Mycophenolate mofetil in liver transplantation.
PHARMACOKINETIC STUDIES. Eleven patients undergoing orthotopic liver transplantation (OLT) received mycophenolate mofetil (MMF) orally for prevention of rejection. Additional immunosuppressives used were cyclosporine (CsA) and steroids. Doses ranged from 3.5 to 4.5 g/d. Pharmacokinetic studies were performed between 11 d and 6 months after OLT. The Cmax and Tmax for mycophenolic acid (MPA) were 3.6-35.2 micrograms/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) between d 11 and d 17 was significantly lower compared with d 21. Biliary diversion did not affect clearance. RESCUE THERAPY. Twenty-three patients with steroid- and OKT3-resistant acute rejection were converted to MMF (2-3.5 g/d) at a mean of 20 wk after OLT. Twenty-one patients responded, 14 with resolution of rejection and 7 with improvement. Sixteen patients remained on the drug. Eight patients had 14 infections, with cytomegalovirus (CMV) being the most common. The most common adverse 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 prednisone as primary prophylaxis of rejection after OLT. Target CsA levels were 125-175 (whole-blood high-performance liquid chromatography). Two patients were terminated from the study for possible study drug-related reasons: pancreatitis in one and unsatisfactory response in the other. Gastrointestinal side effects were the most common (10 patients), including gastritis, esophagitis, and duodenal ulcer. Two patients developed leukopenia and/or pancytopenia. Of 5 culture-proven infections, 2 were CMV. After 3 months of follow-up, 7 of 17 patients had no rejection. Of 10 patients with rejection, 7 were treated with pulse steroids and 3 required OKT3. DUAL THERAPY WITH MMF AND STEROIDS. Four patients 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. After 325-500 d of follow-up, 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 established rejection and primary rejection prophylaxis after OLT. More studies are needed to define its role further.
McDiarmid
S V
SV
Department of Pediatrics and Surgery, UCLA Medical Center 90095-1752, USA.
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D016572:Cyclosporine / Q000627:therapeutic use; D003586:Cytomegalovirus Infections; D003967:Diarrhea / Q000139:chemically induced; D005260:Female; D005500:Follow-Up Studies; D005938:Glucocorticoids / Q000627:therapeutic use; D006084:Graft Rejection / Q000188:drug therapy / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007970:Leukopenia / Q000139:chemically induced; D016031:Liver Transplantation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011241:Prednisone / Q000627:therapeutic use; D012008:Recurrence
D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D011241:Prednisone