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UGT1A9, UGT2B7, and MRP2 genotypes can predict mycophenolic acid pharmacokinetic variability in pediatric kidney transplant recipients.

ABSTRACT: Mycophenolic acid (MPA) exposure in pediatric patients with kidney transplant receiving body surface area (BSA)-based dosing exhibits large variability. Several genetic variants in glucuronosyltransferases (UGTs) and of multidrug resistance-associated protein 2 (MRP2) have independently been suggested to predict MPA exposure in adult patients with varying results. Here, the combined contribution of these genetic variants to MPA pharmacokinetic variability was investigated in pediatric renal transplant recipients who were on mycophenolic mofetil maintenance therapy.MPA and MPA-glucuronide concentrations from 32 patients were quantified by high-performance liquid chromatography. MPA exposure (AUC) was estimated using a 4-point abbreviated sampling strategy (predose/trough and 20 minutes, 1 hour, and 3 hours after dose) using a validated pediatric Bayesian estimator. Genotyping was performed for all of the following single nucleotide polymorphisms (SNPs): UGT1A8 830G>A(*3), UGT1A9 98T>C(*3), UGT1A9-440C>T, UGT1A9-2152C>T, UGT1A9-275T>A, UGT2B7-900A>G, and MRP2-24T>C.Recipients heterozygous for MRP2-24T>C who also had UGT1A9-440C>T or UGT2B7-900A>G (n = 4), and MRP2-24T>C-negative recipients having both UGT1A9-440C>T and UGT2B7-900A>G (n = 5) showed a 2.2 and 1.7 times higher dose-dependent and BSA-normalized MPA-AUC compared with carriers of no or only 1 UGT-SNP (P < 0.001 and P = 0.01, respectively) (n = 7). Dose-dependent and BSA-normalized predose MPA concentrations were 3.0 and 2.4 times higher, respectively (P < 0.001). Interindividual variability in peak concentrations could be explained by the presence of the UGT1A9-440C>T genotype (P < 0.05).Our preliminary study demonstrates that combined UGT1A9-440C>T, UGT2B7-900A>G, and MRP2-24T>C polymorphisms can be important predictors of interindividual variability in MPA exposure in the pediatric population.

SUBMITTER: Fukuda T

PROVIDER: S-EPMC3498586 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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UGT1A9, UGT2B7, and MRP2 genotypes can predict mycophenolic acid pharmacokinetic variability in pediatric kidney transplant recipients.

Fukuda Tsuyoshi T Goebel Jens J Cox Shareen S Maseck Denise D Zhang Kejian K Sherbotie Joseph R JR Ellis Eileen N EN James Laura P LP Ward Robert M RM Vinks Alexander A AA

Therapeutic drug monitoring 20121201 6

<h4>Background</h4>Mycophenolic acid (MPA) exposure in pediatric patients with kidney transplant receiving body surface area (BSA)-based dosing exhibits large variability. Several genetic variants in glucuronosyltransferases (UGTs) and of multidrug resistance-associated protein 2 (MRP2) have independently been suggested to predict MPA exposure in adult patients with varying results. Here, the combined contribution of these genetic variants to MPA pharmacokinetic variability was investigated in p ...[more]

PMID: 23131697

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Project description:Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is used to prevent graft rejection in renal transplant recipients. MPA is glucuronidated to the metabolite MPAG, which exhibits enterohepatic recirculation (EHC). MPA binds for 97% and MPAG binds for 82% to plasma proteins. Low plasma albumin concentrations, impaired renal function and coadministration of cyclosporine have been reported to be associated with increased clearance of MPA. The aim of the study was to develop a population pharmacokinetic model describing the relationship between MMF dose and total MPA (tMPA), unbound MPA (fMPA), total MPAG (tMPAG) and unbound MPAG (fMPAG). In this model the correlation between pharmacokinetic parameters and renal function, plasma albumin concentrations and cotreatment with cyclosporine was quantified. tMPA, fMPA, tMPAG and fMPAG concentration-time profiles of renal transplant recipients cotreated with cyclosporine (n = 48) and tacrolimus (n = 45) were analyzed using NONMEM. A 2- and 1-compartment model were used to describe the pharmacokinetics of fMPA and fMPAG. The central compartments of fMPA and fMPAG were connected with an albumin compartment allowing competitive binding (bMPA and bMPAG). tMPA and tMPAG were modeled as the sum of the bound and unbound concentrations. EHC was modeled by transport of fMPAG to a separate gallbladder compartment. This transport was decreased in case of cyclosporine cotreatment (P < 0.001). In the model, clearance of fMPAG decreased when creatinine clearance (CrCL) was reduced (P < 0.001), and albumin concentration was correlated with the maximum number of binding sites available for MPA and MPAG (P < 0.001). In patients with impaired renal function cotreated with cyclosporine the model adequately described that increasing fMPAG concentrations decreased tMPA AUC due to displacement of MPA from its binding sites. The accumulated MPAG could also be reconverted to MPA by the EHC, which caused increased tMPA AUC in patients cotreated with tacrolimus. Changes in CrCL had hardly any effect on fMPA exposure. A decrease in plasma albumin concentration from 0.6 to 0.4 mmol/l resulted in ca. 38% reduction of tMPA AUC, whereas no reduction in fMPA AUC was seen. In conclusion, a pharmacokinetic model has been developed which describes the relationship between dose and both total and free MPA exposure. The model adequately describes the influence of renal function, plasma albumin and cyclosporine co-medication on MPA exposure. Changes in protein binding due to altered renal function or plasma albumin concentrations influence tMPA exposure, whereas fMPA exposure is hardly affected.

