Ignite Creation Date:
2024-05-06 @ 10:27 AM
Last Modification Date:
2024-10-26 @ 12:30 PM
Study NCT ID:
NCT03262974
Status:
COMPLETED
Last Update Posted:
2023-10-27
First Post:
2017-08-24
Brief Title:
Effect of Pharmacogenetics on Imatinib Plasma Level and Response
Sponsor:
Assiut University
Organization:
Assiut University
Study Overview
Official Title:
Investigation of the Possible Role of Genetic Polymorphism in Certain Metabolizing Enzymes and Membrane Transporters on Both Plasma Level and Molecular Response of Imatinib in Patients With Chronic Myeloid Leukemia
Status:
COMPLETED
Status Verified Date:
2023-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 CYP3A53 rs776746 CYP2C83 rs11572080 and rs10509681 and membrane transporters ABCB1 2677GTA 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
The study aims to investigate the possible effect of genetic polymorphisms in certain metabolizing enzymes CYP3A53 rs776746 CYP2C83 rs11572080 and rs10509681 and membrane transporters ABCB1 2677GTA 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 100000 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 GTA 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 mutations 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 3000 rpm for 10 minutes at room temperature and will be stored at -20C 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 -80C until genotyping
Genotyping will be performed for CYP3A5 3 rs 776746 CYP2C8 3 rs 11572080 and rs 10509681 ABCB1 2677 GTA rs 2032582 and SLC22A1 1222 A G rs 628031 by the PCR
Chronic myeloid leukaemia CML is a myeloproliferative disease with an incidence of one to two cases per 100000 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 GTA 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 mutations 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 3000 rpm for 10 minutes at room temperature and will be stored at -20C 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 -80C until genotyping
Genotyping will be performed for CYP3A5 3 rs 776746 CYP2C8 3 rs 11572080 and rs 10509681 ABCB1 2677 GTA rs 2032582 and SLC22A1 1222 A G rs 628031 by the PCR
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None