FK 506 dose in transplantation: from theory to practice

The Journal of Clinical Pharmacology, 1994

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

Transplantation Proceedings, 1998

Organ Transplantation 1990, 1991

Transplant International, 1994

FK 506 plasma levels were analyzed in 89 liver-grafted patients under FK 506-based immunosuppression. Plasma levels were found to be influenced by the patients' liver function: compared to patients without major liver dysfunction, those with cholestasis had higher plasma levels and these plasma levels were able to differentiate between rejection and toxicity. In patients with stable liver function, no clear difference was observed with regard to the plasma levels detectable during toxicity or rejection. We conclude that plasma levels can be used to determine the FK 506 dose but only in patients with cholestasis (i. e., during the early post-transplant course, or in patients with cholestatic rejection). In patients with stable liver function, plasma levels are only of limited clinical relevance.

1994

Transplantation proceedings, 1993

Clinical …, 1993