Project description:Purpose: The aim of this study is i) to establish a strategy to estimate the area under the curve of the dosing interval (AUC0-12h) of mycophenolic acid (MPA) in the heart transplant recipients and ii) to find the covariates that significantly affect the pharmacokinetics of MPA exposure. Methods: This single-center, prospective, open-label, observational study was conducted in 91 adult heart transplant recipients orally taking mycophenolate mofetil dispersible tablets. Samples collected intensively and sparsely were analyzed by the enzyme-multiplied immunoassay technique, and all the data were used in PPK modeling. Potential covariates were tested stepwise. The goodness-of-fit plots, the normalized prediction distribution error, and prediction-corrected visual predictive check were used for model evaluation. Optimal sampling times by ED-optimal strategy and multilinear regression (MLR) were analyzed based on the simulated data by the final PPK model. Moreover, using intensive data from 14 patients, the accuracy of AUC0-12h estimation was evaluated by Passing-Bablok regression analysis and Bland-Alman plots for both the PPK model and MLR equation. Results: A two-compartment model with first-order absorption and elimination with a lag time was chosen as the structure model. Co-medication of proton pump inhibitors (PPIs), estimated glomerular filtration rate (eGFR), and albumin (ALB) were found to significantly affect bioavailability (F), clearance of central compartment (CL/F), and the distribution volume of the central compartment (V2/F), respectively. Co-medication of PPIs decreased F by 27.6%. When eGFR decreased by 30 ml/min/1.73 m2, CL/F decreased by 23.7%. However, the impact of ALB on V2/F was limited to MPA exposure. The final model showed an adequate fitness of the data. The optimal sampling design was pre-dose and 1 and 4 h post-dose for pharmacokinetic estimation. The best-fit linear equation was finally established as follows: AUC0-12h = 3.539 × C0 + 0.288 × C0.5 + 1.349 × C1 + 6.773 × C4.5. Conclusion: A PPK model was established with three covariates in heart transplant patients. Co-medication of PPIs and eGFR had a remarkable impact on AUC0-12h of MPA. A linear equation was also concluded with four time points as an alternative way to estimate AUC0-12h for MPA.

