Pharmacotherapeutic group: Calcineurin inhibitors. ATC code: L04AD02.
Pharmacology: Pharmacodynamics: Mechanism of Action and Pharmacodynamic Effects: At the molecular level, the effects of tacrolimus appear to be mediated by binding to a cytosolic protein (FKBP12) which is responsible for the intracellular accumulation of the compound. The FKBP12-tacrolimus complex specifically and competitively binds to and inhibits calcineurin, leading to a calcium-dependent inhibition of T-cell signal transduction pathways, thereby preventing transcription of a discrete set of lymphokine genes.
Tacrolimus is a highly immunosuppressive agent and has proven activity in both in vivo and in vitro experiments.
In particular, tacrolimus inhibits the formation of cytotoxic lymphocytes, which are mainly responsible for graft rejection. Tacrolimus suppresses T-cell activation and T-helper-cell dependent B-cell proliferation, as well as the formation of lymphokines (such as interleukins-2,-3 and γ -interferon) and the expression of the interleukin-2 receptor.
Pharmacokinetics: Absorption: In man tacrolimus has been shown to be able to be absorbed throughout the gastrointestinal tract. Following oral administration of Prograf capsules peak concentrations (Cmax) of tacrolimus in blood are achieved in approximately 1 - 3 hours. In some patients, tacrolimus appears to be continuously absorbed over a prolonged period yielding a relatively flat absorption profile. The mean oral bioavailability of tarolimus is in the range of 20% - 25%.
After oral administration (0.30 mg/kg/day) to liver transplant patients, steady-state concentrations of Prograf were achieved within 3 days in the majority of patients.
In healthy subjects, Prograf 0.5 mg, Prograf 1 mg and Prograf 5 mg Capsules, have been shown to be bioequivalent, when administered as equivalent dose.
The rate and extent of absorption of tacrolimus is greatest under fasted conditions. The presence of food decreases both the rate and extent of absorption of tacrolimus, the effect being most pronounced after a high-fat meal. The effect of a high-carbohydrate meal is less pronounced.
In stable liver transplant patients, the oral bioavailability of Prograf was reduced when it was administered after a meal of moderate fat (34% of calories) content. Decreases in AUC (27%) and Cmax (50%), and an increase in tmax (173%) in whole blood were evident.
In a study of stable renal transplant patients who were administered Prograf immediately after a standard continental breakfast the effect on oral bioavailability was less pronounced. Decreases in AUC (2 to 12%) and Cmax (15 to 38%), and an increase in tmax (38 to 80%) in whole blood were evident.
Bile does not influence the absorption of Prograf.
A strong correlation exists between AUC and whole blood trough levels at steady-state. Monitoring of whole blood trough levels therefore provides a good estimate of systemic exposure.
Distribution and Elimination: In man, the disposition of tacrolimus after intravenous infusions may be described as biphasic. In the systemic circulation, tacrolimus binds strongly to erythrocytes resulting in an approximate 20:1 distribution ratio of whole blood/plasma concentrations. In plasma, tacrolimus is highly plasma bound (> 98.8%) to plasma proteins, mainly to serum albumin and α-1 acid glycoprotein. Tacrolimus is extensively distributed in the body. The steady state volume of distribution based on plasma concentrations is approximately 1300L (healthy subjects). Corresponding data based on whole blood data averaged 47.6L.
Tacrolimus is a low-clearance substance. In healthy subjects, the average total body clearance (TBC) estimated from whole blood concentrations was 2.25L/h. In adult liver, kidney and heart transplant patients, values of 4.1 L/h, 6.7 L/h and 3.9 L/h, respectively, have been observed. Paediatric liver transplant recipients have a TBC approximately twice that of adult liver transplant patients. Factors such as low haematocrit and protein levels, which result in an increase in the unbound fraction of tacrolimus, or corticosteroid-induced increased metabolism are considered to be responsible for the higher clearance rates observed following transplantation.
The half-life of tacrolimus is long and variable. In healthy subjects, the mean half-life in whole blood is approximately 43 hours. In adult and paediatric liver transplant patients, it averaged 11.7 hours and 12.4 hours, respectively, compared with 15.6 hours in adult kidney transplant recipients. Increased clearance rates contribute to the shorter half-life observed in transplant recipients.
Metabolism and Biotransformation: Tacrolimus is widely metabolized in the liver, primarily by the cytochrome P450-3A4. Tacrolimus is also considerably metabolized in the intestinal wall. There are several metabolites identified. Only one of these has been shown in vitro to have immunosuppressive activity similar to that of tacrolimus. The other metabolites have only weak or no immunosuppressive activity. In systemic circulation only one of the inactive metabolites is present at low concentrations. Therefore, metabolites do not contribute to pharmacological activity of tacrolimus.
Excretion: Following intravenous and oral administration of 14C-labelled tacrolimus, most of the radioactivity was eliminated in the faeces. Approximately 2% of the radioactivity was eliminated in the urine, less than 1% of unchanged tacrolimus was detected in the urine and the faeces, indicating that tacrolimus is almost completely metabolised prior to elimination: bile being the principal route of elimination.
Toxicology: Preclinical Safety Data: The kidneys and the pancreas were the primary organs affected in toxicity studies performed in rats and baboons. In rats, tacrolimus caused toxic effects to the nervous system and the eyes. Reversible cardiotoxic effects were observed in rabbits following intravenous administration of tacrolimus.
When tacrolimus is administered intravenously as rapid infusion/bolus injection at a dose of 0.1 to 1.0 mg/kg, QTc prolongation has been observed in some animal species. Peak blood concentrations achieved with these doses were above 150 ng/mL which is more than 6-fold higher than mean peak concentrations observed with Prograf in clinical transplantation.
Embryofoetal toxicity was observed in animal studies. Tacrolimus subcutaneously administered to male rats at a doses of 2 or 3 mg/kg/day (1.6 to 6.4 times the clinical dose range based on body surface area) resulted in a dose-related decrease in sperm count.
Tacrolimus given orally at 1.0 mg/kg (0.8 to 2.2 times the clinical dose range based on body surface area) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and adverse effects on female reproduction which were indicated by a higher rate of post-implantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (2.6 to 6.9 times the clinical dose range based on body surface area), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.