FK506 in clinical organ transplantation

The Lancet, 1989

FK 506 was given for immunosuppression in 14 liver recipients. The drug was used in the first 10 cases because the recipients under conventional immunosuppression had rejection, nephrotoxicity, or both. This salvage therapy was successful in 7 of the 10 attempts. 2 of the 10 patients in the original salvage group as well as 4 new patients underwent fresh orthotopic liver transplantation under FK 506 plus low-dose steroids from the outset. None of these 6 patients had rejection although 1 with preexisting cor pulmonale and coronary atherosclerosis died of a myocardial infarction. In addition, 2 of the 14 liver recipients were given cadaveric kidneys, either from the same donor or from a different donor, and a third was given a pancreas as well as a kidney from the liver donor. There were no rejections of the kidney and pancreas grafts, and serious side-effects were not encountered.

Transplantation Proceedings, 2002

Annals of Surgery, 1990

The new immunosuppressive drug FK 506 was used from the outset with low doses of prednisone to treat 120 recipients of primary liver grafts and 20 more patients undergoing liver retransplantation. The patient survival rate after 2 to 8 months in the primary liver transplantation series is 93.3%, with original graft survival of 87.5%. Of the 20 patients in the hepatic retransplant series, 17 (85%) are living. Almost all of the surviving patients have good liver function. In addition 11 hearts, 2 double lungs, and a heart-lung have been transplanted under FK 506, with survival of all 14 patients. With all of the organ systems so far tested, including the kidney (which has been reported elsewhere), rejection usually has been controlled without additional drugs and with lower average steroid doses than in the past. Nephrotoxicity has been observed, but not to an alarming degree, and there has been a notable absence of hypertension. There is a suggestion that serum cholesterol may be lowered by FK 506, but this is unproved. Although the adverse reactions of FK 506

Transplantation proceedings, 1991

The Journal of Clinical Pharmacology, 1993

The fIrst•dose pharmacokinetics of FK506 was studied in nine orthotopic liver transplant patients receiving continuous intravenous infusion of O.lS mg/kg/dav. lvlultiple blood samples were obtained during the infusion and plasma FK506 concentrations were measured by enzyme-linked immunosorbent assay. The plasma clearance ranged from 0.47 to 5.B L/minute, and the half-life ranged from 4.5 hours to 33.1 hours. These results indicate the pharmacokinetics of FK506 to be highly variable between patients. FKS06 is extensively distributed outside the plasma compartment. FK506 is extensively metabolized in the body, with less than 1 %) of the administered dose being excreted in the urine as unchanged FK506. The large variability in FKS06 kinetics during the immediate post• operative period is attributed to the variability in the functional status of the liver in the transplant patients. Because of the long half-life of FKS06, it takes more than 45 hours to reach steady-state concentrations after continuous infusion. Based on the estimated kinetic parameters, it appears that a combination of a bolus or a rapid infusion of .02 mg/kg with a continuous infusion of o.os mg/kg/day will provide and maintain a concentration of more than 2 ng/mL from the beginning of the drug treatment. F K506 is a macrolide isolated from the fungus Streptomyces tsukubaensis. 1 It is nearly 100 times more potent than cyclosporine (CsA) in inhibiting lymphocyte proliferation in mixed lymphocyte cultures. 2 FKS06 has been shown to prevent or reverse the rejection of heart. liver, kidney. pancreas. lung, intestine, and skin grafts in mice. rats. dogs. monkeys, and baboons. 3 FKS06 has been in clinical use since March 1989 at the University of Pittsburgh. It was used initially for rescuing livers that have failed under conventional immunosuppression and later as the primary immunosuppressant for liver, kidney, and heart transplantation. 4-6 Current results indicate that FKS06 provides better immunosuppression in From the Schools of Pharmacy (Drs. Venkataramanan and Abdallah) and Medicine (Drs.

Transplantation proceedings, 1991

FK 506, a novel immunosuppressive agent, was first used to reverse rejection in liver recipients who had failed to respond to conventional therapy. 1 The successful outcome of the initial study has led to clinical trials of FK 506 as the primary immunosuppressive agent for liver allografts and other organ transplants. 2-4 Ongoing studies include dosage protocols for optimal immunosuppression without significant side effects. Monitoring plasma levels of FK 506 in the transplant patient is performed using an enzyme-linked immunosorbent assay (ELISA) in the presence of anti-FK 506 monoclonal antibody. 5 FK 506 exhibits strong immunosuppressive effect on in vitro models of T-cell activation including mixed lymphocyte reaction and secondary proliferative responses (PLT) of alloreactive T cells. 6,7 Recently we have developed another method to monitor plasma levels of FK 506, a bioassay based on the inhibition of the PLT response of an alloreactive T-cell clone. 8 Our results indicate that the levels of active FK 506 determined by the bioassay are consistently lower than those measured by ELISA.

