Role of ADME gene polymorphisms on imatinib disposition: results from a population pharmacokinetic study in chronic myeloid leukaemia

Shriyan, Bharati; Mehta, Padmaja; Patil, Anand; Jadhav, Shraddha; Kumar, Sharath; Puri, Apeksha S.; Govalkar, Ravina; Krishnamurthy, Manjunath Nookala; Punatar, Sachin; Gokarn, Anant; Khattry, Navin; Gota, Vikram

doi:10.1007/s00228-022-03345-8

Cited by 5 publications

(5 citation statements)

References 31 publications

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“…Certain SNPs identified using linear regression show a significantly suggestive association and belong to the same gene. As the haplotype is more informative than a single marker, we conducted a haplotypic association test using Haploview software V4.2 [ 16 ]. Four genes (NIPBL, TCTN2, BPGM, and EXOC6B) with at least two SNPs each were tested for haplotype association.…”

Section: Resultsmentioning

confidence: 99%

“…As already mentioned, very few studies have previously been performed to identify genetic variants potentially associated with ima[C]min. These studies were conducted on a small number of patients using the candidate-gene approach [ 16 , 17 , 18 , 19 ]. However, the candidate-gene approach presents several limitations: the choice of candidate genes may be inappropriate, the causative genes may be either upstream or downstream in signaling pathways, the selected SNPs may provide incomplete coverage of the gene, most studies were underpowered, and importantly, these studies relied on prior hypotheses, which precludes the discovery of genetic variants in previously unknown pathways.…”

Section: Discussionmentioning

confidence: 99%

“…We also did not find any SNPs that we and others had previously found to be associated with the molecular response [ 13 ], with the exception of CYP4F3, which was reported in 2004 but has never been retested [ 25 ]. Furthermore, recently published studies focusing on genes selected for their previously claimed pharmacological functions (such as CYP3A4, CYP3A5, ABCB1, ABCG2, and SCL22A1) have failed to demonstrate an association with imatinib clearance [ 16 ], whereas the hemoglobin concentration and estimated glomerular filtration rate did [ 18 ]. Thus, the question has been raised as to whether measuring plasma imatinib trough levels is an appropriate means to predict the response of CML patients [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…Although we and others have focused on DNA polymorphisms associated with the response to imatinib [ 13 , 14 , 15 ], very few genetic studies have been performed to explore associations between SNPs and imatinib plasma concentrations [ 16 , 17 , 18 , 19 ], with none in relation to RNA expression. Moreover, the SNP studies were limited to the candidate-gene approach, which has several limitations, such as a reliance on a priori hypotheses and frequent arbitrary choices, which have been largely detailed [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Constitutional DNA Polymorphisms Associated with the Plasma Imatinib Concentration in Chronic Myeloid Leukemia Patients

Bruzzoni-Giovanelli,

Zouali,

Sahbatou

et al. 2024

Pharmaceutics

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The tyrosine kinase Inhibitor (TKI) imatinib is approved for the treatment of the chronic phase of chronic myeloid leukemia (CP-CML). Pharmacokinetic studies have highlighted the importance of inter-patient variability on imatinib plasma trough concentrations (ima[C]min). In the OPTIM-imatinib trial, we demonstrated that therapeutic drug monitoring (TDM) is able to improve the molecular response of CP-CML patients treated with imatinib. Here, we analyzed the constitutional exomes and RNAseq data of these patients. We performed an association analysis between the constitutional genetic variants of the patients and their ima[C]min, measured after 12 weeks of treatment with 400 mg once daily. Using linear regression, we identified 50 SNPs that showed excess heterozygosity depending on the ima[C]min. Ten SNPs were from non-coding sequences, and among the 40 remaining, 30 (from 25 genes) could be split into two categories. The first group of 16 SNPs concerns genes encoding extracellular matrix, cell junction, and membrane proteins. Coincidentally, cell adhesion proteins were also identified by RNA-seq as being overexpressed in patients with high ima[C]min. The other group of 14 SNPs were from genes encoding proteins involved in transcription/translation. Although most of the SNPs are intronic variants (28), we also identified missense (3), synonymous (4), 5′/3′ (2), splicing (1), and upstream (4) variants. A haplotype analysis of four genes showed a significant association with high ima[C]min. None of the SNPs were significantly associated with the response. In conclusion, we identified a number of ima[C]min-associated SNPs, most of which correspond to genes encoding proteins that could play a role in the diffusion and transit of imatinib through membranes or epithelial barriers.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Constitutional DNA Polymorphisms Associated with the Plasma Imatinib Concentration in Chronic Myeloid Leukemia Patients

