Pharmacokinetic interactions of mycophenolic acid: population pharmacokinetics and a translational investigation on p-cresol mediated metabolism interaction
Creators: Rong, Yan
Publisher: name: University of Alberta Library
Year: 2022

<p>BackgroundMycophenolic acid (MPA) is a frequently used immunosuppressant after organ transplantation to prevent graft rejection. It is often prescribed concurrently with tacrolimus and corticosteroids. MPA has been associated with significant variations in plasma exposure after kidney transplantation. The therapeutic exposure range of MPA is relatively narrow, under-exposure could result in organ rejection or graft loss, whereas over-exposure may lead to severe hematological complications. If not mitigated, MPA over-exposure could also result in severe infections and patient death. Understanding the factors contributing to MPA pharmacokinetic/dynamic variabilities could help mitigate the occurrences of MPA associated adverse effects and improve the precision dosing of MPA.Overall HypothesisLarge exposure variabilities of MPA can be attributed to extrinsic (i.e., co-administered immunosuppressants such as tacrolimus and corticosteroids) and intrinsic (i.e., endogenous toxins accumulated under uremic conditions such as p-cresol species) factors that alter MPA pharmacokinetics in humans.Methods and ResultsPopulation pharmacokinetic modeling was utilized to characterize the potential clinical variables that may influence MPA pharmacokinetics/dynamics. Using data obtained from adult kidney transplant recipients, a novel population pharmacokinetic model of MPA was constructed to investigate the effects of corticosteroids and tacrolimus on the pharmacokinetics of MPA. It was found that the overall clearance of MPA was markedly reduced in corticosteroid-free patients, indicating that MPA dose adjustment or therapeutic drug monitoring may be required in the clinic to prevent the over-exposure of MPA. On the other hand, tacrolimus dose, trough concentration, and exposure were not identified as significant covariates affecting the pharmacokinetics of MPA, suggesting that dose adjustment may not be warranted when MPA is co-administered with tacrolimus. Furthermore, population pharmacokinetic models of MPA in the literature were comprehensively, critically summarized with respect to modeling techniques, significant covariates, and clinical utilities. Our analyses indicated that albumin, bodyweight, creatinine clearance, cyclosporine, and post-transplant time were consistently identified as significant clinical factors affecting MPA pharmacokinetics/dynamics. In addition, Bayesian predictive models are also now available to aid MPA dose-adjustment in a variety of patient populations.Using a translational investigative approach, the inhibitory effects of p-cresol on the glucuronidation of MPA were determined in a metabolically-competent human hepatoma cell line (i.e., HepaRG model), human liver microsomes, and cDNA-expressed human enzymes. The identified inhibitory concentrations of p-cresol were physiologically attainable in adult kidney transplant patients, suggesting that fluctuations in p-cresol concentrations may be partially responsible for the large variabilities of MPA observed in the clinic. Furthermore, understanding how p-cresol is metabolized can help elucidate factors that may affect p-cresol disposition and indirectly contribute to MPA variabilities. As p-cresol is found in the forms of p-cresol sulfate and glucuronide in the human plasma, their enzyme kinetics were also characterized using human cytosols/microsomes and human recombinant sulfotransferases (SULT)/uridine 5&#39;-diphospho-glucuronosyltransferase (UGT) enzymes. Human SULT1A1 was identified the primary enzyme responsible for the formation of p-cresol sulfate (high efficiency/low capacity), whereas human UGT1A6 exhibited the highest catalytic activities toward the generation of p-cresol glucuronide (low efficiency/high capacity). These data provided the justification for focusing on p-cresol sulfate as the primary metabolite for our clinical investigation, and identified potential targets for mitigating the formation of toxic p-cresol metabolites as an approach to reduce the MPA interaction. Finally, the interaction between MPA and p-cresol sulfate was investigated in adult kidney transplant recipients within the first-year post-transplantation. Significant positive correlations were observed between the total MPA trough concentration and the plasma p-cresol sulfate concentration in a prospective, observational study. These clinical findings confirmed a role of p-cresol as a significant clinical variable affecting the pharmacokinetics of MPA in patients.ConclusionThis PhD thesis has identified potential significant extrinsic and intrinsic factors influencing MPA pharmacokinetics. It also systematically characterized a potent metabolism interaction between p-cresol and MPA, using the translational approach involving in vitro and clinical models. For scientists, this thesis has provided the basis for conducting further mechanistic experiments and for investigating therapeutic approaches for mitigating MPA variability. For physicians, this thesis has presented a comprehensive overview and critique of potential clinical factors that may contribute to MPA variabilities, as well as a novel approach for proactively managing p-cresol accumulation and mitigate MPA variability or toxicity. For patients, this thesis may ultimately improve the clinical outcomes and quality-of-life for the kidney transplant patient in the future.</p>