Rapid Fire Presentation 8th International Conference on Plasmodium vivax Research 2022

Bayesian Within-host Modelling of Red Blood Cell Dynamics and Primaquine-induced Haemolysis in G6PD Deficiency (#309)

Parinaz Mehdipour 1 , James Watson 2 , Sophie Zaloumis 1 , Saber Dini 1 , Robert J Commons 3 , Julie A Simpson 1
  1. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia
  2. Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
  3. Global Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia

Background

G6PD deficiency (G6PDd) is prevalent in malaria-endemic countries. Primaquine is the only widely available drug that targets Plasmodium vivax malaria parasites in the liver, however, this drug can cause dose-dependent haemolysis in G6PD deficient individuals. In this research, we develop a within-host model of red blood cell (RBC) dynamics to explore the safety of primaquine regimens for vivax malaria patients with G6PDd.

Methods

The within-host RBC model captured deviations from the RBC normal process by inferring the dose-dependent effect of primaquine on RBC lifespan. The compartmental mechanistic RBC model was fitted to haemoglobin and reticulocyte measurements from a regimen-adaptive trial of ascending primaquine doses in G6PDd individuals using a Bayesian hierarchical framework. The posterior distributions from the model were then used to determine optimal dosing strategies for G6PDd.

Results

Longitudinal haemoglobin and reticulocyte measurements were available for 24 healthy Thai male volunteers with seven different severe G6PDd variants who were given ascending dose regimens of primaquine over 15-20 days. Posterior predictive checks showed that the RBC model reproduced the change in haemoglobin and reticulocyte counts. The population posterior median for the relative reduction in RBC lifespan due to primaquine was 35% (95% Credible Interval: 30%-40%) and for the dose-response curve a primaquine dose of 0.23 mg/kg/day (e.g., 15 mg in a 65kg adult) resulted in half the maximal effect. This mechanistic model shows that ascending primaquine regimens result in predictable self-limiting haemolysis and could be safer than single high doses (45 mg). The model estimated an optimal dosing regimen of 5mg/kg over 14 days is safe for individuals with Mahidol/Viangchan type variants.

Discussion

The within-host RBC model captured the effect of primaquine on the haemoglobin and reticulocyte profiles of the G6PD deficient individuals. This mechanistic model can be used to simulate haemoglobin profiles to determine safe primaquine dosing schemes.

  1. Watson J, Taylor WR, Menard D, Kheng S, White NJ. Modelling primaquine-induced haemolysis in G6PD deficiency. elife. 2017 Feb 3;6:e23061.