C Pharmacology & Toxicology 2000, 87, 182–184. Copyright C Printed in Denmark . All rights reserved ISSN 0901-9928 Mycophenolate Mofetil Pharmacokinetics in Transplant Patients Receiving Cyclosporine or Tacrolimus in Combination Therapy Elena Vidal 1 , Carmen Cantarell 2 , Luis Capdevila 2 , Victor Monforte 3 , Antonio Roman 3 and Leonor Pou 1 1 Biochemistry Service, 2 Kidney Transplant Unit and 3 Pneumology Service, University Hospital ‘‘Vall d‘Hebron’’, Barcelona, Spain (Received February 16, 2000; Accepted June 13, 2000) Abstract: Mycophenolate mofetil is a highly effective immunosuppressant drug used in the prophylaxis of organ rejection in combination with cyclosporine or tacrolimus and corticosteroids. The present study is a retrospective data analysis of the routinely estimated mycophenolic acid plasma trough levels in 60 transplant patients (kidney, nΩ49; lung, nΩ11) receiving mycophenolate mofetil in combination with prednisone and cyclosporine (nΩ45) or tacrolimus (nΩ15). Co- administration of cyclosporine instead of tacrolimus resulted in a significant increase of median (range) of the ratio of dose-to-concentration 0.92 (0.11–8.33) (nΩ167) versus 0.38 (0.11–14.28) (nΩ66); P∞0.0001. No correlation was seen between mycophenolate mofetil dose and mycophenolic acid trough concentrations. The dose-to-concentration in cyclo- sporine-treated patients increased significantly (P∞0.0001) as the cyclosporine level increased, suggesting a possible inter- action between mycophenolate mofetil and cyclosporine. No correlation was seen between dose-to-concentration and tacrolimus blood levels (P¿0.215). Further studies are necessary to investigate this issue. Mycophenolate mofetil is an ester of mycophenolic acid, a potent inhibitor of the novo pathway of purine biosynthesis (Zucker et al. 1999). It inhibits T and B cell proliferation, which makes mycophenolate mofetil attractive in combi- nations with cyclosporine or tacrolimus. Fixed mycophen- olate mofetil doses have been recommended for its clinical use, but little is known about optimal dosing, value of my- cophenolic acid blood levels, and correlations with efficacy and toxicity (Braun et al. 1998). A highly significant relationship has been demonstrated between mycophenolic acid area-under-the-curve and the risk of rejection (Van Gelder et al. 1999). However, it is unclear whether monitoring of the pharmacologically active metabolite of mycophenolic acid will lead to improved safety and efficacy (Gregoor et al. 1999). In previous pharmacokinetic studies, patients receiving tacrolimus and mycophenolate mofetil displayed signifi- cantly higher levels of mycophenolic acid than those re- ceiving cyclosporine and the same dose of mycophenolate mofetil. However, no effect of mycophenolate mofetil on tacrolimus pharmacokinetics was observed (Zucker et al. 1997a & b; Hübner et al. 1999). A recent paper on kidney allograft recipients treated with and without cyclosporine showed lower mycophenolic acid trough levels in the cyclo- sporine-treated patients (Van Gelder et al. 1999). The authors suggested that cyclosporine influences mycophenol- ic acid pharmacokinetics, although the mechanism by Author for correspondence: Elena Vidal, Therapeutic Drug Moni- toring Unit, Biochemistry Service, University Hospital Vall d’Heb- ron, Pæ Vall d’Hebron 119–129, 08025 Barcelona, Spain (fax π34 3 2746831, e-mail leonor/hg.vhebron.es). which cyclosporine affects mycophenolic acid trough levels remains unknown. The aim of this retrospective study was to investigate the plasma mycophenolic acid trough concentrations attained with usual treatment doses in kidney and lung transplant patients receiving cyclosporine or tacrolimus in combi- nation with mycophenolate mofetil, and to obtain infor- mation on the effect of cyclosporine and tacrolimus on my- cophenolic acid pharmacokinetics. Materials and Methods Sixty patients (36 men and 24 women), with a mean age of 46.5 years (range 21–66 years), who underwent kidney (nΩ49) and lung (nΩ11) transplantation, were evaluated. The patients were treated with a triple immunosuppression regimen of prednisone, mycophen- olate mofetil and cyclosporine (nΩ45) or tacrolimus (nΩ15). Myco- phenolate mofetil was given at fixed doses of 1 g/day (nΩ8), 1.5 g/ day (nΩ23) and 2 g/day (nΩ29). The time post-transplantation ranged from 1 to 50 months (median: 3). All patients had received their specific drug regimen of cyclosporine, tacrolimus and myco- phenolate mofetil in two divided doses per day for at least two weeks before testing. A total of 233 samples were included in the study, 167 from pa- tients receiving mycophenolate mofetil and cyclosporine (kidney nΩ 145, lung nΩ22) and 66 from patients receiving mycophenolate mo- fetil and tacrolimus (kidney nΩ51, lung nΩ15). Blood specimens were drawn into tubes coated with ethylenediaminetetracetic acid 10 to 12 hr after administration of an oral dose of mycophenolate mofetil and before the morning dose. Cyclosporine levels were de- termined from whole blood using the EMIT 2000 Cyclosporine Specific Assay (Behring Diagnostics) on a COBAS MIRA PLUS analyser. Tacrolimus levels were determined from whole-blood using the monoclonal Imx assay system (Abbott). After quantifi- cation of cyclosporine and tacrolimus, the tubes were centrifuged, and plasma was separated and stored at ª20æ until mycophenolic