TORNA ALL’ELENCO

Single-nucleotide polymorphisms of ABCB1 gene influence intracellular concentrations of Dasatinib in Blood

2012
AOU San Luigi di Orbassano

Tipo pubblicazione

Conference Abstract

Autori/Collaboratori (9)Vedi tutti...

D'Avolio A

De Francia S

Ariaudo A


et alii...

Abstract

Background: Use of BCR-ABL TKIs (Tyrosine-Kinase inhibitors) is the standard therapy for chronic myeloid leukemia. Dasatinib at the dosage of 100 mg once daily (QD) has been registered as first-line treatment for chronic phase chronic myeloid leukemia (CML) because it has been shown to be able to elicit faster and deeper cytogenetic and molecular responses than imatinib 400 QD, preventing also some events of progression to advanced phases of the disease, that can still occur during the first 2-3 years of treatment with TKIs. This is likely to be related to the strength of BCR-ABL in inhibiting the BCR-ABL TK activity and to its capacity to inhibit many of the BCR-ABL mutant forms than can escape inhibition by imatinib. However, very little is at present known about the relationship existing between the plasma level of dasatinib and its intracellular concentration, as well as about the factors that can influence drug intracellular penetration. This could help in understanding the relationship existing between drug level and its effectiveness in individual patients, as well as it may potentially help to modulate drug level by dose adjustment, useful to prevent toxicity and unwanted side-effects that could limit the efficacy of this drug in CML treatment. Aim of our study were to perform quantification of dasatinib in human peripheral blood mononuclear cells (PBMC) and evaluated whether single-nucleotide polymorphisms (SNPs) in ABCB1 gene may work as predictors of dasatinib exposure. Materials and Methods: Patients administered with dasatinib since at least 1 month were considered in the study. Sampling was performed after written informed consent was obtained in accordance with local ethics committee indications. Main inclusion criteria were, no concomitant interacting drugs, no hepatic or renal function impairment, self-reported adherence > 95%. Dasatinib PBMC and plasma Ctrough was measured in samples by a validated High Pressure Liquid Chromatography tandem

Keywords

real time polymerase chain reaction; methodology; blood level; statistical analysis; allele; exposure; side effect; gender; chronic myeloid leukemia; weight; toxicity; mutation; genotype; homozygote; peripheral blood mononuclear cell; therapy; patient; human; hematology; society; gene; single nucleotide polymorphism; protein tyrosine kinase inhibitor; imatinib; dasatinib; high performance liquid chromatography; plasma; mutant; kidney function; professional standard; informed consent; sampling; statistical significance; heterozygote; wild type; blood;