Project description:Mycophenolic acid (MPA), an immunosuppressive drug widely used in kidney transplantation, has been suggested to have anti-fibrotic effects. To analyze at a genomic level these effects, we prospectively studied a group of stable kidney transplant recipients (n=35) on cyclosporine (CyA) and azathioprine treatment. Twenty patients were converted from azathioprine to MPA (MPA group) and 15 patients continued on azathioprine (AZA group). RNA was extracted by peripheral blood mononuclear cells at baseline and 3 months thereafter. Genomic analysis, performed on 5 randomly-selected MPA patients, revealed that 17 genes discriminated the transcriptomic profile after conversion. Neutral endopeptidase (NEP), an enzyme degrading angiotensin-II, was the most significant up-regulated gene. NEP expression level was inversely correlated to proteinuria at baseline and after conversion. Immunohistochemistry on graft biopsy of 33 independent patients demonstrated higher glomerular and tubular NEP protein expression in CyA+MPA (n=13) compared to CyA+AZA (n=12) and CyA alone (n=8). Glomerular NEP levels were inversely correlated to proteinuria and glomerulosclerosis. Tubular NEP expression was inversely correlated to interstitial fibrosis. Incubation of proximal tubular cells with MPA led to a dose- and time-dependent increase of NEP gene expression. The direct influence of MPA on NEP expression may suggest a novel therapeutic effect of this drug. For microarray analysis, we studied 5 randomly selected patients included in the training group. Patients included in this group were, at the time of enrollment (T0), on standard maintenance immunosuppression with Cyclosporine (Neoral, Novartis, Basel, mean±SD of daily dose: 160.1±37.1mg), prednisone (5 mg daily) and Azathioprine (50 mg daily). Twenty patients, at T0, were switched from Azathioprine to EC-MPS (Myfortic, Novartis, Basel, 720 mg bid) for their need of allopurinol therapy (EC-MPS group). However, to avoid confounding factors, allopurinol treatment did not start until the end of our study (3 months). For the microarray analysis, we randomly selected 5 patients from the EC-MPS group. PBMC both at T0 and at T1 (3 months after the switching of the therapy) were immediately isolated from 20 ml of whole blood by Ficoll–Hypaque (Flow Laboratories, Irvine, UK) density gradient centrifugation. Total RNA was extracted by RNeasy mini kit (QIAGEN Inc., Valencia, CA) according the manufacturer’s instructions. Total RNA was processed and hybridized to the Affymetrix GeneChips Human Genome U133 Array Set HG-U133A (Affymetrix)(Affymetrix, Santa Clara, CA)

Project description:Background: Tacrolimus (TAC) and mycophenolic acid (MPA) are the main immunosuppressive drugs used in pediatric kidney transplantation. Single nucleotide polymorphisms (SNPs) in metabolizing enzymes and transporters might influence plasma levels of these drugs. Herein, we sought to determine the influence of SNPs on CYP3A5, MRP2 and UGT1A9 genes in Chilean pediatric kidney recipients using TAC and MPA. Patients and Methods: A prospective study was performed on 104 pediatric kidney recipients that used TAC and MPA for immunosuppression. The median age at the time of transplantation was 8.1 years [Q1-Q3 4.5-11.6 years] and the main clinical diagnosis was a structural anomaly. In a subgroup of patients, a complete steroid withdrawal was made at day 7. The CYP3A5 polymorphism (ancestral allele *1; variant allele *3) was determined in the entire cohort, while MRP2 -24G > A, UGT1A9 -275T > A, and UGT1A9 -2152C > T polymorphisms were determined in 53 patients. Genotypes were associated with trough drug concentrations (C0), dose requirements normalized by weight (TAC-D mg/kg) or body surface (MPA-D mg/m2), trough levels normalized by dose requirements (C0/D), and area under the curve in 12 h normalized by dose requirements (AUC0-12h/D). Results: The frequencies of the variant alleles CYP3A5*3, MRP2-24A, UGT1A9-275A, and UGT1A9-2152T were 76.9, 22.1, 6.6, and 2.9%, respectively. AUC0-12h/TAC-D were 1.6-fold higher in CYP3A5*3/*3 patients than in CYP3A5*1 carriers (CYP3A5*1/*3 and CYP3A5*1/*1). When analyzing patients with steroid withdrawal, CYP3A5*3/*3 patients had 1.7-fold higher AUC0-12h/TAC-D than the other genotypes. Patients carrying the CYP3A5*3/*3 genotype had higher TAC-C0, lower TAC-D and higher TAC-C0/D, consistently in a 6-months follow-up. Creatinine clearance was stable during the follow-up, regardless of the genotype. No significant differences between MRP2 and UGT1A9 genotypes were observed in MPA-C0, MPA-D or MPA-C0/D. However, patients carrying the UGT1A9-275A allele had lower AUC0-12h/MPA-D than those carrying the UGT1A9-275T ancestral allele. Conclusions: These results support that CYP3A5 and UGT1A9 genotyping in pediatric recipients might be useful and advisable to guide TAC and MPA dosing and monitoring in children that undergo kidney transplantation.

