Pharmacodynamic Assessment of Mycophenolic Acid-Induced Immunosuppression by Measurement of Inosine Monophosphate Dehydrogenase Activity in a Canine Model

Abstract

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 mediates its effect by the inhibition of inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo biosynthesis of purines. Using 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 +/- 10.0% 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 the 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 parameters investigated (area under the curve, beta half-life, mean residence time, volume of distribution at steady state, and clearance) between the two treatment groups. The half-life was calculated at approximately 8 hr for both dose groups. There was also substantial variability among the dogs in the absorption and clearance of MPA. An inverse relationship was found between the MPA concentration and IMPDH. Maximal inhibition of IMPDH activity of 30-40% occurs approximately 2-4 hr after dosing, followed by a gradual restoration in enzyme activity. After 24 hr, there is an increase in IMPDH activity that exceeds the pre-dosing 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 immunosuppressive efficacy. This combined approach can be used for optimization of doses of this and other immunosuppressive drugs.

Pharmacokinetics of oral mycophenolate mofetil in combination with CsA in dogs after nonmyeloablative allogeneic hematopoietic stem cell transplantation

“…21,22 In the present study, only two dogs were analyzed after nonmyeloablative HSCT in this time frame and a secondary maximum could not be observed. In fact, MPA concentrations at 4 h were already in the range of lower limit of detection.…”

“…Body weight-adjusted apparent oral clearance of MMF following HSCT seems to be comparable between dogs and humans. 16 As in healthy humans a longer median MPA half-life and a considerably higher AUC of 8.1 h and of 62.3 mg/l h were calculated in healthy dogs, 21 respectively, demonstrating the comparability of the canine HSCT model with the clinical situation.…”

Pharmacokinetic and Pharmacodynamic Comparison of Enteric-Coated Mycophenolate Sodium and Mycophenolate Mofetil in Maintenance Renal Transplant Patients

“…Until recently, little was known about the effects of MPA on IMPDH enzyme activity (21,39,40,41), but an assay method has now been devised which is suitable for the evaluation of the pharmacodynamic effects of MPA (22,27). Previous studies have shown large intraindividual and interindividual differences in IMPDH activity (21,22,27,38,41).…”

“…However, there is extensive intraindividual and interindividual variation in MMF pharmacokinetics (16)(17)(18)(19). Because IMPDH is inhibited by MPA, pharmacodynamic determination of the extent of inhibition of the enzyme may provide a better indicator of the degree of immunosuppression than measurement of plasma MPA concentrations (19)(20)(21). A specific and reliable nonradioactive method for determination of IMPDH enzyme…”

Pharmacokinetics and Pharmacodynamics of Mycophenolate in Patients After Renal Transplantation

“…This nonradioactive method for specific measurement of IMPDH activity in isolated peripheral mononuclear cells was developed by direct chromatographic determination of produced xanthosine 5'-monophosphate (XMP). In the canine model MPA in therapeutic doses leads to an 50% inhibition of IMPDH-activity (67) . Application of a single dose of 1 g MMF in dialysis patients resulted in a significant inhibition of IMPDH activity in lysed mononuclear cells.…”