PROSPECTIVE STUDY ON GENETIC DETERMINANTS OF CARBAMAZEPINE RESPONSE: THE CYP3A5-RS15524 GENE POLYMORPHISM IN PASHTUN PATIENTS WITH EPILEPSY

Objective: To evaluate the impact of CYP3A5-rs15524 polymorphism on the pharmacokinetics and clinical response to carbamazepine (CBZ) monotherapy in Pashtun epilepsy patients. Materials and Methods: A longitudinal study was carried out among Pashtun patients with epilepsy in Khyber Pakhtunkhwa from October 2020 to April 2022. Participants were recruited from Lady Reading Hospital, while laboratory work was performed at the Pharmacology Department of Khyber Medical University, Peshawar. Patients were genotyped for the CYP3A5-rs15524 polymorphism using Sanger sequencing, with variants analyzed via Finch TV. The study correlated each genotype with clinical response and serum CBZ levels, which were measured using reversed-phase HPLC during each follow-up visit. Results: A sample of 223 patients was analyzed, including 63.2% males and 36.8% females. Generalized tonic-clonic (GTC) seizures comprised 82.5% of cases, while partial seizures accounted for 17.5%. Genotype analyses showed a significant improvement in CBZ response in subsequent follow-up. At 3rd month, the non-responders / responders were recorded to be 18.3% / 31.3% for AA, 44.6% / 16.9% for AG, and 63.3% / 18.2% for GG genotype carriers. At 6th month it was recorded as 9.5% / 53% for AA, 32.3% / 32.3% for AG, and 27.3% / 54% among GG carriers, demonstrating a highly significant differences in response (p-value=0.001). Highest and lowest plasma levels across both follow-ups were observed in AA & AG genotypes, respectively with a p-value less than 0.001. Conclusion: Our findings suggest that CYP3A5-rs15524 polymorphism may impact the pharmacokinetics and clinical response to carbamazepine in Pashtun patients with epilepsy. Clinical pharmacogenetic research has the potential to greatly enhance personalized treatment within our study population.