Influence of CYP3A53 and ABCB1 C3435T on clinical outcomes and trough plasma concentrations of imatinib in Nigerians with chronic myeloid leukaemia

• Published in: Journal of clinical pharmacy and therapeutics Vol. 41; no. 5; pp. 546 - 551
• Main Authors: Adeagbo, B. A., Bolaji, O. O., Olugbade, T. A., Durosinmi, M. A., Bolarinwa, R. A., Masimirembwa, C.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.10.2016; Hindawi Limited
• Subjects: ABCB1 C3435T; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents - blood; Antineoplastic Agents - therapeutic use; ATP Binding Cassette Transporter, Sub-Family B - genetics; chronic myeloid leukaemia; CYP3A53; Cytochrome P-450 CYP3A - genetics; Female; genetic polymorphism; Genotype; Humans; imatinib; Imatinib Mesylate - blood; Imatinib Mesylate - therapeutic use; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Male; Middle Aged; Nigeria; Pharmacogenetics - methods; Polymorphism, Genetic - genetics; Young Adult; imatinib; genetic polymorphism; ABCB1 C3435T; CYP3A53; chronic myeloid leukaemia
• ISSN: 0269-4727; 1365-2710
• DOI: 10.1111/jcpt.12424

Summary What is known and objective Imatinib mesylate is the first‐line drug for the treatment of Philadelphia/bcr‐abl positive chronic myeloid leukaemia (CML). It is known to be metabolized mostly by CYP3A4 and CYP3A5 isoforms while its efflux is mediated by the transporters ABCB1 and ABCG2. Genetic polymorphism of some of these enzymes and transporters have been linked with inter‐individual variations in the pharmacokinetics of the drug. This study, therefore, investigated the influence of CYP3A5*3, ABCG2 421C>A and ABCB1 3435 C>T genetic polymorphism on the clinical outcome and steady‐state trough plasma concentration (TPC) of imatinib in Nigerians with CML. Methods A total of 110 Nigerians with CML each of whom had been receiving a 400 mg daily dose of imatinib for at least 1 month were genotyped for CYP3A5*3, ABCG2 421C>A and ABCB1 3435 C>T. The TPC of all the patients were determined by a validated HPLC method and possible relationships between genotypes, age, clinical outcome, sex, TPC and ethnicity were analysed. Results and discussion Subjects of TT genotype of ABCB1 C3435T had higher frequencies of complete haematological response (CHR), complete cytogenetic response (CCR) and major molecular response (MMR) but these were not statistically significant (P < 0·05). No genetic polymorphism in ABCG2 421C>A was observed. However, significant associations were observed between TPC and various genotypes in both CYP3A5*3 (P < 0·001) and ABCB1 C3435T (P < 0·001). The GG and TT genotypes in CYP3A5*3 and ABCB1 C3435T, respectively, were linked with higher TPC. What is new and conclusion This is the first pharmacogenetics study of CML patients in the Nigerian population with ethnic differences in the distribution of ABCB1 C3435T. Genetic polymorphisms in CYP3A5*3 and ABCB1 C3435T are associated with TPC in CML patients in this population. We report the first pharmacogenetics study of chronic myeloid leukaemia (CML) patients in the Nigerian population with ethnic differences in the distribution of ABCB1 C3435T. There was significant association between trough plasma concentrations of imatinib and genetic polymorphisms in both CYP3A5*3 and ABCB1 C3435T in the study population.