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Comparative performance of oral midazolam clearance and plasma 4?-hydroxycholesterol to explain interindividual variability in tacrolimus clearance.

ABSTRACT: AIMS:We compared the CYP3A4 metrics weight-corrected midazolam apparent oral clearance (MDZ Cl/F/W) and plasma 4?-hydroxycholesterol/cholesterol (4?-OHC/C) as they relate to tacrolimus (TAC) Cl/F/W in renal transplant recipients. METHODS:For a cohort of 147 patients, 8 h area under the curve (AUC) values for TAC and oral MDZ were calculated besides measurement of 4?-OHC/C. A subgroup of 70 patients additionally underwent intravenous erythromycin breath test (EBT) and were administered the intravenous MDZ probe. All patients were genotyped for common polymorphisms in CYP3A4, CYP3A5 and P450 oxidoreductase, among others. RESULTS:MDZ Cl/F/W, 4?-OHC/C/W, EBT and TAC Cl/F/W were all moderately correlated (r = 0.262-0.505). Neither MDZ Cl/F/W nor 4?-OHC/C/W explained variability in TAC Cl/F/W in CYP3A5 expressors (n = 29). For CYP3A5 non-expressors (n = 118), factors explaining variability in TAC Cl/F/W in a MDZ-based model were MDZ Cl/F/W (R2 = 0.201), haematocrit (R2 = 0.139), TAC formulation (R2 = 0.107) and age (R2 = 0.032; total R2 = 0.479). In the 4?-OHC/C/W-based model, predictors were 4?-OHC/C/W (R2 = 0.196), haematocrit (R2 = 0.059) and age (R2 = 0.057; total R2 = 0.312). When genotype information was ignored, predictors of TAC Cl/F/W in the whole cohort were 4?-OHC/C/W (R2 = 0.167), MDZ Cl/F/W (R2 = 0.045); Tac QD formulation (R2 = 0.036), and haematocrit (R2 = 0.032; total R2 = 0.315). 4?-OHC/C/W, but not MDZ Cl/F/W, was higher in CYP3A5 expressors because it was higher in CYP3A4*1b carriers, which were almost all CYP3A5 expressors. CONCLUSIONS:A MDZ-based model explained more variability in TAC clearance in CYP3A5 non-expressors. However, 4?-OHC/C/W was superior in a model in which no genotype information was available, likely because 4?-OHC/C/W was influenced by the CYP3A4*1b polymorphism.

SUBMITTER: Vanhove T

PROVIDER: S-EPMC5099550 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Comparative performance of oral midazolam clearance and plasma 4β-hydroxycholesterol to explain interindividual variability in tacrolimus clearance.

Vanhove Thomas T de Jonge Hylke H de Loor Henriëtte H Annaert Pieter P Diczfalusy Ulf U Kuypers Dirk R J DR

British journal of clinical pharmacology 20160920 6

<h4>Aims</h4>We compared the CYP3A4 metrics weight-corrected midazolam apparent oral clearance (MDZ Cl/F/W) and plasma 4β-hydroxycholesterol/cholesterol (4β-OHC/C) as they relate to tacrolimus (TAC) Cl/F/W in renal transplant recipients.<h4>Methods</h4>For a cohort of 147 patients, 8 h area under the curve (AUC) values for TAC and oral MDZ were calculated besides measurement of 4β-OHC/C. A subgroup of 70 patients additionally underwent intravenous erythromycin breath test (EBT) and were administ ...[more]

