Background 

Malaria caused by Plasmodium vivax presents a significant challenge to malaria eradication efforts, as the parasite can remain dormant in the liver and cause recurrent infections. Primaquine (PQ) is a key drug capable of eliminating these dormant forms (hypnozoites) but poses a serious risk to individuals with G6PD deficiency (G6PD), an enzyme disorder common in malaria-endemic regions like Indonesia. G6PD affects 4-16% of the population in certain areas, with more severe variants prevalent in eastern Indonesia. When individuals with G6PD take PQ, they are at risk of acute hemolytic anemia (AHA), a severe condition where red blood cells are destroyed, potentially requiring blood transfusions. Despite PQ’s long history of use, the precise mechanism through which it triggers hemolysis in G6PD-deficient cells remains unclear, especially the role of the enzyme cytochrome P450 (CYP2D6), which metabolizes PQ into its active form.

Study Design

The research will utilize an in vitro system that mimics the interaction between human red blood cells and CYP2D6 to study hemolytic toxicity. Comparisons will be made between G6PD-deficient and normal erythrocytes exposed to PQ and other chemical agents, with an emphasis on detecting and quantifying Heinz bodies as a correlate of hemolysis. This model aims to provide insights into PQ’s hemolytic potential and serve as a predictive tool for other antimalarial candidates.

Goal

The primary goal of this study is to explain how the metabolization of primaquine by CYP2D6 leads to hemolysis in G6PD-deficient red blood cells. This will include:

1. Investigating the relationship between Heinz body formation (a marker of damaged red blood cells) and hemolytic anemia in G6PD-deficient individuals.
2. Measuring oxidative stress levels induced by PQ through key markers, such as glutathione and malondialdehyde, in G6PD erythrocytes.
3. Confirming the specific role of CYP2D6 in metabolizing PQ and its contribution to hemolysis.
4. Developing an in vitro system to predict hemolytic toxicity of PQ and other 8-aminoquinoline drugs, which could be used in preclinical drug testing.

Status

Lab tests are currently underway and results are expected in 2025.