Pharmacokinetics and Pharmacodynamics of Intensified versus Standard Dosing of Mycophenolate Sodium in Renal Transplant Patients

Background and objectives: Adequate early mycophenolic acid (MPA) exposure is an important determinant for effective rejection prophylaxis. This pharmacokinetic study investigated whether an intensified dosing regimen of enteric-coated mycophenolate sodium (EC-MPS) could achieve higher mycophenolic acid (MPA) exposure early after transplantation versus a standard dosing regimen.Design, setting, participants, & measurements: De novo kidney transplant recipients (n = 75) who were treated with basiliximab induction and cyclosporine were randomly assigned to receive EC-MPS as either standard dosing (1440 mg/d; n = 37) or intensified dosing (days 0 through 14: 2880 mg/d; days 15 through 42: 2160 mg/d; followed by 1440 mg/d; n = 38). Full 12-hour pharmacokinetic and pharmacodynamic profiles were taken at six time points during the first 3 months. Exploratory analysis of inosine monophosphate dehydrogenase (IMPDH) activity was also performed for better understanding of the pharmacokinetic–pharmacodynamic relationship between MPA exposure and IMPDH activity in the early posttransplantation period. Preliminary efficacy parameters, safety, and tolerability were assessed.Results: Exposure to MPA was significantly higher on days 3 and 10 after transplantation in the intensified versus standard EC-MPS group, with 52.9 versus 22.2% (P < 0.05) of patients reaching MPA exposure >40 mg/h per L in the first week. The intensified regimen resulted in significantly lower IMPDH activity on day 3 after transplantation, and the overall safety was comparable for both groups.Conclusions: These pharmacokinetic and safety data support further research on the hypothesis that early adequate MPA exposure could improve clinical outcome.The combination of mycophenolic acid (MPA), given as mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS), with steroids and calcineurin inhibitors (either cyclosporine A [CsA] or tacrolimus) has become standard immunosuppressive therapy worldwide. MMF and EC-MPS have a similar efficacy and safety profile (1,2) but differ in their pharmacokinetic characteristics (3).A large number of retrospective and prospective studies support the hypothesis that adequate early MPA exposure is an important determinant for effective rejection prophylaxis (4–13). Whereas the majority of tacrolimus-treated patients achieve adequate MPA exposure early after transplantation (13,14), studies have demonstrated that approximately 50% of patients who are treated with CsA and standard MPA dosages are underexposed (4,7,12,13). Larger initial MMF dosages (up to 4 g/d) have been suggested early after transplantation for achievement of sufficient MPA exposure in combination with CsA (13,15,16).There are only limited data on the pharmacokinetics, safety, and efficacy of higher (>3 g/d) MMF dosages (4,5,17), and data on higher EC-MPS dosages are lacking. The aim of this pilot study was to investigate the feasibility and safety of achieving target MPA exposure levels (≥40 mg/h per L), measured as area under time-concentration curve (AUC), using an intensified EC-MPS dosing regimen, compared with a standard dosing regimen, in de novo CsA-treated renal transplant patients. In addition, an exploratory analysis of inosine-monophosphate dehydrogenase (IMPDH) activity was performed for better understanding of the pharmacokinetic–pharmacodynamic relationship between MPA exposure and IMPDH activity early after transplantation.