Oral Bioavailability of Mycophenolate Mofetil in Patients Undergoing Nonmyeloablative Hematopoietic Cell Transplantation (HCT) Is Poor and Highly Variable.
Authors: Jacobson Pamala , Kathleen Green , Rogosheske John , Brunstein Claudio , Barker Juliet , DeFor Todd , McGlave Philip , Weisdorf Daniel 
Published: April 2020

Background: Mycophenolate mofetil (MMF) is a commonly used immune suppressant in nonmyeloablative HCT for establishment of engraftment and prevention of graft vs host disease. MMF is an ester prodrug, which was formulated to enhance the bioavailability of the active form, mycophenolic acid (MPA). MMF is rapidly and extensively (95%) hydrolyzed to MPA by esterases and glucuronidated by UDP glucuronosyltransferases to the primary inactive metabolite, mycophenolic acid glucuronide (MPAG). MPAG is transported to the gut via the bile or excreted into the urine and eliminated. MPAG present in the bile is subject to deglucuronidation where it is converted back to MPA and reabsorbed into the systemic circulation through enterohepatic recycling. Oral MPA AUC is low and highly variable after HCT. Potential reasons for variability are poor and erratic bioavailability due to mucositis, diarrhea, poor motility and diminished oral intake. MPA concentrations are not routinely monitored in many centers, thereby allowing poor oral absorption to go undetected. Since low MPA concentrations are associated with a higher incidence of poor engraftment and graft vs host disease, bioavailability may be of great importance. This study evaluates the oral bioavailability of mycophenolate in the early transplant period, a critical period for immune suppression, when bioavailability is most likely to be perturbed.

Methods: Adult recipients of nonmyeloablative HCT who received a prophylactic MMF (1 gm BID) and cyclosporine (5–7.5 mg/kg/day IV) were studied. Pharmacokinetic sampling was performed at steady state with one IV 1g dose of MMF between day -2 and 0 and then again between days 1–10 post-transplant with one PO 1g dose (four 250mg capsules). Total MPA concentration-time data were analyzed using noncompartmental analysis. Bioavailability was determined by the ratio of PO:IV AUC0–12.

Results: Thirteen subjects have been studied with a median (range) age of 53 (25–68) yrs and weight of 56.6 (82.5–134 kg). Diagnoses leading to HCT were leukemia (n=6), lymphoma (n=6) and multiple myeloma (n=1). Median (range) total MPA AUC0–12 after IV and PO dosing was 28.6 mcg*hr/mL (9.8–70.4) and 16.3 (9.4–35.3), respectively. Oral bioavailability was calculated for each subject. Median oral bioavailability was 71% with high variability (range 20.5–172.0). Median (range) total MPA Cmax after IV and PO dosing was 12.1 mcg/mL (4.4–35.3) and 5.6 (1.49–15.7), respectively.

Conclusion: Oral bioavailability (71%) is substantially less than reported by the manufacturer. Bioavailability was &lt;50% in 5 of the 13 subjects. Variability in bioavailability was high (&gt;8 fold). Standard clinical practice is to convert IV to PO dosing on a 1:1 basis. However, most patients will require higher oral doses to achieve exposure similar to IV therapy. Therapeutic monitoring of MPA during oral therapy and after dosage form conversion is indicated to avoid under dosing and inadequate immunosuppression.