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.
Publication types
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Clinical Trial
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Adult
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Aged
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Aged, 80 and over
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / adverse effects
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Antineoplastic Agents / pharmacokinetics*
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Benzamides
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Cohort Studies
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme System / genetics
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Cytochrome P-450 Enzyme System / metabolism
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Drug Monitoring
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Female
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Gastrointestinal Stromal Tumors / drug therapy
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Gastrointestinal Stromal Tumors / genetics
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Gastrointestinal Stromal Tumors / metabolism*
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Genotype
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Humans
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Imatinib Mesylate
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
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Male
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Metabolic Clearance Rate
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Middle Aged
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Organic Anion Transporters / antagonists & inhibitors
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Organic Anion Transporters / genetics*
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Organic Anion Transporters / metabolism
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Phenotype
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Piperazines / administration & dosage
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Piperazines / adverse effects
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Piperazines / pharmacokinetics*
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Polymorphism, Single Nucleotide*
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / adverse effects
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Protein Kinase Inhibitors / pharmacokinetics*
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Pyrimidines / administration & dosage
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Pyrimidines / adverse effects
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Pyrimidines / pharmacokinetics*
Substances
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ABCB1 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antineoplastic Agents
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Benzamides
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Organic Anion Transporters
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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Imatinib Mesylate
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Cytochrome P-450 Enzyme System
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CYP3A5 protein, human
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Cytochrome P-450 CYP3A