Editorial Drug interactions between mycophenolate and cyclosporine Pape et al. (1) report unexpectedly lower 2-h post-intake cyclosporine (C2) levels in pediatric renal transplant patients who received additional mycophenolate mofetil (MMF) in combination with cyclosporine in comparison with a historical control group from another center (2) that received cyclosporine without additional MMF. They also report a significantly higher dose requirement in order to achieve the same area under the curve (AUC) concentrations. Their findings prompted the group to reassess the feasibility of the proposed formula AUC ¼ 1814 + 3.38x C2 (2) to estimate the AUC from the C2 and derive a new formula that is specific for the combination therapy of cyclosporine Neoral and MMF. There is growing evidence for a drug inter- action between cyclosporine Neoral and MMF (3). It appears that it is not only the concomitant medication that influences the drug requirements (4), but also the differing cyclosporine AUC may influence the AUC of the active compound of MMF, mycophenolic acid (MPA) (5, 6). The pharmacokinetics of MPA differ from those of cyclosporine as after rapid initial absorption a sharp first peak followed by a second peak occurs 6–8 h after intake. This second peak is due to enterohepatic recirculation of the main meta- bolite of MPA, which is 7-O-MPA-beta-glucuro- nide (MPAG). MPAG is formed in the liver together with three other metabolites of which AcMPAG is the most important (7). The second MPA peak is reduced in combination with high cyclosporine concentrations (6), and the concen- tration of MPAG is much lower in the absence of cyclosporine (5). These results are consistent with the hypothesis that cyclosporine attenuates the enterohepatic recirculation of MPAG/MPA. As yet, there has been no report to date about MMF affecting the cyclosporine exposure as well, and the findings proposed by Pape et al. are of major importance. The pharmacodynamics of cyclosporine play a major role, and there is growing evidence that high-target AUCs are to be achieved early after transplantation in order to prevent rejection (8). Similar suggestions have been made for pediatric renal transplantation with an average AUC of 7500 ng h/mL early after transplantation (9). If the addition of MMF to a cyclosporine Neoral-based immunosuppres- sion reduces the cyclosporine C2 and thus the AUC, this may have an unfavorable effect on the outcome after transplantation. The best way to look at the effect of adding MMF to the AUC and the C2 of cyclospo- rine microemulsion is to compare complete pharmacokinetic (PK) profiles before and after adding MMF, and to compare the dose-normal- ized AUCs, as the cyclosporine dose may have been changed. Fortunately such patients exist in our transplant clinic, as we used to replace azathioprine with MMF and lower the cyclosp- orine dose in case of deteriorating graft function secondary to chronic cyclosporine toxicity. A retrospective chart review revealed 12 pediatric renal transplant patients who had a PK profile on a cyclosporine Neoral-based immunosuppres- sion before and after MMF. All 12 patients had been on azathioprine that was discontinued and replaced by MMF. Nine of the 12 patients received concomitant steroids (median dose 5.0 mg/m 2 /day, range 0.0–7.1, mean 4.1 ± 2.7 mg/ m 2 /day) at the time of the first PK profile, and this was identical after adding MMF. Mean age of patients at transplantation was 9.8 ± 4.3 yr. The pre-conversion cyclosporine Neoral PK profile was obtained at 6.1 ± 3.5 yr after trans- plantation, and at a mean of 9 ± 6 months prior to adding MMF. The PK profile after adding MMF was performed at a median of 23 (range 17–349) days, after establishing stable pharma- cokinetics. Mean cyclosporine Neoral dose at the first PK profile prior to adding MMF was 152 ± 38 mg/m 2 /day, and mean AUC was Pediatr Transplantation 2004: 8: 201–204 Printed in UK. All rights reserved Copyright Ó 2004 Blackwell Munksgaard Pediatric Transplantation 201