Tacrolimus
Brand Names: Prograf®, Protopic®
Classification:
Biologic Response Modifiers
» Immunosuppressives
Dermatological Agents
Dermatological Agents
» Topical Antiinflammatory Agents
Description: Tacrolimus is a macrolide immunosuppressive agent that is derived from the fungus Streptomyces tsukubaensis, originally found in a soil sample taken from the base of Mt. Tsukuba in Japan. Tacrolimus has been studied in patients receiving heart, kidney, liver, lung, pancreas, small bowel, or bone marrow transplants. Tacrolimus has been shown to be effective in graft rejection prophylaxis and in the management of acute and steroid- or cyclosporine-resistant transplant rejection. Tacrolimus is considered an alternative to cyclosporine immunosuppression. Tacrolimus has been shown to be 10 - 100 times more potent than cyclosporine. A review of clinical trials in liver and kidney transplantation suggests comparable patient and graft survival rates between patients receiving cyclosporine and those receiving tacrolimus, and a consistent statistically significant advantage for tacrolimus with respect to acute rejection rate. Tacrolimus has also been used for the treatment of refractory or chronic graft rejection. Tacrolimus was approved by the FDA for the prevention of liver transplant rejection in April 1994. A topical formulation of tacrolimus (Protopic®) for the treatment of atopic dermatitis was FDA-approved for use in adults and children in December 2000. On February 15, 2005, the FDA announced the addition of a Black Box warning to the professional label for Protopic® (tacrolimus topical), instructing prescribers to use only after failure of other eczema treatments due to a possible increased cancer risk; a Medication Guide will also accompany all prescriptions for Protopic®.
Mechanism of Action: Tacrolimus induces immunosuppression by inhibiting the first phase of T-cell activation. The first phase of T-cell activation causes transcriptional activation of immediate and early proteins (e.g., interleukin (IL)-2, IL-3, IL-4, granulocyte-macrophage colony stimulating factor (GM-CSF), and interferon gamma) that allow T-cells to progress from the G0- to G1-phase. Tacrolimus binds to an immunophilin termed FK binding protein (FKBP), specifically FKBP12. Immunophilins (cyclophilin and FK binding proteins) are immunosuppressant-binding proteins that are distributed in all cellular compartments and play an important role in protein activation. The tacrolimus-FK binding protein complex binds to and inhibits the phosphatase activity of calcineurin. The calcineurin enzyme catalyzes critical dephosphorylation reactions necessary for early lymphokine gene transcription. Calcineurin inhibition results in blockade of signal transduction by the cytosol component of the nuclear factor of activated T-cells (NF-AT), which results in a failure to activate NF-AT regulated genes. NF-AT activated genes include those required for B-cell activation (e.g., IL-4 and CD40 ligand) and those required for T-cell activation (e.g., IL-2, TNF-alpha, and interferon gamma). Reduced circulating levels of T-cell activators result in inhibition of T-cell proliferative responses to antigens and mitogens including mixed lymphocyte reactivity and cytotoxic T-cell generation. Compared to cyclosporine, tacrolimus is about 100-times more potent in inhibiting T-cell proliferative responses.
 Prograf Capsules (Cap 5 mg)
In atopic dermatitis, topical tacrolimus acts to inhibit inflammation primarily by inhibiting T-cells. Tacrolimus may also bind to cell surface steroid receptors, inhibit the release of mast cell mediators, down-regulate IL-8 receptors, and decrease intracellular adhesion molecule-1 and E-selectin lesional blood vessel expression. These activities lead to decreased antigen recognition and down-regulation of the entire inflammatory cascade leading to a clinical response. Topical tacrolimus does not inhibit collagen synthesis and, therefore, does not cause skin atrophy as seen with corticosteroid therapy.
