Effect of Pharmacogenetics on Imatinib Plasma Level and Response

NCT ID: NCT03262974

Last Updated: 2023-10-27

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 60 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2017-10-29
• Study Completion Date: 2023-10-01

Brief Summary

Imatinib, the tyrosine kinase inhibitor, is used for treatment of Philadelphia positive chronic myeloid leukemia. Despite its efficacy and favorable pharmacokinetic profile, there is a large inter-individual variability in imatinib plasma concentrations, which may lead to treatment failure and disease progression. Polymorphisms in genes related to absorption, distribution, metabolism and excretion of imatinib may affect the bioavailability and consequently the response to the drug.

The study aims to investigate the possible effect of genetic polymorphisms in certain metabolizing enzymes [CYP3A5*3 (rs776746), CYP2C8*3 (rs11572080 and rs10509681)] and membrane transporters [ABCB1 2677G>T/A (rs2032582) and SLC22A1 1222A > G (rs628031)] by PCR on the plasma level (by HPLC-UV) and molecular response (MMR) of imatinib in patients with CML.

The study also aims to provide CML patients with a personalized treatment option, thereby probably improving the response and reducing the side effects.

Detailed Description

Introduction:

Chronic myeloid leukaemia (CML) is a myeloproliferative disease with an incidence of one to two cases per 100,000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults.

The introduction of imatinib, the tyrosine kinase inhibitor (TKI), in the early 21st century is considered a breakthrough in the treatment of CML. In the vast majority of patients, treatment with imatinib induces cytogenetic and even molecular responses with very low or undetectable BCR-ABL1 transcript levels. These patients remain free from progression to blast crisis. However, imatinib does not cure the disease because it is unable to eradicate the leukaemic stem cells, which therefore provides a potential reservoir for relapse.

Despite its efficacy and favorable pharmacokinetic profile, there is a large inter-individual variability in imatinib plasma concentrations, which may lead to treatment failure and disease progression.

Polymorphisms in genes related to absorption, distribution, metabolism and excretion of imatinib may affect the bioavailability and consequently the response to the drug.

Aim of the study:

The study aims to investigate the possible effect of genetic polymorphisms in certain metabolizing enzymes [CYP3A5 * 3 (rs 776746), CYP2C8 * 3 (rs 11572080 and rs 10509681)] and membrane transporters [ABCB1 2677 G>T/A (rs 2032582) and SLC22A1 1222 A > G (rs 628031)] on the plasma level and molecular response (MMR) of imatinib in patients with CML.

These polymorphisms were selected based on their relevance to the pharmacokinetics of imatinib and on their frequency in Caucasians.

The study also aims to provide CML patients with a personalized treatment option, thereby probably improving the response and reducing the side effects.

Patients and methods:

Patients:

The study will include patients with documented hematological, cytogenetic and molecular diagnosis of chronic phase CML, who are on continuous treatment with 400 mg oral dose of imatinib per day for at least 12 month at Medical Oncology Department, South Egypt Cancer Institute (SECI), Assiut. Egypt.

Exclusion criteria are: duration of imatinib therapy less than 12 months, poor compliance to treatment and identification of gene mutation(s) in the kinase domain of BCR- ABL1.

The patients will be divided into 2 groups according to their molecular response to imatinib as follow:

Group I: CML patients with MMR Group II: CML patients without MMR Patients in both groups will be compared as regard the plasma level of imatinib and the selected genetic polymorphisms.

Methods:

Blood sampling:

Three blood samples (3 ml for each) will be collected into EDTA-containing tubes by venipuncture for measurement of imatinib plasma level, measurement of BCR- ABL1 transcription level and for genotyping.

Measurement of Imatinib trough level:

Blood samples will be collected after 24 hours from the previous dose (trough) and after at least 5 days of regular use of the drug to ensure that the steady state is reached. Within 1 hour of collection, the blood samples will be centrifuged at 3,000 rpm for 10 minutes at room temperature and will be stored at -20°C until analysis.

Plasma level of imatinib will be measured by high-performance liquid chromatography with ultraviolet detection (HPLC-UV) according to the method described by Barratt et al.

Measurement of BCR- ABL1 transcription level:

Total RNA will be extracted from peripheral blood leucocytes by the available RNA extraction kits. The BCR- ABL1 transcription level will be quantified by using real-time polymerase chain reaction (PCR) analysis to assess the molecular response to imatinib after 12 months of treatment with imatinib.

Genotyping:

The DNA will be extracted from leukocytes by the available DNA extraction kits and will be stored at -80°C until genotyping.

Genotyping will be performed for CYP3A5 * 3 (rs 776746), CYP2C8 * 3 (rs 11572080 and rs 10509681), ABCB1 2677 G>T/A (rs 2032582) and SLC22A1 1222 A > G (rs 628031) by the PCR

Conditions

Chronic Myeloid Leukemia

Study Design

• Observational Model Type: OTHER
• Study Time Perspective: RETROSPECTIVE

Study Groups

CML patients with MMR

CYP3A5\*3 , CYP2C8\*3 , ABCG2 421 C\>A and SLC22A1 1222A \> G SNPs on the plasma level by HPLC-UV and molecular response of imatinib by PCR

PCR

Intervention Type: DIAGNOSTIC_TEST

PCR

HPLC-UV

Intervention Type: DIAGNOSTIC_TEST

HPLC-UV

CML patients without MMR

CYP3A5\*3 , CYP2C8\*3 , ABCG2 421 C\>A and SLC22A1 1222A \> G SNPs on the plasma level by HPLC-UV and molecular response of imatinib by PCR

PCR

Intervention Type: DIAGNOSTIC_TEST

PCR

HPLC-UV

Intervention Type: DIAGNOSTIC_TEST

HPLC-UV

Interventions

PCR

PCR

Intervention Type: DIAGNOSTIC_TEST

HPLC-UV

HPLC-UV

Intervention Type: DIAGNOSTIC_TEST

Eligibility Criteria

Inclusion Criteria

• Documented hematological, cytogenetic and molecular diagnosis of Philadelphia positive CML
• Imatinib treatment for at least 12 months

Exclusion Criteria

• Poor compliance to treatment
• identification of gene mutation(s) in the kinase domain of BCR- ABL1.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assiut University

OTHER

Sponsor Role: lead

Responsible Party

Mohammed Sayed Molla

Assistant lecturer

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Safwat Mangoura

Role: STUDY_CHAIR

Pharmacology department, Faculty of Medicine, Assiut University

Locations

South Egypt Cancer Institute

Asyut, , Egypt

Countries

Egypt

Other Identifiers

Imatinib Pharmacogenetics

Identifier Type: -

Identifier Source: org_study_id