Transplantation, 2004

Background. In organ transplantation, several immunosuppressants are currently used to control graft rejection. Clinically, no single immunosuppressive agent can completely prevent posttransplantation immunoreaction; thus, combination therapy is usually performed. Novel agents with more powerful immunosuppressive activity and less toxicity need to be developed. Methods. Lewis rat livers were orthotopically transplanted into Brown-Norway recipients. FK778 was administered orally from day 0 to day 6 to prevent acute rejection and from day 7 to day 13 to rescue ongoing rejection. To assess the combined effects, recipients were treated with intramuscular injection of FK506 and oral administration of FK778 from day 0 to day 6. Blood chemistry and histopathologic findings were measured to determine the patient's general condition and the graft condition. Allospecific antibodies were measured using enzyme-linked immunosorbent assays. The FK778 trough concentration was examined by using high-performance liquid chromatography. Results. The acute immune response was suppressed by FK778 alone in a dose-dependent manner. The optimal FK778 dosage was determined to be 20 mg/kg per day, because adverse effects (weight loss and intestinal bleeding) occurred at 30 mg/kg per day. FK778 treatment from day 7 to day 13 rescued liver grafts from ongoing rejection. The intramuscular FK506 (0.125 mg/kg per day) injection and the oral FK778 (20 mg/kg per day) gavages suppressed acute liver graft rejection effectively and maintained better graft condition compared with monotherapy. Conclusions. FK778 treatment effectively prevented acute rejection and rescued ongoing rejection after liver transplantation. The optimal dosage was determined to be 20 mg/kg per day. Combination therapy with FK506 was more beneficial than FK778 monotherapy.

JAMA: The Journal of the American Medical Association, 1990

The experimental immunosuppressive drug FK 506 was given to 36 renal transplant recipients, many of whom were highly sensitized. Ten were undergoing kidney retransplantation, 10 also underwent liver transplantation at an earlier time (6 patients) or concomitantly (4 patients), and 2 patients received a third organ (heart or pancreas) in addition to a liver and kidney. With follow-ups of 4 to 13 months, all but 2 of the 36 patients are alive, 29 (81 %) are dialysis free, and most have good renal function. Twenty of the 29 dialysis-free patients are receiving no or low-dose (2.5 to 5.0 mg/d) prednisone therapy. Only one kidney was lost to cellular rejection. However, patients who had antidonor cytotoxic antibodies in current or historical serum samples had a high rate (3 of 9) of irreversible humoral rejection. A low incidence of posttransplant hypertension was noteworthy. Hirsutism and gingival hyperplasia were not observed. Serum cholesterol levels in patients who took FK 506 were unexpectedly low, and the effect on the level of uric acid was minimal. The side effects of FK 506 therapy include nephrotoxicity, neurotoxicity, and potential induction of a diabetic state. These are similar to the side effects of cyclosporine use, but probably less severe. The seeming safety, efficacy, and relative freedom from side effects of FK 506 encourage further trials in kidney transplantation. Encouraging clinical trials in liver transplantation have been reported with the new immunosuppressive agent FK 506, 1-3 which is produced by the fungus Streptomyces tsukubaensis. 4,5 Although the molecular structure of FK 506 is unrelated to cyclosporine and has a different cytosolic binding site, 6,7 the two drugs have similar effects on the immune system. 8,9 We report here a trial of FK 506 in kidney recipients, of whom the majority had complex clinical problems or were at high risk because of adverse medical or immunologic factors. METHODS Recipient Case Material Complexity factors in the 36 patients included concomitant or prior liver transplantation (29%), previous kidney transplantation (29%), and causes of renal failure that increase the risk of transplantation (Table 1). The only child in the series (10 years old) had hemolytic uremic syndrome. Hemolytic uremic syndrome is a known complication of cyclosporine use 10 that has been treated successfully with FK 506.11 Five patients were older than 60 years.

PubMed, 1990