Dataset Information

Effects of NR1I2 and ABCB1 Genetic Polymorphisms on Everolimus Pharmacokinetics in Japanese Renal Transplant Patients.

ABSTRACT: The purpose of this study was to evaluate the effects of NR1I2 (7635G>A and 8055C>T) and ABCB1 (1236C>T, 2677G>T/A, and 3435C>T) genetic polymorphisms on everolimus pharmacokinetics in 98 Japanese renal transplant patients. On day 15 after everolimus administration, blood samples were collected just prior to and 1, 2, 3, 4, 6, 9, and 12 h after administration. The dose-adjusted area under the blood concentration−time curve (AUC0-12) of everolimus was significantly lower in patients with the NR1I2 8055C/C genotype than in those with other genotypes (p = 0.022) and was significantly higher in male patients than female patients (p = 0.045). Significant correlations between the dose-adjusted AUC0-12 of everolimus and age (p = 0.001), aspartate transaminase (p = 0.001), and alanine transaminase (p = 0.005) were found. In multivariate analysis, aging (p = 0.008) and higher alanine transaminase levels (p = 0.032) were independently predictive of a higher dose-adjusted everolimus AUC0-12. Aging and hepatic dysfunction in patients may need to be considered when evaluating dose reductions in everolimus. In renal transplant patients, management using everolimus blood concentrations after administration may be more important than analysis of NR1I2 8055C>T polymorphism before administration.

SUBMITTER: Yagishita H

PROVIDER: S-EPMC9570057 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Effects of <i>NR1I2</i> and <i>ABCB1</i> Genetic Polymorphisms on Everolimus Pharmacokinetics in Japanese Renal Transplant Patients.

Yagishita Hironobu H Kagaya Hideaki H Saito Mitsuru M Numakura Kazuyuki K Yamamoto Ryohei R Sagehashi Ryuichiro R Habuchi Tomonori T Satoh Shigeru S Miura Masatomo M

International journal of molecular sciences 20221003 19

The purpose of this study was to evaluate the effects of NR1I2 (7635G>A and 8055C>T) and ABCB1 (1236C>T, 2677G>T/A, and 3435C>T) genetic polymorphisms on everolimus pharmacokinetics in 98 Japanese renal transplant patients. On day 15 after everolimus administration, blood samples were collected just prior to and 1, 2, 3, 4, 6, 9, and 12 h after administration. The dose-adjusted area under the blood concentration−time curve (AUC0-12) of everolimus was significantly lower in patients with the NR1I ...[more]

PMID: 36233042

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Project description:Affected by differences in the pharmacokinetics (PK) of lenalidomide, the toxicity of lenalidomide varies among different patients, with serious toxicity leading to dose reduction or discontinuation. The differences in the PK of lenalidomide may be related to factors such as patients' physiological characteristics, pathological characteristics and gene polymorphisms etc., which may also affect its toxicity. The aim of this study is to establish a population pharmacokinetic (PPK) model of lenalidomide and explore factors associated with the adverse events (AEs) of lenalidomide from a PK perspective. Blood samples were collected by opportunistic blood collection. Drug concentrations were determined by using HPLC/MS and genotype of ABCB1 3435 C > T (rs1045642), ABCB1 1236 A > G (rs1128503) and ABCB1 2677 A > C/T (rs2032582) was tested by the first-generation DNA sequencing technology. NONMEM software and SPSS 26.0 software were used respectively to establish PPK model of lenalidomide and explore the correlation between PK parameters and the incidence of serious AEs of lenalidomide. 51 patients were enrolled in the PPK study, and one-compartment model with first-order absorption and elimination agreed well with the observed data. The significant covariate affecting lenalidomide apparent volume of distribution (V/F) were the gene polymorphism of ABCB1 3435 C > T and diet. Safety studies could be conducted in 39 patients. The V/F value in patients suffering from serious AEs was significantly higher than that in others ( median = 67.04 L vs 37.17 L, P = 0.033). According to the covariates screened, the incidence of serious AEs was higher in patients with genotype CT or TT at ABCB1 3435 C > T locus than that in patients with genotype CC (P = 0.039). Additionally, V/F value was the highest in patients carrying genotype TT with postprandial medication, in whom the incidence of serious AEs was higher than others (P = 0.037). In conclusion, the genotype of ABCB1 3435 C > T locus and diet had pharmacokinetically relevant impact on lenalidomide, which may also be related to the incidence of serious AEs. Patients with gene variants of CT or TT at ABCB1 3435 C > T locus may be more susceptible to serious AEs, and monitoring of adverse reactions should be particularly strengthened in patients who carried genotype TT with postprandial medication.

Project description:Background and objectiveThe association between the CYP3A4*1B single nucleotide polymorphism (SNP) and tacrolimus pharmacokinetics in different studies is controversial. Therefore, a meta-analysis was employed to evaluate the correlation between the CYP3A4*1B genetic polymorphism and tacrolimus pharmacokinetics at different post-transplantation times in adult renal transplant recipients.MethodsStudies evaluating the CYP3A4*1B genetic polymorphism and tacrolimus pharmacokinetics were retrieved through a systematical search of Embase, PubMed, the Cochrane Library, ClinicalTrials.gov and three Chinese literature databases (up to Sept. 2014). The pharmacokinetic parameters (weight-adjusted tacrolimus daily dose and tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio) were extracted, and the meta-analysis was performed using Stata 12.1.ResultsSeven studies (involving 1182 adult renal transplant recipients) were included in this meta-analysis. For the weight-adjusted tacrolimus daily dose, in all included renal transplant recipients (European & Indian populations), CYP3A4*1/*1 recipients required a significantly lower weight-adjusted tacrolimus daily dose than did CYP3A4*1B carriers at 7 days (WMD -0.048; 95% CI -0.083 ~ -0.014), 6 months (WMD -0.058; 95% CI -0.081 ~ -0.036) and 12 months (WMD - 0.061; 95% CI -0.096 ~ -0.027) post-transplantation. In light of the heterogeneity, the analysis was repeated after removing the only study in an Indian population, and CYP3A4*1/*1 European recipients (mostly Caucasian) required a lower weight-adjusted tacrolimus daily dose within the first year post-transplantation. The tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio (C0/Dose ratio) was significantly higher in CYP3A4*1/*1 recipients than in CYP3A4*1B carriers at 6 months (WMD 52.588; 95% CI 22.387 ~ 82.789) and 12 months (WMD 62.219; 95% CI 14.218 ~ 110.221) post-transplantation. When the only study in an Indian population was removed to examine European recipients (mostly Caucasian), the significant difference persisted at 1 month, 6 months and 12 months post-transplantation.ConclusionBased on our meta-analysis, the CYP3A4*1B genetic polymorphism affects tacrolimus dose requirements and tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio within the first year post-transplantation in adult renal transplant recipients, especially in European recipients (mostly Caucasian).

Dataset Information

Effects of NR1I2 and ABCB1 Genetic Polymorphisms on Everolimus Pharmacokinetics in Japanese Renal Transplant Patients.

Publications

Effects of <i>NR1I2</i> and <i>ABCB1</i> Genetic Polymorphisms on Everolimus Pharmacokinetics in Japanese Renal Transplant Patients.

Similar Datasets

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