Imatinib disposition and ABCB1 (MDR1, P-glycoprotein) genotype

H. Gurney; M. Wong; R. L. Balleine; L. P. Rivory; A. J. McLachlan; J. M. Hoskins; N. Wilcken; C. L. Clarke; G. J. Mann; M. Collins; S. E. Delforce; K. Lynch; H. Schran

doi:10.1038/sj.clpt.6100201

Imatinib disposition and ABCB1 (MDR1, P-glycoprotein) genotype

H. Gurney^*, M. Wong, R. L. Balleine, L. P. Rivory, A. J. McLachlan, J. M. Hoskins, N. Wilcken, C. L. Clarke, G. J. Mann, M. Collins, S. E. Delforce, K. Lynch, H. Schran

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

The aim of this study was to explore the impact of individual variation in drug elimination on imatinib disposition. Twenty-two patients with gastrointestinal stromal tumor or chronic myeloid leukemia initially received imatinib 600 mg daily with dosage subsequently toxicity adjusted. Pharmacokinetic parameters on day 1 and at steady-state were compared with elimination phenotype and single-nucleotide polymorphisms of CYP3A5 and ABCB1. A fivefold variation in estimated imatinib clearance (CL/F) was present on day 1 and mean CL/F had fallen by 26% at steady state. This reduction in imatinib CL/F was associated with ABCB1 genotype, being least apparent in thymidine homozygotes at the 1236T>C, 2677G>T/A and 3435C>T loci. Toxicity-related dose reduction also tended to be less common in these individuals. ABCB1 genotype was associated with steady-state CL/F due to an apparent genotype-specific influence of imatinib on elimination. Further evaluation of ABCB1 genotype and imatinib dosage is warranted.

Original language	English
Pages (from-to)	33-40
Number of pages	8
Journal	Clinical Pharmacology and Therapeutics
Volume	82
Issue number	1
DOIs	https://doi.org/10.1038/sj.clpt.6100201
Publication status	Published - 14 Jul 2007
Externally published	Yes

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title = "Imatinib disposition and ABCB1 (MDR1, P-glycoprotein) genotype",

abstract = "The aim of this study was to explore the impact of individual variation in drug elimination on imatinib disposition. Twenty-two patients with gastrointestinal stromal tumor or chronic myeloid leukemia initially received imatinib 600 mg daily with dosage subsequently toxicity adjusted. Pharmacokinetic parameters on day 1 and at steady-state were compared with elimination phenotype and single-nucleotide polymorphisms of CYP3A5 and ABCB1. A fivefold variation in estimated imatinib clearance (CL/F) was present on day 1 and mean CL/F had fallen by 26% at steady state. This reduction in imatinib CL/F was associated with ABCB1 genotype, being least apparent in thymidine homozygotes at the 1236T>C, 2677G>T/A and 3435C>T loci. Toxicity-related dose reduction also tended to be less common in these individuals. ABCB1 genotype was associated with steady-state CL/F due to an apparent genotype-specific influence of imatinib on elimination. Further evaluation of ABCB1 genotype and imatinib dosage is warranted.",

author = "H. Gurney and M. Wong and Balleine, {R. L.} and Rivory, {L. P.} and McLachlan, {A. J.} and Hoskins, {J. M.} and N. Wilcken and Clarke, {C. L.} and Mann, {G. J.} and M. Collins and Delforce, {S. E.} and K. Lynch and H. Schran",

year = "2007",

month = jul,

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doi = "10.1038/sj.clpt.6100201",

language = "English",

volume = "82",

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journal = "Clinical Pharmacology and Therapeutics",

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T1 - Imatinib disposition and ABCB1 (MDR1, P-glycoprotein) genotype

AU - Gurney, H.

AU - Wong, M.

AU - Balleine, R. L.

AU - Rivory, L. P.

AU - McLachlan, A. J.

AU - Hoskins, J. M.

AU - Wilcken, N.

AU - Clarke, C. L.

AU - Mann, G. J.

AU - Collins, M.

AU - Delforce, S. E.

AU - Lynch, K.

AU - Schran, H.

PY - 2007/7/14

Y1 - 2007/7/14

N2 - The aim of this study was to explore the impact of individual variation in drug elimination on imatinib disposition. Twenty-two patients with gastrointestinal stromal tumor or chronic myeloid leukemia initially received imatinib 600 mg daily with dosage subsequently toxicity adjusted. Pharmacokinetic parameters on day 1 and at steady-state were compared with elimination phenotype and single-nucleotide polymorphisms of CYP3A5 and ABCB1. A fivefold variation in estimated imatinib clearance (CL/F) was present on day 1 and mean CL/F had fallen by 26% at steady state. This reduction in imatinib CL/F was associated with ABCB1 genotype, being least apparent in thymidine homozygotes at the 1236T>C, 2677G>T/A and 3435C>T loci. Toxicity-related dose reduction also tended to be less common in these individuals. ABCB1 genotype was associated with steady-state CL/F due to an apparent genotype-specific influence of imatinib on elimination. Further evaluation of ABCB1 genotype and imatinib dosage is warranted.

AB - The aim of this study was to explore the impact of individual variation in drug elimination on imatinib disposition. Twenty-two patients with gastrointestinal stromal tumor or chronic myeloid leukemia initially received imatinib 600 mg daily with dosage subsequently toxicity adjusted. Pharmacokinetic parameters on day 1 and at steady-state were compared with elimination phenotype and single-nucleotide polymorphisms of CYP3A5 and ABCB1. A fivefold variation in estimated imatinib clearance (CL/F) was present on day 1 and mean CL/F had fallen by 26% at steady state. This reduction in imatinib CL/F was associated with ABCB1 genotype, being least apparent in thymidine homozygotes at the 1236T>C, 2677G>T/A and 3435C>T loci. Toxicity-related dose reduction also tended to be less common in these individuals. ABCB1 genotype was associated with steady-state CL/F due to an apparent genotype-specific influence of imatinib on elimination. Further evaluation of ABCB1 genotype and imatinib dosage is warranted.

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DO - 10.1038/sj.clpt.6100201

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AN - SCOPUS:34250676807

SN - 0009-9236

VL - 82

SP - 33

EP - 40

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

IS - 1

ER -

Imatinib disposition and ABCB1 (MDR1, P-glycoprotein) genotype

Abstract

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