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Effect of Cyclosporine on Mycophenolic Acid Area Under the Concentration–Time Curve in Pediatric Kidney Transplant Recipients

Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), shows substantial interindividual and intraindividual variability. It was recently shown that in vitro calcineurin inhibitors alter the bioavailability of MPA by dose-dependent inhibition of MPA glucuronidation. The authors retrospectively analyzed full 10-point profiles for both MPA and cyclosporine (CyA) in 23 pediatric patients receiving MMF and cyclosporine microemulsion (Neoral; Novartis Pharmaceuticals Canada; Dorval, Quebec, Canada). Mycophenolic acid was measured using a commercially available EMIT (Novartis Pharmaceuticals, Canada) assay. As the majority of patients were treated with low doses of cyclosporine after adding MMF, the area under the concentration–time curve (AUC) for cyclosporine showed a wide scatter ranging from 296 to 6400 ng × h/mL. The mean cyclosporine dose was 100 ± 76 mg/m 2 per day (range: 28 to 331). There was no correlation between MPA AUC and MPA dose, and there was substantial interindividual variation. However, there was a significant negative correlation between dose-normalized MPA AUC and cyclosporine AUC (r 2 = 0.23, p < 0.0220). When dividing the MPA profiles into two groups (11 and 12 patients) with a CyA AUC less than or greater than 1600 ng × h/mL, there was a significantly higher 8-hour concentration in the patients with the lower CyA AUC, secondary to a higher second peak. The data demonstrate that the cyclosporine AUC is a determining factor for the MPA AUC and that MPA dose should be reduced when cyclosporine dose is reduced to achieve the same MPA AUC. The significantly higher peak in the group with a lower CyA profile supports the concept of a dose-dependent cyclosporine-induced inhibition of MPA glucuronidation.