KW - Allometric scaling
KW - Plasmodium vivax
KW - Primaquine
KW - Weight-based dosing
UR - http://www.scopus.com/inward/record.url?scp=85114678743&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s12936-021-03886-w
DO - https://doi.org/10.1186/s12936-021-03886-w
M3 - Article
C2 - 34503519
SN - 1475-2875
VL - 20
JO - Malaria journal
JF - Malaria journal
IS - 1
M1 - 366
ER -