MYCOPHENOLATE MOFETIL IN LIVER-TRANSPLANTATION

Pharmacokinetic studies: Eleven patients undergoing orthotopic liver t ransplantation (OLT) received mycophenolate mofetil (MMF) orally for p revention of rejection. Additional immunosuppressives used were cyclos porine (CsA) and steroids. Doses ranged from 3.5 to 4.5 g/d. Pharmacok inetic studies were performed between 11 d and 6 months after OLT. The C-max and T-max for mycophenolic acid (MPA) were 3.6-35.2 mu g/mL and 0.5-4 h, respectively, and did not significantly change over 6 months . Oral clearance of MMF (dose of MMF/area under the curve for MPA) bet ween d 11 and d 17 was significantly lower compared with d 21. Biliary diversion did not affect clearance. Rescue therapy. Twenty-three pati ents with steroid- and OKT3-resistant acute rejection were converted t o MMF (2-3.5 g/d) at a mean of 20 wk after OLT. Twenty-one patients re sponded, 14 with resolution of rejection and 7 with improvement. Sixte en patients remained on the drug. Eight patients had 14 infections, wi th cytomegalovirus (CMV) being the most common. The most common advers e events were diarrhea (4 patients) and leukopenia (3 patients). Four patients with chronic rejection all failed to improve after conversion to MMF. Dose escalation studies - primary therapy: Seventeen patients received 3.5-5.0 g of MMF per d orally with reduced-dose CsA and pred nisone as primary prophylaxis of rejection after OLT. Target CsA level s were 125-175 (whole-blood high-performance liquid chromatography). T wo patients were terminated from the study for possible study drug-rel ated reasons: pancreatitis in one and unsatisfactory response in the o ther. Gastrointestinal side effects were the most common (10 patients) , including gastritis, esophagitis, and duodenal ulcer. Two patients d eveloped leukopenia and/or pancytopenia. Of 5 culture-proven infection s, 2 were CMV. After 3 months of follow-up, 7 of 17 patients had no re jection. Of 10 patients with rejection, 7 were treated with pulse ster oids and 3 required OKT3. Dual therapy with MMF and steroids. Four pat ients with rejection and unacceptable toxicity secondary to either CsA or FK-506 were treated with MMF 2-4 g/d and 20 mg of prednisone. Afte r 325-500 d of followup, 3 had resolved their rejection episode and 1 had recurrent rejection and was restarted on low-dose CsA.Conclusion: MMF is a promising new immunosuppressive agent for both treatment of e stablished rejection and primary rejection prophylaxis after OLT. More studies are needed to define its role further.