Pharmacogenetic Profiling of Cytochrome P450 Enzymes in Plasmodium vivax Patients Treated with Chloroquine and Primaquine: Implications for Personalized Malaria Therapy

This study aimed to investigate the impact of common polymorphisms in key cytochrome P450 (CYP) genes (CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A5) on drug levels and treatment responses in Plasmodium vivax-infected patients treated with chloroquine (CQ) and primaquine (PQ). CYP2C8 and CYP3A5 are the key enzymes that metabolize CQ, whereas CYP2D6, CYP2C9, and CYP2C19 are those that metabolize PQ. A total of 99 DNA samples from Burmese patients with microscopically confirmed P. vivax monoinfection, who received standard doses of CQ (25 mg/kg) and PQ (15 mg/kg/day for 14 days), were included for genotyping of CYP polymorphisms using polymerase chain reaction-restriction fragment length polymorphism assays. The relationship between CYP polymorphisms and patients' clinical outcomes and drug level data was assessed. All patients achieved complete parasite clearance and resolution of fever without recurrence. The most frequent alleles were CYP3A5*3 (71.7%) and CYP2D6*10 (30.6%). The CYP3A5*3 variant was significantly associated with altered desethylchloroquine levels, whereas CYP2C19*3 was associated with faster parasite clearance. No significant associations were found between CYP2D6 or CYP2C8 variants and PQ levels or clinical efficacy. Notably, a patient homozygous for CYP2D6*4 (a poor metabolizer) responded successfully to treatment, suggesting the presence of alternative or compensatory metabolic pathways. Despite a high prevalence of reduced-function CYP variants, CQ-PQ therapy was effective in all patients, indicating that genetic polymorphisms may influence drug metabolism without compromising clinical outcomes. Nevertheless, CYP3A5*3 and CYP2C19*3 variants appear to modulate drug pharmacokinetics and parasite clearance kinetics. These findings underscore the importance of pharmacogenetic surveillance to optimize antimalarial therapy, particularly in elimination settings.