Pharmacokinetics: Tacrolimus is administered orally, parenterally, and topically. Following oral administration, tacrolimus absorption is poor and variable. The absolute bioavailability of tacrolimus varies from 17 - 22%. The presence of food can alter both the rate and extent of tacrolimus absorption. In healthy volunteers, the mean AUC and Cmax are decreased 37% and 77%, respectively, following a high-fat meal. A high carbohydrate meal also decreases the mean AUC and Cmax 28% and 65%, respectively. The time of the meal in relation to the dose also affects tacrolimus bioavailability in healthy volunteers. When given immediately following the meal the Cmax and AUC are decreased 71% and 39%, respectively, relative to the fasted condition. When administered 1.5 hours following the meal the Cmax is reduced 63% and the mean AUC is reduced 39%, relative to the fasted condition. Tacrolimus is a substrate and inhibitor of P-glycoprotein, which is an energy-dependent drug-efflux pump located in intestinal epithelium and the blood brain barrier. There appears to be overlap between inhibitors and/or substrates of cytochrome P450 (CYP) 3A4 and P-glycoprotein. The P-glycoprotein efflux of tacrolimus from intestinal cells back into the gut lumen allows for CYP3A4 metabolism prior to absorption, thus limiting tacrolimus availability. When tacrolimus is administered with inhibitors of both CYP3A4 and P-glycoprotein (e.g., diltiazem, erythromycin, or ketoconazole) increased tacrolimus bioavailability leads to increased concentrations.
The absolute bioavailability of tacrolimus applied topically is unknown. Following topical administration of single or multiple doses of the 0.1% ointment to adults, peak tacrolimus blood concentrations ranged from undetectable to 20 ng/ml. Most patients had peak blood concentrations < 5 ng/ml. In pediatric patients, application of the 0.1% ointment resulted in peak blood concentrations below 1.6 ng/ml. There is no evidence that tacrolimus accumulates systemically following topical administration. The lowest tacrolimus blood concentration that may elicit systemic effects is unknown.
Due to high lipophilicity, tissue distribution of tacrolimus following oral or parenteral therapy is extensive. Tacrolimus crosses the placenta creating fetal cord plasma concentrations that are 35% of the maternal plasma concentration. The drug is also excreted in breast milk with concentrations similar to those in plasma. Protein binding is approximately 99%. Tacrolimus is mainly bound to albumin and alpha1-acid glycoprotein. Erythrocytes bind 75 - 80% of the drug resulting in whole blood concentrations that are 10- to 30-times higher than plasma concentrations. The distribution of tacrolimus between erythrocytes and plasma is dependent upon tacrolimus concentration, hematocrit, and temperature. Metabolism of tacrolimus is mainly by demethylation and hydroxylation via the hepatic cytochrome P450 enzyme 3A4. The formation of 8 possible metabolites has been proposed. The major metabolite identified in vitro is 13-demethyl tacrolimus, which in vitro has been reported to have the same activity as tacrolimus. The elimination half-life of tacrolimus in liver transplant patients is about 12 hours. Less than 1% of the dose is excreted unchanged in the urine.
Special Populations: Systemic tacrolimus administration to patients with hepatic dysfunction is associated with increased whole blood concentrations, prolonged half-life, and reduced clearance. The half-life of tacrolimus in patients with mild hepatic impairment ranges from 28 - 141 hours. In a study of 6 patients with severe hepatic dysfunction (mean Pugh score > 10), the mean tacrolimus clearance was substantially lower, irrespective of the route of administration. Pediatric transplant patients have a greater clearance of tacrolimus as compared to adults resulting in the need for higher doses relative to body weight in pediatric patients to achieve appropriate whole blood concentrations. Black patients may also require increased doses to achieve therapeutic whole blood levels.
References
. Fleischer AB. Treatment of atopic dermatitis: role of tacrolimus ointment as a topical noncorticosteroid therapy. J Allergy Clin Immunol 1999;104:S126 - 30.
. Plosker GL, Foster RH. Tacrolimus: a further update of its pharmacology and therapeutic use in the management of organ transplantation. Drugs 2000;59:323 - 89.
[1 of 5 - Click here to see more photos]
[ Revised 5/2/2006 8:44:00 PM ]
Related entries
Syndicate
|
