CYP3A and CYP2D6 variability in antimalarial pharmacokinetics and pharmacogenetics across populations: a narrative review.

Malaria remains a global health burden, requiring optimised antimalarial therapies. This review examines the role of CYP450 3A family and 2D6 alleles in antimalarial drug metabolism, highlighting pharmacogenetics and distribution across populations. A narrative literature review was conducted using a structured literature search of PubMed, Web of Science, and Google Scholar to evaluate how CYP3A and CYP2D6 alleles affect the metabolism of quinine, artemether-lumefantrine, primaquine and tafenoquine. The review analysed genetic variations and interactions with other drugs. CYP3A alleles influence quinine metabolism, with normally functioning alleles (CYP3A4*1 or CYP3A5*1) associated with higher metabolism rates, while decreased- or non-functional alleles (CYP3A4*1B or CYP3A5*3, *6, *7) are associated with reduced metabolism. The impact of CYP3A alleles on artemether-lumefantrine metabolism is less clear but may be relevant in pregnancy, individuals with HIV receiving efavirenz, and individuals with tuberculosis receiving rifampicin. CYP2D6 alleles associated with poor or intermediate metaboliser phenotypes may contribute to primaquine treatment failure, while interactions with drugs like chloroquine or dihydroartemisinin-piperaquine may elevate primaquine plasma concentrations. Tafenoquine could represent a potential alternative in individuals with reduced CYP2D6 activity, as current human studies have not shown an increased relapse risk, although clinical evidence remains limited. Understanding these genetic differences could help explain variability in antimalarial drug exposure and treatment response across diverse malaria-endemic populations. Genotyping may help explain variability in drug exposure or treatment response in selected clinical settings. Pharmacogenetic insights may therefore support safer and more effective antimalarial therapies worldwide.