Pharmacodynamics of mycophenolic acid in heart allograft recipients: Correlation of lymphocyte proliferation and activation with pharmacokinetics andgraft histology

Background. Assays of drug blood levels are used for therapeutic immunosupp ressive drug monitoring (pharmacokinetics, PK). We monitored lymphocyte fun ctions (pharmacodynamics, PD) in allograft recipients treated with mycophen olic acid (MPA) to determine its mechanisms and the relationships among dos e levels, PK, PD, and histological severity of graft rejection. Methods. Lewis rats transplanted with Brown Norway (BN) rat hearts were tre ated with different dose levels of MPA for 8, 15, or 29 days at which times grafts were removed and scored for rejection grade. Blood was analyzed (hi gh-performance liquid chromatography) for MPA plasma concentrations (area u nder the concentration-time curve(0-24 hr), C-6 hr, trough) and for lymphoc yte functions using concanavalin A-stimulated whole blood assays to measure lymphocyte proliferation (tritium labled thymidine incorporation and flow cytometric bivariate proliferating nuclear cell antigen/DNA analysis) and a ctivation (percent lymphocytes expressing CD25 or CD134). PD values were AU E(0-24 hr) (area under the PD effect-time curve), maximum inhibition and tr ough. Results. MPA equipotently suppressed (by flow cytometry) both proliferation and activation and these effects correlated with MPA plasma levels (r(2)=0 .80-0.91). Relationships among MPA dose levels, PK and PD were clear, direc t, and reproducible. Correlation coefficients after 8 days of MPA treatment were: 0.90, 0.87, and 0.49 for MPAPK (AUC(0-24 hr), C-6 hr and trough) ver sus rejection scores; 0.80-0.89, 0.86-0.92, and 0.25-0.52 for PD flow cytom etric assays (AUE(0-24 hr), maximum inhibition, and trough) versus rejectio n scores. Conclusions. MPA inhibits both lymphocyte proliferation and activation. PD by flow cytometry (FCM) correlates highly with severity of graft rejection, showing that PD of MPA measured in peripheral blood predicts immune cell a ctivity in graft tissue.