Role of OCT1 and MAP3K5 Genetic Polymorphisms in Hydroxyurea Pharmacokinetics

Background: Hydroxyurea is approved for the treatment of paediatric and adult sickle cell disease patients. It causes the synthesis of foetal haemoglobin and decreases platelets and granulocytes, but with a high interindividual variability, requiring higher dosages and escalating toxicity. Hereditary variables should be investigated to personalise treatment. We evaluated the possible influences of OCT1 and MAP3K5 gene polymorphisms on hydroxyurea pharmacokinetics. Methods: We conducted a retrospective analysis on 79 treated patients. The polymorphisms of OCT1 (rs683369 G > C) and MAP3K5 (rs9376230 C > A and rs9483947 C > T) were genotyped. Results: Sub-Saharan patients with the OCT1 rs683369 GG genotype showed a lower drug half-life, compared to those with the GC genotype. In sub-Saharan paediatric female patients, the OCT1 rs683369 GG genotype was associated with a lower t1/2 than the GC genotype. Conclusions: The findings demonstrate for the first time how crucial it is to assess the pharmacogenetics of hydroxyurea by taking into account the two sexes in different groups. Additionally, the data were evaluated with consideration for ethnic groups and individually for adults and children. Pharmacogenetic studies could improve the clinical management of hydroxyurea.