Modelling primaquine-induced haemolysis in G6PD deficiency.

James Watson,Walter Rj Taylor,Sim Kheng,Nicholas J White,Didier Menard

doi:10.7554/elife.23061

Abstract

Primaquine is the only drug available to prevent relapse in vivax malaria. The main adverse effect of primaquine is erythrocyte age and dose-dependent acute haemolytic anaemia in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDd). As testing for G6PDd is often unavailable, this limits the use of primaquine for radical cure. A compartmental model of the dynamics of red blood cell production and destruction was designed to characterise primaquine-induced haemolysis using a holistic Bayesian analysis of all published data and was used to predict a safer alternative to the currently recommended once weekly 0.75 mg/kg regimen for G6PDd. The model suggests that a step-wise increase in daily administered primaquine dose would be relatively safe in G6PDd. If this is confirmed, then were this regimen to be recommended for radical cure patients would not require testing for G6PDd in areas where G6PDd Viangchan or milder variants are prevalent.

Highlights

Primaquine is the only drug available to prevent relapse in vivax malaria
The control and elimina on of vivax malaria requires both cure of the blood stage infecon and the preven on of later relapses which derive from dormant hypnozoites in the liver
P. vivax infec ons in tropical regions are associated with frequent relapses whilst relapses in P. vivax infec ons from Central America, Northern India and temperate regions are associated with longer intervals from acute infec on to first relapse (White, 2011)

Summary

Introduction

Primaquine is the only drug available to prevent relapse in vivax malaria. The main adverse effect of primaquine is erythrocyte age and dose dependent acute haemoly c anaemia in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDd), a common inherited enzymopathy in many areas of the tropics. A compartmental model of the dynamics of red blood cell produc on and destruc on was designed to characterise primaquine-induced haemolysis using a holis c analysis of all published data on primaquine-induced haemolysis and was used to predict a safer alterna ve to the currently recommended once weekly 0.75mg/kg regimen for radical treatment in G6PDd pa ents. The model was fi ed to data from a recent study of the effects of weekly high-dose primaquine (0.75 mg PQ base/kg body weight) in G6PD deficient vivax malaria pa ents from Cambodia. For G6PD normal pa ents, the primaquine regimen for radical cure that is recommended in SE Asia and Oceania (where relapse rates are high) is 0.5 mg base/kg/day for 14 days. Elsewhere it is 0.25 mg/kg/day for 14 days. These RDTs are currently too expensive to deploy on a wide scale and can be difficult to interpret, and are not generally available (Brito et al, 2016; Satyagraha et al, 2016; Oo et al, 2016)

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