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Pharmacokinetics and limited sampling strategies of mycophenolic acid in lung transplant recipients Ting, Lillian S.L.

Abstract

Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), an immunosuppressive agent used in organ transplantation, exhibits wide inter-patient variability in its pharmacokinetic (PK) parameters in various transplant groups. However, there are few studies in the lung transplant population. The objectives of this study were to investigate the pharmacokinetics and limited sampling strategies (LSSs) of MPA in lung transplant recipients. Twenty-one lung transplant recipients on steady-state MPA therapy were recruited. Patients were also receiving either cyclosporine (CSA; n=11) or tacrolimus (TAC; n=9) as co-medications. Blood samples were collected at 0, 20, 40, 60, 90 minutes, and at 2, 4, 6, 8, 10, 12 hours post-dose. Concentrations of MPA, free MPA, 7-O-mycophenolate glucuronide (MPAG) and acyl mycophenolic acid glucuronide (AcMPAG) in the plasma samples were measured by a high performance liquid chromatography-ultraviolet detection assay. Conventional PK parameters were determined using non-compartmental methods. There was large inter-patient variability in all PK parameters of MPA, MPAG and AcMPAG. Similar variability was observed after stratifying patients into concomitant medication groups, CSA and TAC. The CSA group had lower MPA, higher MPAG and AcMPAG levels than the TAC group. The mean MPA free fraction was 7.0%, more than twice the expected value. Nineteen of the twenty-one subjects were included in the LSS study. Multiple regression analysis was used to develop the LSSs. Subjects were randomly divided into the index (n=10) and the validation groups (n=9). Index group data were used to develop the LSSs, which were tested with the validation group data. Accuracy and precision of the LSSs were determined by calculating the mean prediction error and the root mean square error, respectively. Two single-concentration LSSs, eight 2-concentration LSSs, and eight 3-concentration LSSs met predetermined criteria. However, considering both cost and clinical feasibility, the recommended LSSs were: LogAUC=0.241 LogCO+0.406 LogC2+1.140; LogAUC=0.202 LogC0+0.411 LogC1.5+1.09 Because of the large inter-patient variability in the PK parameters of MPA, MPAG, and AcMPAG, therapeutic drug monitoring of MPA and its metabolites in lung transplant recipients may be beneficial. Adoption of the LSSs developed in this study should provide convenient and cost-effective estimation of MPA exposure in lung transplant recipients.

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