P0223 CYP3A4∗18 and CYP3A5∗3 gene polymorphisms and imatinib resistance in Malaysian patients with chronic myeloid leukaemia

Ankathil, Ravindran; Zian, A. Au; Nizam, Z.M.; Husin, Azlan; Baba, Aziz

doi:10.1016/j.ejca.2014.03.267

Cited by 2 publications

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“…Although the authors found that the CYP3A5 * 3 gene polymorphism was linked to unfavorable outcome ( P < 0.001) ( 27 ), contrary to our result that did not detect an association between CYP3A5 gene as and pharmacokinetic parameters or response. Similarly, to our data, Takahashi et al ( 13 ) and Ankathil et al ( 44 ) reported insignificant relations between CYP3A5 gene polymorphism and IM trough concentration ( P = 0.645). Despite the important role of CYP activity in the regulation of IM metabolism, it may be due to its activity and not the rate-limiting step in IM metabolism and excretion ( 45 ).…”

Section: Discussionsupporting

confidence: 90%

Association of the Trough, Peak/Trough Ratio of Imatinib, Pyridine–N-Oxide Imatinib and ABCG2 SNPs 34 G>A and SLCO1B3 334 T>G With Imatinib Response in Egyptian Chronic Myeloid Leukemia Patients

et al. 2020

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Imatinib mesylate (IM) is highly efficacious in the treatment of chronic myeloid leukemia (CML). Therapeutic drug monitoring and pharmacogenetic screening are affirmed for better management of IM therapy. The goal of this study was to gain a greater mechanistic understanding of the factors controlling variability in IM level and its relation to the response. One hundred and two patients with CML at chronic phase were recruited in this study. Blood samples were withdrawn at least 30 days after drug administration, and trough and peak concentrations of imatinib, N-des-methyl imatinib, and pyridine-N-oxide imatinib were determined by HPLC/MS/MS. Genetic polymorphism of the genes ABCG2 SNPs 34 G>A and 421C >A; ABCB1 SNPs 2677 G>A/T, 1236 C>T, 3435 C>T; SLCO1B3 SNPs 334 T>G and CYP3A5 were studied using PCR-RFLP technique. Our study presented significant higher trough IM (1,281 ± 578 ng/ml), lower Peak/Trough ratio, clearance (Cl), and elimination rate constant, k e , among patients who achieved favorable responses ( N = 64) than those for patients who suffered unfavorable response ( N = 37). The P/T ratio was the only significant independent factor affecting response, as the P/T ratio increased by one, the risk of unfavorable response increased by more than double as compared to favorable response with 95% CI (1.28–3.92, P = 00.005). Moreover, like the results of IM, the trough concentration of Pyridine-N-oxide imatinib was significantly higher ( P = 0.01) and its P/T ratio was significantly lower ( P = 0.008) in patients achieved favorable response than those without. The wild GG genotype of the ABCG2.34 G>A gene was associated with favorable response ( P = 0.01), lower Cl, K e and high plasma IM trough level than both (AA+GA) genotypes. ABCG2.421C >A (CC) genotype had a significantly higher plasma peak of IM, N-des-methyl imatinib and higher C ss . The GG and TG alleles of the SLCO1B3.334 T>G gene were significantly correlated to favorable response, while the wild allele TT was linked to unfavorable response ( P = 0.03). In conclusion, the trough and P/ T ratio for both IM and Pyridine-N-oxide imatinib, in addition to Polymorphism of ABCG2 SNPs 34 G>A and SLCO1B3.334 T>G gene, is a good predictor for response of IM in CML Egyptian patients.

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Section: Discussionsupporting

confidence: 90%

Association of the Trough, Peak/Trough Ratio of Imatinib, Pyridine–N-Oxide Imatinib and ABCG2 SNPs 34 G>A and SLCO1B3 334 T>G With Imatinib Response in Egyptian Chronic Myeloid Leukemia Patients

et al. 2020

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“…More recent clinical trials have indicated even higher survival rates, with a 10-year overall survival as high as 83.3% [ 200 ]. Imatinib mesylate (IM) is a highly efficient first-line therapy for the treatment of chronic myeloid leukaemia; however, resistance to this therapy has emerged as a serious clinical problem [ 201 ]. CYP3A4 is the chief enzyme involved in the first-pass metabolism of imatinib.…”

Section: The Impact Of Genetic Variations On Anticancer Treatment Eff...mentioning

confidence: 99%

Pharmacogenetics of Drugs Used in the Treatment of Cancers

Franczyk

Rysz

Gluba-Brzózka

2022

Genes

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Pharmacogenomics is based on the understanding of the individual differences in drug use, the response to drug therapy (efficacy and toxicity), and the mechanisms underlying variable drug responses. The identification of DNA variants which markedly contribute to inter-individual variations in drug responses would improve the efficacy of treatments and decrease the rate of the adverse side effects of drugs. This review focuses only on the impact of polymorphisms within drug-metabolizing enzymes on drug responses. Anticancer drugs usually have a very narrow therapeutic index; therefore, it is very important to use appropriate doses in order to achieve the maximum benefits without putting the patient at risk of life-threatening toxicities. However, the adjustment of the appropriate dose is not so easy, due to the inheritance of specific polymorphisms in the genes encoding the target proteins and drug-metabolizing enzymes. This review presents just a few examples of such polymorphisms and their impact on the response to therapy.

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P0223 CYP3A4∗18 and CYP3A5∗3 gene polymorphisms and imatinib resistance in Malaysian patients with chronic myeloid leukaemia

Cited by 2 publications

References 0 publications

Association of the Trough, Peak/Trough Ratio of Imatinib, Pyridine–N-Oxide Imatinib and ABCG2 SNPs 34 G>A and SLCO1B3 334 T>G With Imatinib Response in Egyptian Chronic Myeloid Leukemia Patients

Association of the Trough, Peak/Trough Ratio of Imatinib, Pyridine–N-Oxide Imatinib and ABCG2 SNPs 34 G>A and SLCO1B3 334 T>G With Imatinib Response in Egyptian Chronic Myeloid Leukemia Patients

Pharmacogenetics of Drugs Used in the Treatment of Cancers

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