CYP2C8 Genotype Significantly Alters Imatinib Metabolism in Chronic Myeloid Leukaemia Patients

Daniel T Barratt; Hannah K Cox; Andrew Menelaou; David T Yeung; Deborah L White; Timothy P Hughes; Andrew A Somogyi

doi:10.1007/s40262-016-0494-0

CYP2C8 Genotype Significantly Alters Imatinib Metabolism in Chronic Myeloid Leukaemia Patients

Clin Pharmacokinet. 2017 Aug;56(8):977-985. doi: 10.1007/s40262-016-0494-0.

Authors

Daniel T Barratt^{1

2}, Hannah K Cox³, Andrew Menelaou⁴, David T Yeung^{4

5

6}, Deborah L White^{4

6}, Timothy P Hughes^{4

5

6}, Andrew A Somogyi^{3

7

8}

Affiliations

¹ Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, Adelaide, SA, 5005, Australia. [email protected].
² Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia. [email protected].
³ Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, Adelaide, SA, 5005, Australia.
⁴ South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
⁵ Department of Haematology, SA Pathology, Adelaide, SA, Australia.
⁶ Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
⁷ Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia.
⁸ Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, SA, Australia.

PMID: 27995529
DOI: 10.1007/s40262-016-0494-0

Abstract

Objective: The aims of this study were to determine the effects of the CYP2C8*3 and *4 polymorphisms on imatinib metabolism and plasma imatinib concentrations in chronic myeloid leukaemia (CML) patients.

Methods: We genotyped 210 CML patients from the TIDELII trial receiving imatinib 400-800 mg/day for CYP2C8*3 (rs11572080, rs10509681) and *4 (rs1058930). Steady-state trough total plasma N-desmethyl imatinib (major metabolite):imatinib concentration ratios (metabolic ratios) and trough total plasma imatinib concentrations were compared between genotypes (one-way ANOVA with Tukey post hoc).

Results: CYP2C8*3 (n = 34) and *4 (n = 15) carriers had significantly higher (P < 0.01) and lower (P < 0.01) metabolic ratios, respectively, than CYP2C8*1/*1 (n = 147) patients (median ± standard deviation: 0.28 ± 0.08, 0.18 ± 0.06 and 0.22 ± 0.08, respectively). Plasma imatinib concentrations were consequently > 50% higher for CYP2C8*1/*4 than for CYP2C8*1/*1 and CYP2C8*3 carriers (2.18 ± 0.66 vs. 1.45 ± 0.74 [P < 0.05] and 1.36 ± 0.98 μg/mL [P < 0.05], respectively).

Conclusions: CYP2C8 genotype significantly alters imatinib metabolism in patients through gain- and loss-of-function mechanisms.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Clinical Trials, Phase II as Topic
Cytochrome P-450 CYP2C8 / drug effects
Cytochrome P-450 CYP2C8 / genetics*
Cytochrome P-450 CYP2C8 / metabolism
Female
Genotype
Humans
Imatinib Mesylate / administration & dosage
Imatinib Mesylate / blood
Imatinib Mesylate / metabolism
Imatinib Mesylate / pharmacokinetics*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
Male
Middle Aged
Pharmacogenetics / methods
Polymorphism, Genetic
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / blood
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacokinetics*
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / genetics

Substances

Protein Kinase Inhibitors
Imatinib Mesylate
CYP2C8 protein, human
Cytochrome P-450 CYP2C8
Receptor Protein-Tyrosine Kinases