Project description:ObjectivesThe population pharmacokinetic (popPK) characteristics of total mycophenolic acid (tMPA) have been investigated in various ethnic populations. However, investigations of popPK of unbound MPA (uMPA) are few. Thus, a popPK analysis was performed to: (1) characterize the PK of uMPA and tMPA and its 7-O-mycophenolic acid glucuronide (MPAG) metabolite in kidney transplant patients cotreated with cyclosporine (CsA), and (2) identify the clinically significant covariates that explain variability in the dose-exposure relationship.MethodsA total of 740 uMPA, 741 tMPA, and 734 total MPAG (tMPAG) concentration-time data from 58 Chinese kidney transplant patients receiving MPA in combination with CsA were analyzed using NONMEM® software with the stochastic approximation expectation maximization (SAEM) followed by the important sampling (IMP) method. The influence of covariates was tested using a stepwise procedure.ResultsThe PK of uMPA and unbound MPAG (uMPAG) were characterized by a two- and one-compartment model with first-order elimination, respectively. A linear protein binding model was used to link uMPA and tMPA. Apparent clearance (CL/F) and central volume of distribution (VC/F) of uMPA (CLuMPA/F and VCuMPA/F, respectively) and protein binding rate constant (k B) were estimated to be 851 L/h [relative standard error (RSE), 7.1%], 718 L (18.5%) and 53.4/h (2.3%), respectively. For uMPAG, the population values (RSE) of CL/F (CLuMPAG) and VC/F (VCuMPAG/F) were 5.71 L/h (4.4%) and 29.9 L (7.7%), respectively. Between-subject variability (BSVs) on CLuMPA/F, VCuMPA/F, CLuMPAG/F, and VCuMPAG/F were 51.0, 80.0, 31.8 and 48.4%, respectively, whereas residual unexplained variability (RUVs) for uMPA, tMPA, and uMPAG were 47.0, 45.9, and 22.0%, respectively. Significant relationships were found between k B and serum albumin (ALB) and between CLuMPAG/F and glomerular filtration rate (GFR). Additionally, model-based simulation showed that changes in ALB concentrations substantially affected tMPA but not uMPA exposure.ConclusionsThe established model adequately described the popPK characteristics of the uMPA, tMPA, and MPAG. The estimated CLuMPA/F and unbound fraction of MPA (FUMPA) in Chinese kidney transplant recipients cotreated with CsA were comparable to those published previously in Caucasians. We recommend monitoring uMPA instead of tMPA to optimize mycophenolate mofetil (MMF) dosing for patients with lower ALB levels.

Project description:Mycophenolic acid exhibits significant interpatient pharmacokinetic variability attributed to factors including race, sex, concurrent medications, and enterohepatic circulation of the mycophenolic acid glucuronide metabolite to mycophenolic acid. This conversion by enterohepatic circulation is mediated by the multidrug resistance-associated protein 2, encoded by ABCC2. This study investigated ABCC2 haplotype associations with mycophenolic acid pharmacokinetics in 147 stable kidney transplant recipients receiving mycophenolic acid in combination with calcineurin inhibitors. The role of the ABCC2 genotypes -24C>T (rs717620), 1249C>T (rs2273697), and 3972C>T (rs3740066) were evaluated in prospective, cross-sectional pharmacokinetic studies of stable recipients receiving mycophenolic acid and either tacrolimus or cyclosporine. Haplotype phenotypic associations with mycophenolic acid pharmacokinetic parameters were computed using THESIAS (v. 3.1). Four ABCC2 haplotypes with estimated frequencies greater than 10% were identified (H1:CGC [wild type], H9:CGT, H2:CAC, H12:TGT). There were no differences in haplotype frequencies by either race or sex. There were significant associations of pharmacokinetic parameters with ABCC2 haplotypes for mycophenolic acid clearance (L/h), mycophenolic acid AUC0-12h (mg·h/L), and the ratio of mycophenolic acid glucuronide to mycophenolic acid AUC0-12h . The wild-type haplotype ABCC2 CGC had greater mycophenolic acid AUC0-12h (P = .017), slower clearance (P = .013), and lower mycophenolic acid glucuronide to mycophenolic acid AUC0-12h ratio (P = .047) compared with the reduced function ABCC2 haplotype CGT. These differences were most pronounced among patients receiving tacrolimus cotreatment. No phenotypic associations were found with the cyclosporine-mycophenolic acid regimen. Variation in ABCC2 haplotypes contributes to subtherapeutic mycophenolic acid exposure and influences interpatient variability in pharmacokinetic phenotypes based on concurrent calcineurin inhibitor treatment.

Dataset Information

UGT1A9, UGT2B7, and MRP2 genotypes can predict mycophenolic acid pharmacokinetic variability in pediatric kidney transplant recipients.

Publications

UGT1A9, UGT2B7, and MRP2 genotypes can predict mycophenolic acid pharmacokinetic variability in pediatric kidney transplant recipients.

Similar Datasets

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