PMID: 27501475

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Project description:BackgroundApproximately 2.6 million children live with HIV globally, and efavirenz (EFV) is one of the most widely used antiretroviral agents for HIV treatment in children and adults. There are concerns about the appropriateness of current EFV dosing and it has been discussed whether EFV dosing should be adapted according to genotype in children as suggested for adults.AimTo investigate if pediatric EFV dosing should be guided by genetic variation in drug metabolizing enzymes rather than by body weight.MethodEFV plasma concentrations measured for clinical purposes from all children less than 18 years old at Karolinska University Hospital, Stockholm, Sweden, treated with EFV were collected retrospectively. They were genotyped for eleven polymorphisms in genes coding for drug-metabolizing enzymes and P-glycoprotein, of potential importance for EFV disposition. Data on country of origin, sex, age, weight, HIV RNA, viral resistance patterns, CD4 cells, adherence to treatment, subjective health status and adverse events were collected from their medical records.ResultsThirty-six patients and 182 (mean 5 samples/patient) EFV plasma concentration measurements from children of African, Asian and Latin American origin were included. EFV plasma concentration varied 21-fold between measurements (n = 182) (0.85-19.3 mg/L) and 9-fold measured as mean EFV plasma concentration across the subjects (1.55-13.4 mg/L). A multivariate mixed-effects restricted maximum likelihood regression model, including multiple gene polymorphisms, identified CYP2B6*6 T/T (p < 0.0005), CYP2B6*11 G/G (p < 0.0005), CYP2A6*9 A/C (p = 0.001) genotypes, age at treatment initiation (p = 0.002) and time from treatment initiation (p < 0.0005) as independent factors significantly related to loge concentration/(dose/weight). The contribution of the model to the intra- and interindividual variation were 6 and 75%, respectively (Bryk/Raudenbush R-squared level).ConclusionGenetic polymorphisms in CYP2B6 and CYP2A6 explained a significant proportion of variability in EFV plasma concentration in HIV-infected children in a multi-ethnic outpatient clinic. Knowledge about individual variants in key drug metabolizing enzyme genes could improve clinical safety and genotype directed dosing could achieve more predictable EFV plasma concentrations in HIV-infected children.

Project description:BackgroundPharmacogenomic variability can contribute to differences in pharmacokinetics and clinical responses. Pediatric patients with cerebral palsy with genetic variations have not been studied for these potential differences.ObjectiveTo determine the genetic sources of variation in oral baclofen clearance and clinical responses.DesignPharmacogenomic add-on study to determine variability in oral baclofen clearance and clinical responses.SettingMulticenter study based in academic pediatric cerebral palsy clinics.ParticipantsA total of 49 patients with cerebral palsy who had participated in an oral baclofen pharmacokinetic/pharmacodynamic study.Methods or interventionsOf 53 participants in a pharmacokinetic/pharmacodynamic trial, 49 underwent genetic analysis of 307 key genes and 4535 single-nucleotide polymorphisms involved in drug absorption, distribution, metabolism, and excretion. Associations between genotypes and phenotypes of baclofen disposition (weight-corrected and allometrically scaled clearance) and clinical endpoints (improvement from baseline in mean hamstring Modified Tardieu Scale scores from baseline for improvement of R1 spastic catch) were determined by univariate analysis with correction for multiple testing by false discovery rate.Main outcome measurementsPrimary outcome measures were the genotypic and phenotypic variability of oral baclofen in allometrically scaled clearance and change in the Modified Tardieu Scale angle compared to baseline.ResultsAfter univariate analysis of the data, the SNP of ABCC9 (rs11046232, heterozygous AT versus the reference TT genotype) was associated with a 2-fold increase in oral baclofen clearance (mean 0.51 ± standard deviation 0.05 L/h/kg for the AT genotype versus 0.25 ± 0.07 L/h/kg for the TT genotype, adjusted P < .001). Clinical responses were associated with decreased spasticity by Modified Tardieu Scale in allelic variants with SNPs ABCC12, SLC28A1, and PPARD.ConclusionsGenetic variation in ABCC9 affecting oral baclofen clearance highlights the need for continued studies of genetic polymorphisms to better characterize variable drug response in children with cerebral palsy. Single-nucleotide polymorphisms in ABCC12, SLC28A1, and PPARD were associated with varied responses, which warrants further investigation to determine their effect on spasticity.Level of evidenceII.

Dataset Information

Comparative performance of oral midazolam clearance and plasma 4?-hydroxycholesterol to explain interindividual variability in tacrolimus clearance.

Publications

Comparative performance of oral midazolam clearance and plasma 4β-hydroxycholesterol to explain interindividual variability in tacrolimus clearance.

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