Pharmacodynamic monitoring of mycophenolic acid in rabbit heterotopic heart transplant model.

Pharmacodynamic (PD) monitoring of immunosuppressive drugs provides a novel approach to optimization of drug therapy in transplant recipients. We chose to investigate this using mycophenolic acid (MPA), an immunosuppressive drug that mediates its effect by the inhibition of inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo biosynthesis of purines. A comparison of the relationship between PD versus drug level monitoring was performed using a heterotopic cardiac transplant in New Zealand white rabbits. The animals were divided into four different treatment groups. Control animals were administered the drug vehicle, the treatment groups were administered mycophenolate mofetil (MMF) at doses of 40, 80, and 160 mg/kg/day. Statistically significant (p < 0.05) prolongation of graft survival was obtained at the 160 mg/kg/day dose group. The mean MPA concentration at this dose was approximately 2.5 mg/l, suggesting that this concentration may provide adequate immunosuppression. An increase in IMPDH activity appeared a few days prior to rejection, suggesting that measurement of enzyme activity may have potential for use as a marker of graft rejection. A significant (p < 0.05) relationship exists between MPA concentration and graft survival and the former with dose of MMF. There was a negative correlation (p = 0.17) between MPA concentration and IMPDH activity, while a trend (p = 0.37) to inverse relationship between graft survival and IMPDH activity was found. The data suggests that the measurement of the biological response may provide a useful adjunct to traditional therapeutic drug monitoring (TDM) for optimization of dosing of immunosuppressive drugs.