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Lupu M., McCune J. S., Kuhr C. S., Gooley T., Storb R. Pharmacokinetics of oral mycophenolate mofetil in dog: bioavailability studies and the impact of antibiotic therapy. Biology of blood and marrow transplantation, Dec;12(12), pp. 1352-4, 2006.

Abstract: An improved understanding of the pharmacokinetics of mycophenolic acid (MPA), the active metabolite of the immunosuppressant mycophenolate mofetil (MMF), is needed because of the increasing use of MMF in patients undergoing either solid organ or hematopoietic cell transplantation (HCT). Our study sought to determine bioavailability and interdose variability of oral (PO) MMF and the effects of prior and concomitant PO nonabsorbable antibiotics (i.e., neomycin sulfate and polymyxin B sulfate) on PO MMF pharmacokinetics in the preclinical canine model of HCT. In order to define a PO MMF dose that provides a similar bioavailability as a 10 mg/kg subcutaneous (SC) dose, pharmacokinetic parameters of PO MMF were determined in a beagle using single MMF doses of 10, 15, and 20 mg/kg, with the fractions absorbed being 54%, 65%, and 86%, respectively. The impacts of preceding and concomitant non-absorbable antibiotics on MPA pharmacokinetics were evaluated using single PO MMF doses of 15 mg/kg. The variances of the pharmacokinetic parameter measurements were compared using the F-test. Results showed statistically significant interdose variability after PO, but not SC, MMF administration in MPA clearance and total MPA maximum plasma concentration (Cmax) (P = 0.02 and P = 0.006, respectively). Nonabsorbable antibiotics did not impact the MPA free fraction, MPA apparent oral clearance, and Cmax; however, the average of the secondary MPA peaks to the AUC0-12h was reduced by 17.2%. The results suggest that interdose variability after PO MMF administration occurs even in well-controlled conditions, and provide preliminary data regarding the effects of non-absorbable antibiotics upon enterohepatic circulation of MPA, which could be further investigated in HCT patients.

Keywords: mycophenolate mofetil, pharmacokinetics, hematopoietic cell transplantation, immunosuppression, preclinical canine model

Posted by Marilena Plesu (Lupu)

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