Effect of Cyclosporine Withdrawal on Mycophenolic Acid Pharmacokinetics in Kidney Transplant Recipients With Deteriorating Renal Function: Preliminary Report

Abstract

Mycophenolic acid (MPA) concentrations are lower in transplant recipients receiving mycophenolate mofetil (MMF) and cyclosporine compared with MMF with tacrolimus. It is not clear whether this is due to an effect of cyclosporin or tacrolimus on MPA pharmacokinetics. To study this effect, kidney transplant recipients with deteriorating renal function (n = 5) receiving cyclosporin and steroids were given mycophenolate mofetil over 4 weeks during a run-in phase (1 g/d in week 1, 1.5 g/d in week 2, 2 g/d starting from week 3). From week 5 the cyclosporin dose was reduced, and it was completely withdrawn at week 10. Creatinine, MPA, and MPA glucuronide metabolites (MPAG, AcMPAG) were determined before (week 4) and after (week 11 and week 32) cyclosporin was withdrawn. Cyclosporin withdrawal was associated with increased MPA areas under the curve (AUCs) and predose concentrations in four of the five patients. In contrast, MPAG and AcMPAG AUCs as well as predose MPAG concentrations significantly decreased. Six months after cyclosporin withdrawal, MPA AUC and predose values tended to return to initial values, whereas metabolite concentrations remained low. Cyclosporin discontinuation caused an acute increase in MPA exposure and a concomitant reduction in metabolite concentrations. The results are consistent with the hypothesis that cyclosporin attenuates the enterohepatic recirculation of MPAG/MPA.

Effects of Calcineurin Inhibitors on Pharmacokinetics of Mycophenolic Acid and Its Glucuronide Metabolite during the Maintenance Period Following Renal Transplantation

“…25,26) In addition, we showed that the MPAG/MPA ratio in CNI(Ϫ) patients was not higher than the median ratio in patients treated with TAC. It has been reported that CyA interferes with the enterohepatic circulation of MPAG, and that TAC may interfere with the activity of UGT.…”

The Rationale for and Limitations of Therapeutic Drug Monitoring for Mycophenolate Mofetil in Transplantation

“…Of particular relevance is the impact of CNIs, including CsA and tacrolimus, on MPA exposure. In general, renal allograft recipients receiving MMF in combination with CsA have lower MPA plasma concentrations per unit dose of MMF than patients not receiving CsA (27), and MPA plasma concentrations have been shown to rise significantly following CsA discontinuation (28,29). CsA decreases biliary excretion of MPAG (30,31) by a mechanism that involves inhibition of multidrug resistance-associated protein 2, a multispecific organic anion transporter present in the bile canalicular membrane of hepatocytes (32)(33)(34)(35).…”

Mycophenolate Mofetil for Solid Organ Transplantation: Does the Evidence Support the Need for Clinical Pharmacokinetic Monitoring?

“…Further studies to define the nature of this interaction have included a control group receiving MMF alone, without addition of a calcineurin inhibitor (80)(81)(82). A small study (80) compared the mean MPA predose concentrations (measured by EMIT) of 11 renal transplant patients receiving MMF and prednisone with those of 18 patients receiving MMF, CsA, and prednisone.…”