Anti-CYP2D6 polyclonal antibody

This study was aimed to investigate the prevalence of CYP2C9*2 (p.430C > T, rs1799853), CYP2C9*3 (p.1075A > C, rs1057910), CYP4F2*3 (p.1297G > A, rs2108622), CYP2C19*2 (p.681G > A, rs4244285), CYP2C19*3 (p.636G > A, rs4986893), CYP2C19*17 (p.1260C > A, rs12248560), ABCB1 (p.3435C > T, rs1045642), CYP2D6*4 (p.1846G > A, rs3892097), SLCO1B1*5 (p.521T > C, rs4149056) and CES1 (p.1168-33A > C, rs2244613) among Tatars and Balkars ethnic groups living in Russia to provide a basis for future clinical studies concerning on understanding of population-level differences in drug response. The study involved 341 apparently healthy, unrelated, and chronic medication-free volunteers of both sexes of ethnic groups of Tatars and Balkars living in Volga and Caucasus regions of Russia. Genotyping was performed using real-time polymerase chain reaction-based methods. The allelic prevalence of studied markers in ethnic groups were compared with Russians as a largest ethnic group in Russia. Statistically significant differences for the following gene polymorphisms were found between both ethnic groups in respect of different markers and with Russians. Our study shows differences in prevalence of the main relevant pharmacogenetic markers in Tatars and Balkars. These findings should be taken into consideration for personalization algorithms development and pharmacogenetics implementation in regions with ethnic minorities as Russia has.

Background and Objective Ibrutinib is used for the treatment of chronic lymphocytic leukemia and other lymphoid malignancies. The aim of this work is to develop a population pharmacokinetic model for ibrutinib and its dihydrodiol metabolite to quantify pharmacokinetic inter- and intra-individual variability, to evaluate the impact of several covariates on ibrutinib pharmacokinetic parameters, and to examine the relationship between exposure and clinical outcome. Methods Patients treated with ibrutinib were included in the study and followed up for 2 years. Pharmacokinetic blood samples were taken from months 1 to 12 after inclusion. Ibrutinib and dihydrodiol-ibrutinib concentrations were assessed using ultra-performance liquid chromatography tandem mass spectrometry. A population pharmacokinetic model was developed using NONMEM version 7.4. Results A total of 89 patients and 1501 plasma concentrations were included in the pharmacokinetic analysis. The best model consisted in two compartments for each molecule. Absorption was described by a sequential zero first-order process and a lag time. Ibrutinib was either metabolised into dihydrodiol-ibrutinib or excreted through other elimination routes. A link between the dosing compartment and the dihydrodiol-ibrutinib central compartment was added to assess for high first-pass hepatic metabolism. Ibrutinib clearance had 67% and 47% inter- and intra-individual variability, respectively, while dihydrodiol-ibrutinib clearance had 51% and 26% inter- and intra-individual variability, respectively. Observed ibrutinib exposure is significantly higher in patients carrying one copy of the cytochrome P450 3A4*22 variant (1167 ng.h/mL vs 743 ng.h/mL, respectively, p = 0.024). However, no covariates with a clinically relevant effect on ibrutinib or dihydrodiol-ibrutinib exposure were identified in the PK model. An external evaluation of the model was performed. Clinical outcome was expressed as the continuation or discontinuation of ibrutinib therapy 1 year after treatment initiation. Patients who had treatment discontinuation because of toxicity had significantly higher ibrutinib area under the curve (p = 0.047). No association was found between cessation of therapy due to disease progression and ibrutinib area under the curve in patients with chronic lymphocytic leukemia. For the seven patients with mantle cell lymphoma studied, an association trend was observed between disease progression and low exposure to ibrutinib. Conclusions We present the first population pharmacokinetic model describing ibrutinib and dihydrodiol-ibrutinib concentrations simultaneously. Large inter-individual variability and substantial intra-individual variability were estimated and could not be explained by any covariate. Higher plasma exposure to ibrutinib is associated with cessation of therapy due to the occurrence of adverse events within the first year of treatment. The association between disease progression and ibrutinib exposure in patients with mantle cell lymphoma should be further investigated.