Pharmacokinetics of FK 506: preclinical and clinical studies

Organ Transplantation 1990, 1991

Transplantation proceedings, 1991

FK 506 has established itself as a promising immunosuppressive drug in organ transplantation and in the treatment of autoimmune disease. Therapeutic monitoring of plasma concentrations of FK 506 is essential to ensure appropriate dosage for adequate immunosuppression and to minimize potential side effects. Routine monitoring of FK 506 plasma concentration is performed with an enzyme-linked immunoassay (ELISA) previously developed by Tamura et al 1 and modified by Cadoff et al.2 Plasma FK 506 levels also have been measured with an in vitro bioassay.3 This assay is based on the inhibition of the alloantigen driven proliferation of cloned alloreactive T cells. These activated lymphocytes show a narrow sensitivity range to FK 506 and the IC50 is 0.07 to 0.12 nmol/L. In liver allograft recipients. the FK 506 levels as determined by bioassay are consistently lower than those measured by ELISA (Fig 1). These results suggest that the plasma may contain biologically less active FK 506 metabolites, which can be detected by ELISA.

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 is currently used as the primary immunosuppressant in over 800 organ transplant patients at the University of Pittsburgh. FK 506 is a macrolide and is chemically very different from any other immunosuppressive drug used currently in transplant patients. However, FK 506 is very similar to cyclosporine (CyA) in a number of physicochemical properties and its mechanism of action (Table 1). 1,2 The objective of the present study is to determine the pharmacokinetics of FK 506 after oral administration, to compare its kinetic properties with CyA, and to discuss the clinical relevance of the differences in the kinetic properties.

PubMed, 1990

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, 1991

In the transplant populations and patients with autoimmune diseases, the quality of liver function significantly influences FK 506 doses, drug trough plasma levels, and kidney function. The interrelationship of these variables has been previously discussed in patients with different kinds of organ transplantation. 1 In this report, however, we will concentrate only on liver recipients with different degrees of graft dysfunction, particularly in the perioperative period. From this study, a better understanding has been achieved of FK 506 management strategy in patients with variable quality of liver function.

Springer Seminars in Immunopathology, 1993

1994