Pharmacokinetics of oral mycophenolate mofetil in combination with CsA in dogs after nonmyeloablative allogeneic hematopoietic stem cell transplantation.

Abstract

Mycophenolate mofetil (MMF) has been used successfully in solid organ transplantation (SOT) and more recently in nonmyeloablative hematopoietic stem cell transplantation (HSCT) for prophylaxis of graft rejection and acute graft-versus-host disease. However, the pharmacokinetics of MMF seem to differ when applied in HSCT compared to SOT. Here, we analyzed pharmacokinetics of mycophenolic acid (MPA), the active metabolite of MMF, in a nonmyeloablative canine HSCT model. Dogs received nonmyeloablative TBI for conditioning followed by leukocyte antigen-identical littermate HSCT and immunosuppression containing cyclosporin A (CsA) and different doses of MMF. Pharmacokinetics were performed on days 2, 14 and 27. Dose escalation of MMF from 10 to 30 mg/kg tended to increase area under the curve (AUC) and the apparent oral clearance by 45 and 110%, respectively. Doses applied had no linear association with MPA concentration or blood trough level. No significant drug accumulation occurred over time. Using a twice daily MMF regimen, we conclude that an AUC of 30-60 mug/ml h as recommended for SOT cannot be reached in HSCT. Toxicities did not permit single doses higher than 30 mg/kg. Thus, if larger AUCs are desired in order to assure sufficient immunosuppression in HSCT, MMF might have to be administered at least three times daily.