General Guidelines for the Use of Tacrolimus in Adult Liver Transplant Patients

Since tacrolimus (FK506, Prograf) was approved for use in adult recipients of liver transplants, there has been extensive experience and numerous reports on the success achieved with this agent. Our own experience with tacrolimus in adult liver transplant patients has led us to formulate general guidelines that address pragmatic clinical concerns regarding the use of this agent in the adult population. It is our hope that these guidelines will be helpful to others already using this immunosuppressant or those contemplating its use. We hope also to stimulate an open dialogue that will help build on the success already attained with tacrolimus in adult liver transplant recipients. Dosing. Our experience indicates that the use of intravenous tacrolimus should be avoided, largely to prevent the development of nephrotoxicity (1). If intravenous use is necessary, we recommend a dosage of 0.01-0.05 mg/kg as a 24-hour continuous infusion. In patients who demonstrate initially good graft and renal function, we suggest a starting oral dose of 0.1-0.15 mg/kg/day tacrolimus in divided doses, beginning within 24 hours of liver reperfusion. Administration of tacrolimus is accomplished by dissolving the desired amount of the capsule's contents in water and giving the mixture through the nasogastric tube or orally. With respect to oral administration of drug, consistency of drug administration with regard to mealtimes should be observed. Dose adjustment. For patients who exhibit poor graft function (transaminases >2500, INR>2, and/or inadequate bile output), it is advisable to start with a reduced dose of tacrolimus (0.05-0.075 mg/kg/day). Lower doses of tacrolimus are also warranted in patients who receive grafts of marginal quality (prolonged ischemia, older donors >60 years of age, steatotic grafts). Reduced hepatic metabolism will result in higher circulating levels and possible toxicity. If toxicity occurs in the recipients of these older organs, the tacrolimus dosage should be decreased further. Patients with poor renal function may benefit from delaying tacrolimus therapy for 72 hours or until the urine output exceeds 60 ml/hr or serum creatinine concentration decreases. Tacrolimus should also be delayed in comatose patients with acute or acute on chronic liver failure who demonstrate stage III-IV encephalopathy until awakening. Induction therapy with OKT3 may be appropriate for these patients or those who manifest severe renal failure. Steroid taper and monitoring. The concomitant use of steroids in tacrolimus-treated patients should follow a relatively rapid taper. On the first postoperative day, we typically administer 100-200 mg/day i.v. prednisolone in four divided doses. This is tapered by approximately 25% every 48 hours until a dosage of 20 mg/day is reached by postoperative day 9. Thereafter, the steroid dose is tapered with a target dose of oral prednisone being 10-15 mg/day by postoperative day 30, 7.5-10 mg/day by day 60, 5-7.5 mg/day by day 90, and 2.5-5 mg/day by day 180. After 1 year, it may be possible to discontinue steroids entirely in selected patients. With regard to other immunosuppressive agents, azathioprine may be used as an adjunctive therapy in some patients. However, the concomitant administration of tacrolimus and cyclosporine should be avoided. We suggest that tacrolimus blood trough levels be monitored on a daily basis until good graft and renal function are achieved and at a minimum of every other day afterward during the initial period of posttransplant hospitalization. Daily monitoring is also indicated at times of changing liver function or when metabolic interaction with other agents is anticipated. In the presence of good graft function and the absence of toxicity, tacrolimus blood trough levels should range between 10 and 20 ng/ml during the first month after transplantation, 5 and 15 ng/ml during the subsequent 2 months, and 5 and 10 ng/ml after 3 months (2). Adjustment for toxicity. Tacrolimus dosage adjustments may be necessary in certain circumstances. For example, if nephrotoxic or neurotoxic side effects occur, it is prudent to lower the tacrolimus dosage to the lowest level possible while still avoiding rejection. The addition of another immunosuppressant such as azathioprine may be helpful. It may be necessary to reduce tacrolimus doses below the therapeutic range to avoid toxicity (3-7). In some patients, particularly those who exhibit neurotoxic side effects, conversion to cyclosporine may be required. Decreasing the tacrolimus dosage is also indicated in patients with symptoms of gastrointestinal toxicity (e.g., diarrhea, nausea, vomiting, crampy abdominal pain) and in those in whom diabetes mellitus develops. Insulin is generally required in the patients with diabetes and, over the long term, it may be necessary to switch some of these patients to an alternative immunosuppressive regimen (3, 5, 7-9). Lowering the tacrolimus dosage may be effective in patients in whom alopecia, rash, or pruritus develops. Conversion to an alternate immunosuppressant may be considered in selected patients. Hyperkalemia may respond to dosage adjustment. It is wise to avoid potassium-sparing diuretics in patients on tacrolimus therapy. When conversion from a tacrolimus- to a cyclosporine- based immunosuppressive regimen is justified, we suggest stopping tacrolimus for a 24-hour period and then beginning treatment with an appropriate dosage of cyclosporine. Conversion from cyclosporine. Patients may be converted from cyclosporine to tacrolimus therapy following steroid-and/or OKT3-refractory rejection, late rejection (>6 months after transplantation), or histologically diagnosed chronic rejection, when toxicity to cyclosporine ensues (e.g., hirsutism, gingivitis, severe hypertension, and other persistent, troublesome toxic side effects), and in cases of gastrointestinal malabsorption, severe cholestasis, or biliary fistula (9-11). When converting a patient from cyclosporine to tacrolimus, our recommended procedure is to discontinue cyclosporine for 24 hours and then to initiate tacrolimus, using a dosage of 0.1-0.15 mg/kg/day every 12 hours for patients undergoing conversion therapy for rejection and 0.05-0.1 mg/kg/day every 12 hours for those being converted due to cyclosporine toxicity. Interactions with other drugs in tacrolimus-treated patients are similar to those observed in patients on cyclosporine. Table 1 provides a list of agents that are known to affect tacrolimus blood trough levels (12-14) Alcohol may also affect tacrolimus levels and should be avoided by patients on tacrolimus immunosuppression. As our experience with the use of tacrolimus in adult liver transplant patients grows, we continue to fine tune the management of our patients. The guidelines offered here represent our consensus view of the current situation. Ronald W. Busuttil1; Goran B.G. Klintmalm2; John R. Lake3; Charles M. Miller4; Michael Porayko5 UCLA Medical Center; Baylor University Medical Center; University of California, San Francisco; Mt. Sinai Medical Center; Mayo Clinic Medical School