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Mycophenolate mofetil in liver transplantation
1Department of Pediatrics and Surgery, UCLA Medical Center 90095-1752, USA.
Abstract:
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.
Insights
Mycophenolate mofetil (MMF) shows promise in preventing and treating organ rejection after liver transplants. While generally well-tolerated, further studies are needed to fully establish its role in immunosuppression.
Area of Science:
- Immunology
- Transplantation Medicine
- Pharmacology
Background:
- Orthotopic liver transplantation (OLT) requires effective immunosuppression to prevent rejection.
- Mycophenolate mofetil (MMF) is an immunosuppressive agent evaluated in OLT recipients.
- Combination therapy with other immunosuppressants is common in OLT.
Purpose of the Study:
- To evaluate the pharmacokinetics of MMF in OLT patients.
- To assess the efficacy of MMF as rescue therapy for acute rejection post-OLT.
- To investigate MMF as primary prophylaxis for rejection after OLT.
Main Methods:
- Pharmacokinetic studies were conducted in 11 OLT patients receiving MMF, cyclosporine (CsA), and steroids.
- Rescue therapy involved converting 23 patients with resistant rejection to MMF.
- Dose escalation studies assessed MMF (3.5-5.0 g/d) with reduced CsA and prednisone for primary prophylaxis.
- Dual therapy with MMF and steroids was studied in 4 patients with intolerance to CsA or FK-506.
Main Results:
- MMF pharmacokinetics (Cmax, Tmax, clearance) were characterized and showed no significant changes over 6 months.
- Twenty-one of 23 patients receiving MMF for rescue therapy responded, with 14 achieving resolution of rejection.
- In primary prophylaxis, 7 of 17 patients had no rejection after 3 months; gastrointestinal side effects were common.
- Dual MMF and steroid therapy resulted in resolved rejection in 3 of 4 patients.
Conclusions:
- MMF demonstrates potential as an effective immunosuppressive agent for both primary prophylaxis and treatment of rejection in OLT.
- Adverse events like GI issues and leukopenia were noted.
- Further research is necessary to fully define the role of MMF in OLT immunosuppression.