Pharmacogenetics of Drug Transporters in Modulating Imatinib Disposition and Treatment Outcomes in Chronic Myeloid Leukemia &amp; Gastrointestinal Stromal Tumor Patients

Chen, Sylvia; Sutiman, Natalia; Chowbay, Balram

doi:10.2217/pgs-2016-0124

Cited by 4 publications

(3 citation statements)

References 59 publications

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“…The impact of the ABCB1 genotype on imatinib disposition and pharmacokinetics showed conflicting results in the published literature, leaving plenty of room for further devoted investigations [ 10 ]. It is also worth considering that P-gP is a common player in drug–drug interactions [ 27 , 32 ], and that its expression can be modulated by the concurrent intake of P-gP inducer or inhibitor agents.…”

Section: Discussionmentioning

confidence: 99%

“…Several clinical investigations have highlighted the association between ABCB1 / ABCG2 polymorphisms and the efficacy of imatinib in both CML and GIST [ 10 ]. To what extent ABCB1 / ABCG2 polymorphisms contribute to the inter-individual variability in treatment efficacy by specifically affecting the imatinib pharmacokinetics has not been clarified.…”

Section: Introductionmentioning

confidence: 99%

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Impact of ABCG2 and ABCB1 Polymorphisms on Imatinib Plasmatic Exposure: An Original Work and Meta-Analysis

Fratte

Polesel

Gagno

et al. 2023

IJMS

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Adequate imatinib plasma levels are necessary to guarantee an efficacious and safe treatment in gastrointestinal stromal tumor (GIST) and chronic myeloid leukemia (CML) patients. Imatinib is a substrate of the drug transporters ATP-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily G member 2 (ABCG2) that can affect its plasma concentration. In the present study, the association between three genetic polymorphisms in ABCB1 (rs1045642, rs2032582, rs1128503) and one in ABCG2 (rs2231142) and the imatinib plasma trough concentration (Ctrough) was investigated in 33 GIST patients enrolled in a prospective clinical trial. The results of the study were meta-analyzed with those of other seven studies (including a total of 649 patients) selected from the literature through a systematic review process. The ABCG2 c.421C>A genotype demonstrated, in our cohort of patients, a borderline association with imatinib plasma trough levels that became significant in the meta-analysis. Specifically, homozygous carriers of the ABCG2 c.421 A allele showed higher imatinib plasma Ctrough with respect to the CC/CA carriers (Ctrough, 1463.2 ng/mL AA, vs. 1196.6 ng/mL CC + AC, p = 0.04) in 293 patients eligible for the evaluation of this polymorphism in the meta-analysis. The results remained significant under the additive model. No significant association could be described between ABCB1 polymorphisms and imatinib Ctrough, neither in our cohort nor in the meta-analysis. In conclusion, our results and the available literature studies sustain an association between ABCG2 c.421C>A and imatinib plasma Ctrough in GIST and CML patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Impact of ABCG2 and ABCB1 Polymorphisms on Imatinib Plasmatic Exposure: An Original Work and Meta-Analysis

Fratte

Polesel

Gagno

et al. 2023

IJMS

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“…Imatinib is metabolized in the liver by CYP3A5, CYP3A4 and CYP2A8 to its predominant metabolite N-desmethyl-imatinib [27]. In Malaysian patients, heterozygous (AG) and homozygous variant (GG) genotype of CYP3A5*3 were significantly associated with low risk of imatinib resistance [28].…”

Section: Impact Of Cytochrome P450 On Clinical Outcomesmentioning

confidence: 99%

Pharmacology of tyrosine kinase inhibitors in chronic myeloid leukemia; a clinician’s perspective

Pushpam

Bakhshi

2020

DARU J Pharm Sci

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Objective In this review, we have summarized the pharmacokinetics, pharmacodynamics and adverse effects of imatinib, dasatinib, nilotinib, bosutinib, ponatinib and radotinib with focus on pharmacogenomic studies with clinical end points. We have discussed the key phase 3 trials of tyrosine kinase inhibitors (TKI) comparing with each other, treatment free remission (TFR) and selection of TKI. Upcoming concepts and related trials in the management of chronic myeloid leukemia (CML) along with future directions have been touched upon. Evidence acquisition PubMed, Embase, Google, Cochrane library and Medline were searched to identify relevant literature for the review. Clinicaltrial.gov was searched for upcoming data and trials. Results There are lot of gap in pharmacokinetics and pharmacodynamics of TKI. Imatinib appears to be the safest TKI. Newer TKI's achieve better achievement of therapeutic milestones, deeper molecular response and less chances of progression of CML compared to imatinib. Newer TKI appears to be better choice for achieving TFR. When the objective is survival, imatinib is still the TKI of choice. Primary prophylaxis with antiplatelet drugs for TKI having cardiovascular and thromboembolic side effects should be considered. Conclusion Pharmacogenetic data of TKI is still immature to guide in therapeutic decision making in clinical practice. There is need for further research in pharmacology and pharmacogenomics of newer TKI's. Randomized controlled trials are required to decide the optimum TKI for TFR. Safe and effective TKI for targeting T315I mutation, CML accelerated phase and blast crisis are an active area of research.

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Impact of SLC22A1 and CYP3A5 genotypes on imatinib response in chronic myeloid leukemia: A systematic review and meta-analysis

Cargnin

Ravegnini

Soverini

et al. 2018

Pharmacological Research

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Pharmacogenetics of Drug Transporters in Modulating Imatinib Disposition and Treatment Outcomes in Chronic Myeloid Leukemia & Gastrointestinal Stromal Tumor Patients

Cited by 4 publications

References 59 publications

Impact of ABCG2 and ABCB1 Polymorphisms on Imatinib Plasmatic Exposure: An Original Work and Meta-Analysis

Impact of ABCG2 and ABCB1 Polymorphisms on Imatinib Plasmatic Exposure: An Original Work and Meta-Analysis

Pharmacology of tyrosine kinase inhibitors in chronic myeloid leukemia; a clinician’s perspective

Impact of SLC22A1 and CYP3A5 genotypes on imatinib response in chronic myeloid leukemia: A systematic review and meta-analysis

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