PHARMACODYNAMIC ASSESSMENT OF MYCOPHENOLIC ACID-INDUCED IMMUNOSUPPRESSION BY MEASUREMENT OF INOSINE MONOPHOSPHATE DEHYDROGENASE-ACTIVITY INA CANINE MODEL

The combination of pharmacokinetic and pharmacodynamic (measurement of the biological effect) monitoring of immunosuppressive drugs provides a method for the optimization of drug dosing. We chose to investigate this using mycophenolic acid (MPA), an immunosuppressive drug that me diates its effect by the inhibition of inosine monophosphate dehydroge nase (IMPDH), a key enzyme in the de novo biosynthesis of purines. Usi ng an assay developed for measurement of IMPDH activity in whole blood , the concentration required for 50% inhibition of IMPDH activity was approximately 200 mg/L (58 +/- 8.3% for whole blood [n=6] and 55 +/- 1 0.0% for isolated lymphocytes). To ascertain the relationship between MPA concentration and IMPDH inhibition in vivo, dogs were administered a single dose of mycophenolate mofetil, the pro-drug of MPA, at 20 or 40 mg/kg orally. Pharmacokinetic analysis revealed that the Cmax of t he 40-mg/kg group was statistically greater than that of the 20-mg/kg group (P<0.05). There were no statistical differences in the other par ameters investigated (area under the curve, beta half-life, mean resid ence time, volume of distribution at steady state, and clearance) betw een the two treatment groups. The half-life was calculated at approxim ately 8 hr for both dose groups. There was also substantial variabilit y among the dogs in the absorption and clearance of MPA. An inverse re lationship was found between the MPA concentration and IMPDH. Maximal inhibition of IMPDH activity of 30-40% occurs approximately 2-4 hr aft er dosing, followed by a gradual restoration in enzyme activity. After 24 hr, there is an increase in IMPDH activity that exceeds the pre-do sing levels in some cases by 3-fold. Evaluation of the pharmacokinetic and the pharmacodynamic responses to MPA in the canine model suggests that the drug should be administered ever 8 hr to optimize its immuno suppressive efficacy. This combined approach can be used for optimizat ion of doses of this and other immunosuppressive drugs.