Pharmacokinetics of mycophenolic acid in renal transplant patients with delayed graft function

The pharmacokinetics of mycophenolic acid (MPA), the immunosuppressant form of the prodrug mycophenolate mofetil (MMF), and the primary glucuronide metabolite, MPAG, were characterized in renal transplant patients with delayed graft function using random effects piecewise linear models. Eight patients were evaluated after receiving their first and subsequent daily oral doses of 1.5 g mycophenolate mofetil twice daily on study days 1 (n = 8), 7 (n = 8), 14 (n = 5), 21 (n = 2), and 28 (n = 7). The area under the concentration-time curve from zero to 12 hours (AUC(0-12)) for MPA, MPAG, MPA free fraction, and free MPA were analyzed in serial plasma samples using validated high-performance liquid chromatography and ultrafiltration procedures. Random effects piecewise linear models, fit by maximum likelihood methods, Mere applied to AUC(0-12) of MPA and MPAG, MPA free fraction, AUC(0-12) of free MPA, and serum creatinine concentration, the index of renal function used in this study. Two hemodialysis sessions did not lower MPA plasma concentration, although some MPAG was removed. The AUC(0-12) of MPA increased as a function of time, although it rr as not possible to fit a statistical model to the data due to considerable among-patient variation in the pattern of increase with time. The AUC(0-12) of MPAG, MPA free fraction, and AUC(0-12) of free MPA reached maximal values on day 7; each of these parameters had unique day 1 to 7 positive slope values and unique day 7 to 28 negative slope values., The average creatinine concentration was maximal at day 2 and a unique negative slope was obtained between days 7 and 28. Thus, this study provides statistical models for the alteration of AUC(0-12) of MPAG, MPA free fraction, AUC(0-12) of free MPA, and serum creatinine in renal transplant patients with delayed graft function. These results provide evidence that renal dysfunction is associated with altered pharmacokinetics of MPA, particularly increased AUC(0-12) of MPAG, MPA free fraction, and AUC(0-12) of free MPA. The perturbed pharmacokinetics normalized with improving ren al function.