Highly variable mycophenolate mofetil bioavailability following nonmyeloablative hematopoietic cell transplantation

Area of Science:

• Pharmacology
• Transplantation Medicine
• Immunosuppression

Background:

• Mycophenolate mofetil is a key immunosuppressant used in nonmyeloablative hematopoietic cell transplantation.
• Its active metabolite, mycophenolic acid (MPA), is essential for preventing graft rejection.
• Understanding MPA's oral bioavailability is critical for optimizing therapeutic efficacy and patient outcomes.

Purpose of the Study:

• To determine the oral bioavailability of mycophenolic acid in patients undergoing nonmyeloablative hematopoietic cell transplantation.
• To assess the pharmacokinetic variability of MPA following both intravenous and oral administration.
• To provide dosing recommendations for MPA in this patient population.

Main Methods:

• Study included 18 adult patients receiving a preparative regimen of fludarabine, cyclophosphamide, and total body irradiation.
• Patients received immunosuppression with cyclosporine and mycophenolate 1 g twice daily.
• Pharmacokinetic parameters, including area under the curve (AUC) and maximum concentration (Cmax), were measured after intravenous and oral dosing.

Main Results:

• High pharmacokinetic variability was observed for MPA after both intravenous and oral administration.
• Median oral bioavailability of MPA was 72.3% (range, 20.5%-172%), with significant inter-individual variability (8-fold).
• Twenty-eight percent of patients exhibited oral bioavailability less than or equal to 50%, and 83% had an AUC(0-12) below 30 microg x h/mL.

Conclusions:

• Significant variability in mycophenolic acid oral bioavailability necessitates careful dosing strategies.
• An initial oral dose at least 25% higher than the intravenous dose is suggested.
• Close monitoring of plasma concentrations is recommended to ensure adequate immunosuppression.