Bruzzoni-Giovanelli,

Zouali,

Sahbatou

et al. 2024

Pharmaceutics

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“…29 The connection between WBC and imatinib clearance was also investigated in this study; however, no such correlation was found in the population described in this study, which is consistent with the results obtained by Delbaldo et al and Shriyan et al, who both excluded WBC in the backward elimination process, although the latter was performed in a CML population. 24,31…”

Section: Discussionmentioning

confidence: 99%

Personalized Dose of Adjuvant Imatinib in Patients with Gastrointestinal Stromal Tumors: Results from a Population Pharmacokinetic Analysis

Jiang¹,

Fu²,

Jin³

et al. 2023

DDDT

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Imatinib is the first-line treatment for patients with gastrointestinal stromal tumors (GIST) after surgery. However, its pharmacokinetic profile varies remarkably between individuals and has not been well characterized in postoperative Chinese patients with GIST. Therefore, this study aimed to develop a population pharmacokinetic (PPK) model and recommend appropriate doses for different patients to achieve the target trough concentration in such a population. Patients and Methods: A total of 110 surgically treated GIST patients were enrolled, of which 85 were applied to conduct a PPK analysis with a nonlinear mixed-effect model and 25 for external validation of the model. Demographic and biomedical covariates, as well as six single nucleotide polymorphisms were tested to explore the sources of variation in pharmacokinetic parameters of imatinib. Monte Carlo simulations were performed to establish the initial dosing regimens. Results: A one-compartment model was established in postoperative GIST patients. The red blood cell count (RBC) and ABCG2 rs2231142 were observed to have a significant effect on the clearance of imatinib. The typical values estimated by the final model were 9.72 L/h for clearance (CL/F) and 229 L for volume of distribution (V/F). Different from the fixed dose regimen of 400 mg each day, patients carrying rs2231142 heterozygous type and with a lower level of RBC (2.9 × 10 12 /L), 300 mg imatinib daily is enough to achieve the target trough concentration. When RBC rises to 4.9 × 10 12 /L, 500 mg daily is recommended. For patients with rs2231142 GG genotype, 500 mg a day is required at RBCs of 3.9 × 10 12 /L and 4.9 × 10 12 /L. Conclusion: RBC and rs2231142 contribute to the pharmacokinetic variation of imatinib and personalized dose recommendations based on patient characteristics may be necessary.

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Population pharmacokinetics and pharmacogenetics analyses of imatinib in Chinese patients with chronic myeloid leukemia in a real-world situation

He,

Shao,

Zhao

et al. 2023

Cancer Chemother Pharmacol

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Role of ADME gene polymorphisms on imatinib disposition: results from a population pharmacokinetic study in chronic myeloid leukaemia

Cited by 5 publications

References 31 publications

Constitutional DNA Polymorphisms Associated with the Plasma Imatinib Concentration in Chronic Myeloid Leukemia Patients

Constitutional DNA Polymorphisms Associated with the Plasma Imatinib Concentration in Chronic Myeloid Leukemia Patients

Personalized Dose of Adjuvant Imatinib in Patients with Gastrointestinal Stromal Tumors: Results from a Population Pharmacokinetic Analysis

Population pharmacokinetics and pharmacogenetics analyses of imatinib in Chinese patients with chronic myeloid leukemia in a real-world situation

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