P.J.H. Smak Gregoor

Effect of cyclosporine on mycophenolic acid trough levels in kidney transplant recipients.

BACKGROUND Triple drug treatment consisting of mycophenolate mofetil (MMF), in a standard dose of 2 g daily, combined with cyclosporine (CsA) and prednisone, has become the standard immunosuppressive regimen after kidney transplantation in many centers. The need for therapeutic drug monitoring of mycophenolic acid (MPA) has not yet been established. Several drug interactions with MMF are known. We investigated the influence of CsA withdrawal on MPA trough levels in renal transplant patients. METHODS Fifty-two patients were treated with 1 g of MMF twice daily, and prednisone and CsA targeted between 125 and 175 ng/ml for 6 months after transplantation. At 6 months after transplantation, 19 patients were randomized for continuation of triple therapy (group A), 19 patients discontinued CsA (group B), and 14 patients discontinued prednisone (group C). We compared 12-hr fasted MPA trough levels at 6 and 9 months after transplantation within and between these groups. RESULTS MPA trough levels during treatment with CsA, MMF, and prednisone were significantly lower than those during treatment with MMF and prednisone only (group B); median levels were 1.87 mg/L (range: 0.56-5.27) vs. 3.16 mg/L (range: 0.32-7.78), respectively (P=0.002). MPA trough levels in groups A and C did not change between 6 and 9 months after transplantation; group A median levels were 1.87 (range: 0.31-4.32) vs. 1.53 mg/L (range: 0.36-3.70), and group C median levels were 1.62 (range: 0.69-10.34) vs. 1.79 mg/L (range: 0.54-6.00), respectively. At 9 months after transplantation, patients in whom CsA was discontinued had higher MPA trough levels as compared with patients who continued the use of triple therapy (P=0.001) or patients in whom steroids were withdrawn (P=0.014). CONCLUSION A significant increase of MPA trough levels was found after discontinuation of CsA (6 months after transplantation), resulting in almost a doubling of MPA trough levels at 9 months after transplantation. This resulted in increased MPA levels in patients without CsA as compared to MPA levels in patients continuing triple therapy or discontinuing prednisone.

Unusual presentation of herpes virus infections in renal transplant recipients exposed to high mycophenolic acid plasma concentrations

Abstract:  Viral infections constitute an important problem for transplant recipients and their physicians. Often the balance between adequate and over‐immunosuppression is hard to find and therapeutic drug monitoring might be a welcome adjunct in the management of transplant patients. We report four renal transplant recipients with extra‐ordinary presentations of viral disease who were all treated with mycophenolate mofetil and in whom high mycophenolic acid (MPA) trough levels were found. High MPA levels may reflect over‐immunosuppression resulting in infectious complications.

Down-regulated donor-specific T-cell reactivity during successful tapering of immunosuppression after kidney transplantation

Stable cadaveric renal transplant patients were routinely converted from cyclosporin A (CsA) to either azathioprine (AZA) or mycophenolate mofetil (MMF) 1 year after transplantation to reduce the side effects of long‐term immunosuppressive therapy. Thereafter, the AZA and MMF dose was gradually tapered to 50% at 2 years after transplantation. We questioned whether a reduction of immunosuppressive treatment results in a rise of donor‐specific T‐cell reactivity. Before transplantation (no immunosuppression), 1 year (high dose immunosuppression) and 2 years (low dose immunosuppression) after transplantation, the T‐cell reactivity of peripheral blood mononuclear cells (PBMC) against donor and third‐party spleen cells was tested in mixed lymphocyte cultures (MLC) and against tetanus toxoid (TET) to test the general immune response. We also measured the frequency of donor and third‐party reactive helper (HTLpf) and cytotoxic (CTLpf) T‐lymphocyte precursors in a limiting dilution assay. Donor‐specific responses, calculated by relative responses (RR = donor/third‐party reactivity), were determined. Comparing responses after transplantation during high dose immunosuppression with responses before transplantation (no immmunosuppression), the donor‐specific MLC‐RR (P = 0·04), HTLp‐RR (P = 0·04) and CTLp‐RR (P = 0·09) decreased, while the TET‐reactivity did not change. Comparing the responses during low dose with high dose immunosuppression, no donor‐ specific differences were found in the MLC‐RR, HTLp‐RR and CTLp‐RR, although TET‐reactivity increased considerably (P = 0·0005). We observed a reduction in donor‐specific T‐cell reactivity in stable patients after renal transplantation during in vivo high dose immunosuppression. Tapering of the immunosuppressive load had no rebound effect on the donor‐specific reactivity, while it allowed recovery of the response to nominal antigens.

Mycophenolic acid trough levels after kidney transplantation in a cyclosporine-free protocol

Abstract Twenty‐seven stable kidney transplant recipients treated with cyclosporine and prednisone were converted to mycophenolate mofetil (MMF) and prednisone 1 year after transplantation. After conversion the patients were treated with a standard daily dose of 1 g MMF b.i.d. and 10 mg prednisone for 4 months. Thereafter, two MMF dose reductions were performed with a 4‐month interval. Mycophenolic acid (MPA) trough levels were measured at regular intervals. A relation was found between MPA trough levels and MMF dose. The median MPA trough level for patients treated with 1 g MMF b. i. d. was 4.3 μg/ml (0.95‐15.5) and 3.0 μg/ml (0.73‐7.8) for patients treated with 750 mg b. i. d. (P = 0.0002). The MPA trough levels further decreased from 3.0 to 2.3 μg/ml (0.6‐6.63) in patients treated with 500 mg MMF b. i. d. (P = 0.01). Dose reduction of MMF from 1 g to 750 mg b.i.d. could be performed without acute rejections. A further dose reduction to 500 mg b.i.d. elicited 3 rejections. Patients experiencing an acute rejection had a median MPA trough level of 2.3 μg/ml (1.26‐3.38) compared to 3.8 μg/ml (1.48‐6.52) in patients without an acute rejection (P = 0.25). We conclude that there is a significant relation between MPA trough levels and MMF dose. MPA trough levels were not predictive of rejection in the present study.

Tacrolimus Dose Requirement Is Significantly Higher When Used in Combination With Cortico‐Steroids

Clinical Pharmacology & Therapeutics (2003) 73, P81–P81; doi: