Pharmacokinetics and Concentration-Control Investigations of Mycophenolic Acid in Adults After Transplantation

Abstract

Data have emerged that provide the scientific basis for therapeutic drug monitoring of mycophenolic acid (MPA) in transplant patients receiving mycophenolate mofetil (MMF), the parent drug, in combination with other immunosuppressive agents. There is a significant relationship between the dose-interval MPA AUC and risk for acute rejection based on retrospective investigations in renal and heart transplant patients and on prospective investigations in renal transplant patients. The MPA dose-interval AUC varies naturally by more than 10-fold in renal and heart transplant patients. Other significant sources of pharmacokinetic variability for MPA include the effects of concomitant medications, and the effects of disease states such as renal dysfunction and liver disease on the steady state MPA AUC. Individualized MMF dose evaluation, guided by MPA plasma concentrations, is becoming the standard of practice at a growing number of transplant centers worldwide because of these factors and because of the need to closely evaluate the immunosuppression afforded by MPA when a change in the immunosuppression regimen in stable transplant patients is planned. Investigations of therapeutic drug monitoring strategies with an emphasis on identifying an optimal abbreviated sampling strategy for MPA AUC estimation are ongoing. Based on the concentration-outcome studies and experience at the authors' institutions and other centers, the authors propose a set of therapeutic drug monitoring guidelines for MPA in stable renal and heart transplant patients for the immediate (first 3 months posttransplant) and maintenance (>3 months) periods. When MPA binding to human serum albumin is altered, as occurs in patients with significant renal dysfunction, liver disease, or a substantial reduction in human serum albumin concentration, the possibility of increased MPA free fraction and free concentration will need to be taken into account in the interpretation of MPA total concentrations.

Pharmacokinetics of mycophenolic acid in Chinese kidney transplant patients

“…Analysis of MPA concentration in the 29 Chinese patients in this study revealed that the pattern of the concentration-time profile was similar to the results of other studies (Pescovitz et al, 2003;Cho et al, 2004), although there was some variability of AUC (0−12) , C max and t max . The mean MPA AUC ((52.546±13.215) µg·h/ml) of Chinese kidney transplant patients treated with 1000 mg MMF twice daily was higher than that of Caucasian patients ((33.3±13.7) µg·h/ml), African American patients ((26.8±14.3) µg·h/ml) who took the same dose as that in our study (Shaw et al, 2000), and Korean patients ((18.45±4.25) µg·h/ml) taking MMF 750 mg twice a day. Only 3 of our 29 patients experienced acute rejection within 1 month after operation, maybe it was partly due to the high MPA AUC in the target range of 30 to 60 µg·h/ml reported to decrease the risk of acute rejection (Shaw et al, 2000).…”

“…The mean MPA AUC ((52.546±13.215) µg·h/ml) of Chinese kidney transplant patients treated with 1000 mg MMF twice daily was higher than that of Caucasian patients ((33.3±13.7) µg·h/ml), African American patients ((26.8±14.3) µg·h/ml) who took the same dose as that in our study (Shaw et al, 2000), and Korean patients ((18.45±4.25) µg·h/ml) taking MMF 750 mg twice a day. Only 3 of our 29 patients experienced acute rejection within 1 month after operation, maybe it was partly due to the high MPA AUC in the target range of 30 to 60 µg·h/ml reported to decrease the risk of acute rejection (Shaw et al, 2000). But we must be careful when the patient simultaneously has CsA and MPA AUC concentrations such as above 3 acute rejection patients.…”

Mycophenolic acid pharmacokinetics and related outcomes early after renal transplant

“…The pharmacokinetic variability of MPA and its glucuronide using 6-h AUC was comparable to that using 12-h AUC [6][7][8]14]. Contributory factors may include concomitant medication effects as well as renal and hepatic disease (e.g.…”

“…Patients in the cyclosporin cohort were significantly older and had a significantly higher median plasma bilirubin concentration than those in the tacrolimus group (median [IQR] =13 [10][11][12][13][14][15][16][17][18] and 7 [5][6][7][8][9][10][11][12] mmol l -1 , respectively; P = 0.01). Otherwise there were no other significant differences between groups relating to race, sex, body weight, body mass index (BMI), diabetes, CAPD, transplant type, HLAM, PRA, ischaemic time, creatinine clearance, graft function or blood biochemistry.…”

Validation of a Rapid and Sensitive Liquid Chromatography–Tandem Mass Spectrometry Method for Free and Total Mycophenolic Acid

“…The potential utility of monitoring plasma total mycophenolic acid (tMPA) 3 concentrations for optimizing therapy with the prodrug mycophenolate mofetil (MMF) has been demonstrated in several studies (1)(2)(3)(4)(5). Because MPA is highly protein bound, there is also a need to investigate free MPA (fMPA).…”