Background and Objectives: Primaquine is the only drug available that targets the dormant Plasmodium vivax parasites in the liver, in order to prevent relapse. However, its major adverse reaction is haemolysis in the G6PD deficient patients. The underlying mechanism of this adverse reaction is still unclear. This study aimed to develop a mechanistic pharmacokinetic-haemodynamic model of primaquine in G6PD normal and deficient patients.
Methods: Weekly primaquine were given to patients with P. vivax infections (18 patients with G6PD deficiency and 57 patients with normal G6PD activity). Haemodynamic outcomes (e.g. haemoglobin, methaemoglobin, and reticulocytes) were observed for 8 weeks. These haemodynamic data were characterised using non-linear mixed-effects modelling. G6PD activity was investigated and implemented into the model as covariates. The final model was used to simulate the haematological outcome associated with different dosing regimens, in order to determine the optimal and safe primaquine dose in G6PD deficient patients.
Results: Haemoglobin and reticulocyte levels were modelled by a transit compartment life-span model. Primaquine exposure was positively correlated with the destruction rate of red-blood-cells. In G6PD deficient patients, the haemoglobin levels dropped substantially after the initial primaquine treatment and returned to normal levels during the continuation of the drug course. The red-blood-cell destruction rate was significantly higher in the G6PD deficient patients. However, the average G6PD activity increased during the treatment course which might suggest that older red-blood-cells were eliminated more rapidly during primaquine treatment, and that the young red-blood-cell tolerate primaquine better since they have a higher G6PD activity. This final pharmacokinetic-haematodynamic model suggested that a stepwise-increased dosing regimen would be safe in G6PD deficient patients.
Conclusions: A mechanistic pharmacokinetic-haemodynamic model of primaquine was successfully developed. This model suggested that G6PD deficient patients showed a significant reduction of red-blood-cells after starting primaquine administration. An optimal primaquine dosing regimen was proposed.