INFLUENCE OF CYP1A2, CYP3A5 AND CYP2C19 POLYMORPHISMS ON IMATINIB MESYLATE DRUG RESPONSES IN THREE MAJOR ASIAN ETHNIC GROUPS AND VARIATION OF IM AND ACTIVE METABOLITE (M1) TROUGH LEVEL AMONG CHRONIC MYELOID LEUKEMIA PATIENTS

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Abstract

Introduction

Imatinib mesylate (IM) is the first-line treatment and gold standard for treatment of chronic myeloid leukemia (CML). Pharmacokinetic profile of IM and its active metabolite, N-desmethylimatinib (M1) in CML patients are clinically important.

Objectives

This study aimed to determine the influence of CYP1A2, CYP3A5 and CYP2C19 polymorphisms on the drug response of IM in Asian CML. We also aimed to determine the pharmacokinetic profile for both IM and M1 in CML patients with prescription 400 mg PO.

Methodology

A total of 250 healthy volunteers (controls) and 50 CML patients (cases) receiving IM were enrolled in a prospective pharmacogenetic study. CYP1A2, CYP3A5 and CYP2C19 polymorphisms were genotyped in both control and case groups using PCR-RFLP. In the pharmacokinetic study, serum IM and M1 concentrations were measured using the validated ultra-high performance liquid chromatography method on first three CML patients with 400 mg IM PO. The χ2 test was used to correlate CYP1A2, CYP3A5 and CYP2C19 genotypes to good responder and resistant group.

Results

The genotype frequencies of CYP1A2, CYP3A5 and CYP2C19 SNP will be discussed in Malays, Chinese and Indians. In the pharmacokinetic study, we observed high standard deviation (>20% of mean) in volume of distributions (Vd), clearance (CL) and area under curve (AUC) for both IM and M1. For IM, Vd = 113.32 ± 43.52 l, CL = 5.01 ± 1.19 l h−1 and AUC = 62 953.33 ± 9791.38 ng h l−1, whereas for M1, Vd = 415.27 ± 228.72 l, CL = 4.84 ± 3.85 l h−1 and AUC = 5585.15 ± 2950.42 ng h l−1. This preliminary study suggested a high interindividual pharmacokinetic variability in Malaysian CML patients. M1 concentration during steady state (C0) and its time concentration profile were different as per reported in Caucasian population. It suggested that Asians may have a different IM metabolism profile from Caucasians.

Summary

In short, the preliminary pharmacokinetic data highlighted the potential differences of metabolism profile between Asian and Caucasian. Future validation in a larger sample size is ongoing.

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