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Mycophenolic Acid and Its Metabolites in Kidney Transplant Recipients: A Semimechanistic Enterohepatic Circulation Model to Improve Estimating Exposure.

ABSTRACT: Mycophenolic acid (MPA) is an approved immunosuppressive agent widely prescribed to prevent rejection after kidney transplantation. Wide between-subject variability (BSV) in MPA exposure exists which in part may be due to variability in enterohepatic recirculation (EHC). Several modeling strategies were developed to evaluate EHC as part of MPA pharmacokinetics, however mechanistic representation of EHC is limited. These models have not provided a satisfactory representation of the physiology of EHC in their modeling assumptions. The aim of this study was i) to develop an integrated model of MPA (total and unbound) and its metabolites (MPAG and acyl-MPAG) in kidney recipients, where this model provides a more physiological representation of EHC process, and ii) to evaluate the effect of donor and recipient clinical covariates and genotypes on MPA disposition. A five-compartment model with first-order input into an unbound MPA compartment connected to the MPAG, acyl-MPAG, and gallbladder compartment best fit the data. To represent the EHC process, the model was built based on the physiological concepts related to the hepatobiliary system and the gallbladder filling and emptying processes. The effect of cyclosporine versus tacrolimus on clearance of unbound MPA was included in the base model. Covariate analysis showed creatinine clearance to be significant on oral clearance of unbound MPA. The hepatic nuclear factor 1 alpha (HNF1A) genetic single nucleotide polymorphism (SNP) (rs2393791) in the recipient significantly affected the fraction of enterohepatically-circulated drug. Oral clearance of MPAG was affected by recipient IMPDH1 SNP (rs2288553), diabetes at the time of transplant, and donor sex.

SUBMITTER: Okour M

PROVIDER: S-EPMC5910266 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Mycophenolic Acid and Its Metabolites in Kidney Transplant Recipients: A Semimechanistic Enterohepatic Circulation Model to Improve Estimating Exposure.

Okour Malek M Jacobson Pamala A PA Ahmed Mariam A MA Israni Ajay K AK Brundage Richard C RC

Journal of clinical pharmacology 20180112 5

Mycophenolic acid (MPA) is an approved immunosuppressive agent widely prescribed to prevent rejection after kidney transplantation. Wide between-subject variability (BSV) in MPA exposure exists which in part may be due to variability in enterohepatic recirculation (EHC). Several modeling strategies were developed to evaluate EHC as part of MPA pharmacokinetics, however mechanistic representation of EHC is limited. These models have not provided a satisfactory representation of the physiology of ...[more]

PMID: 29329489

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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:Older kidney transplant recipients are susceptible to cognitive impairment, frailty, comorbidities, immunosuppression-related complications, and chronic graft failure, however, there has been limited focus on their concerns and expectations related to transplantation. This study aims to describe the perspectives of older kidney transplant recipients about their experience of kidney transplantation, self-management, and treatment goals to inform strategies and interventions that address their specific needs.Face-to-face semistructured interviews were conducted with 30 kidney transplant recipients aged 65-80 years from five renal units in Australia. Transcripts were analyzed thematically.Six themes were identified: restoring vitality of youth (with subthemes of revived mindset for resilience, embracing enjoyment in life, drive for self-actualization); persisting through prolonged recovery (yielding to aging, accepting functional limitations, pushing the limit, enduring treatment responsibilities); imposing sicknesses (combatting devastating comorbidities, painful restrictions, emerging disillusionment, anxieties about accumulating side effects, consuming treatment burden); prioritizing graft survival (privileged with a miracle, negotiating risks for longevity, enacting a moral duty, preserving the last opportunity); confronting health deterioration (vulnerability and helplessness, narrowing focus to immediate concerns, uncertainty of survival); and value of existence (purpose through autonomy, refusing the burden of futile treatment, staying alive by all means).Older kidney transplant recipients felt able to enjoy life and strived to live at their newly re-established potential and capability, which motivated them to protect their graft. However, some felt constrained by slow recuperation and overwhelmed by unexpected comorbidities, medication-related side effects, and health decline. Our findings suggest the need to prepare and support older recipients for self-management responsibilities, clarify their expectations of post-transplant risks and outcomes, and provide assistance through prolonged recovery after kidney transplantation.

Dataset Information

Mycophenolic Acid and Its Metabolites in Kidney Transplant Recipients: A Semimechanistic Enterohepatic Circulation Model to Improve Estimating Exposure.

Publications

Mycophenolic Acid and Its Metabolites in Kidney Transplant Recipients: A Semimechanistic Enterohepatic Circulation Model to Improve Estimating Exposure.

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