Pharmacokinetics of FK506 in Liver Transplant Recipients After Continuous Intravenous Infusion

Abstract

The first-dose pharmacokinetics of FK506 was studied in nine orthotopic liver transplant patients receiving continuous intravenous infusion of 0.15 mg/kg/day. Multiple blood samples were obtained during the infusion and plasma FK506 concentrations were measured hy enzyme-linked immunosorbent assay. The plasma clearance ranged from 0.47 to 5.8 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. FK506 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 FK506 kinetics during the immediate postoperative period is attributed to the variability in the functional status of the liver in the transplant patients. Because of the long half-life of FK506, 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 0.05 mg/kg/day will provide and maintain a concentration of more than 2 ng/mL from the beginning of the drug treatment.FKC506 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 FK506 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 FK506 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 FK506 provides better immunosuppression in liver and heart transplant recipients than does CsA. 4,[6][7][8] After transplantation, FK506 is administered intravenously as a continuous infusion at a dose of 0.15 mg/kg/day and then orally at a dose of 0.3 mg/kg/ day twice daily, when the patient can tolerate oral intake. Further dose alterations are normally made based on patient's liver function, episodes of rejection or toxicity, and trough plasma FK506 concentrations. The intravenous dosage form of FK506 is a 10-mg/mL FK506 solution with polyethoxylated hydrogenated castor oil (HCO-60, a nonionic surfactant) and alcohol. This solution is diluted in 100 mL of 5% dextrose and infused at a rate of 4 mL/hour over 24 hours. The Address for reprints: Raman Venkataramanan,

Chrono and clinical pharmacokinetic study of tacrolimus in continuous intravenous administration

“…To achieve an adequate drug concentration, the initiation of tacrolimus therapy via the continuous intravenous route is probably a better method of administration. 14 The pharmacokinetics of tacrolimus have been clarified in healthy volunteers and liver and kidney transplant patients. [13][14][15][16] Several studies have been undertaken on the circadian changes of various drugs.…”

“…14 The pharmacokinetics of tacrolimus have been clarified in healthy volunteers and liver and kidney transplant patients. [13][14][15][16] Several studies have been undertaken on the circadian changes of various drugs. 15 Pharmacokinetics due to circadian rhythms are affected by various factors, such as alteration in absorption and liver function.…”

“…8 However, there are large interindividual variations in the pharmacokinetics of tacrolimus from this and other studies. 9,10,13,14,16,19,20 It can be concluded that initiation of tacrolimus therapy via the intravenous route is a better method of administration. The conversion dosage cannot be calculated from preoperative oral or postoperative intravenous pharmacokinetics.…”

Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation

“…27,[38][39][40][41] Less than 1% of an intravenous or oral dose is found in the urine. 27,42 The drug undergoes demethylation, hydroxylation and conjugation in the liver with most of the metabolites, and possibly conjugates, of tacrolimus eliminated in the bile. 27,40,43 Although many metabolites exist, their immunosuppressive activity is not well characterized.…”

Altered metabolism of tacrolimus in hepatic veno-occlusive disease

“…Tacrolimus undergoes an extensive metabolism in the liver, which is mainly mediated by cytochrome P450 (CYP) 3A4 isoenzymes [1]. Therefore, liver dysfunction has been associated with a prolonged half-life and reduced clearance of tacrolimus [2][3][4][5]. Veno-occlusive disease (VOD) of the liver is one of the serious early complications after HSCT; it is characterized by a syndrome of jaundice, fluid retention, and painful hepatomegaly.…”