Mode of Action
Tacrolimus is a macrolide immunosuppressant produced by the fungus Streptomyces tsukubaensis. It suppresses both humoral and cellular immune responses. The drug inhibits a calcium/calmodulin- dependent phosphatase enzyme, calcineurin,which prevents the activation of T-cell-specific transcription factors that are involved in lymphokine expression. Other mechanisms are probably also involved in the pharmacologic and toxic effects of tacrolimus. (Schwaninger M et al. Naunyn Schmiedbergs Arch Pharmacol. 1993; 348: 541-545.)
Absorption of the drug from the gastrointestinal tract after administration of an oral dose is variable. The absorption half-life as measured in 16 patients is 5.7±4.6 hours. Maximum blood and plasma concentrations are reached 1.5 to 3.5 hours after administration. Disposition of the drug is biphasic. The terminal elimination half-life is 11.7±3.9 hours in transplant patients, compared with 21.2 hours in healthy volunteers. The two capsule forms may not be equivalent: the absolute bioavailability of one 5-mg capsule was 14.4%, compared with 17.4% with five 1-mg capsules. Protein binding was found to be 75% in one study and 99% in another.
Approval of tacrolimus was based on the results of two clinical studies comparing a tacrolimus-based immunosuppressant regimen with a cyclosporine-based regimen. In a US study of 529 patients, use of tacrolimus was associated with an 88% 1-year survival rate for the patients and an 81% survival rate for the transplanted livers. In a European study of 545 patients, the 1-year survival rates were 78% for the patients and 73% for the transplanted organs. The results were equivalent to those obtained with the cyclosporine-based regimen with respect to efficacy and safety.
Clinical evidence suggests that tacrolimus reduces the need for adjunctive immunotherapy (e.g., antilymphocyte preparations) for treatment of rejection episodes, compared with cyclosporine. In addition, tacrolimus therapy may make it possible to reduce or withdraw corticosteroid therapy. (Peters DH, et al. Drugs. 1993; 46: 747-794.) Although the FDA approval is limited to the liver transplant indication, at least one team has found tacrolimus to be very effective in treating severe recalcitrant psoriasis, a disease of unknown cause that involves faulty immune processes. (Jegasothy BV et al. Arch Dermatol. 1992; 128: 781-785.)
The principal safety concern with tacrolimus therapy is the potential for damage to the kidneys and nervous system. The most common adverse events reported in clinical use have been tremors, headache, insomnia, diarrhea, hypertension, nausea, and renal impairment. Side effects tend to appear early in treatment, and they may subside as time passes.
Prograf is to be marketed in two capsule forms and as an injectable solution. The capsules contain 1 or 5 mg anhydrous tacrolimus. The solution contains 5 mg tacrolimus/mL in castor oil and alcohol. The manufacturer recommends that the drug be used concomitantly with adrenal corticosteroids. The injectable form of tacrolimus should be used only in patients who are unable to take the drug orally, to minimize the risk of anaphylactic reactions. (Altman LK. New York Times. Apr 13, 1994, p. A17. Some information provided by the manufacturer.)