Tacrolimus

TACROLIMUS- tacrolimus capsule
UDL Laboratories, Inc.

WARNING

Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe tacrolimus capsules. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

DESCRIPTION

Tacrolimus capsules are available for oral administration as capsules containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus. Inactive ingredients in capsules: anhydrous lactose, black iron oxide, colloidal silicon dioxide, croscarmellose sodium, gelatin, hypromellose, lactose monohydrate, magnesium stearate, sodium lauryl sulfate, titanium dioxide and yellow iron oxide. In addition, the 0.5 mg capsules contain D&C Red No. 28, D&C Yellow No. 10 and FD&C Red No. 40, the 1 mg capsules contain FD&C Blue No. 1 and FD&C Red No. 3 and the 5 mg capsules contain D&C Red No. 33, D&C Red No. 28 and D&C Yellow No. 10.

The imprinting ink contains the following: black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze.

Tacrolimus, previously known as FK506, is the active ingredient in tacrolimus capsules. Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as (-)-(3S ,4R ,5S ,8R ,9E ,12S ,14S ,15R ,16S ,18R ,19R ,26aS)-8-allyl-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[(E)-2-[(1R ,3R ,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylvinyl]-14,16-dimethyoxy-4,10,12,18-tetramethyl-15,19-epoxy-3H -pyrido[2,1-c ][1,4]oxaazacyclotricosine-1,7,20,21(4H ,23H)-tetrone-monohydrate.

The chemical structure of tacrolimus is:

structural formula
(click image for full-size original)

Tacrolimus has a molecular formula of C44 H69 NO12 •H2 O and a formula weight of 822.03. Tacrolimus appears as a white to off-white powder. It is insoluble in water, freely soluble in ethanol, very soluble in chloroform and soluble in methanol.

CLINICAL PHARMACOLOGY

Mechanism of Action

Tacrolimus prolongs the survival of the host and transplanted graft in animal transplant models of liver, kidney, bone marrow, small bowel and pancreas, lung and trachea, skin, cornea, and limb.

In animals, tacrolimus has been demonstrated to suppress some humoral immunity and, to a greater extent, cell-mediated reactions such as allograft rejection, delayed type hypersensitivity, collagen-induced arthritis, experimental allergic encephalomyelitis, and graft versus host disease.

Tacrolimus inhibits T-lymphocyte activation, although the exact mechanism of action is not known. Experimental evidence suggests that tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin inhibited. This effect may prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). The net result is the inhibition of T-lymphocyte activation (i.e., immunosuppression).

Pharmacokinetics

Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters (mean ± S.D.) of tacrolimus have been determined following intravenous (IV) and/or oral (PO) administration in healthy volunteers, and in kidney transplant and liver transplant patients. (See table below.)

*
not applicable
AUC0-120
AUC0-72
§
Corrected for individual bioavailability
AUC0-inf
#
not available
Population N Route (Dose) Parameters
Cmax (ng/mL) Tmax (hr) AUC(ng●hr/mL) t½ (hr) CI(L/hr/kg) V(L/kg)
Healthy Volunteers 8 IV(0.025 mg/kg/4 hr) * * 598 ± 125 34.2 ± 7.7 0.040 ± 0.009 1.91 ± 0.31
16 PO(5 mg) 29.7 ± 7.2 1.6 ± 0.7 243± 73 34.8 ± 11.4 0.041§ ± 0.008 1.94§ ± 0.53
Kidney Transplant Patients 26 IV(0.02 mg/kg/12 hr) * * 294± 262 18.8 ± 16.7 0.083 ± 0.050 1.41 ± 0.66
PO(0.2 mg/kg/day) 19.2 ± 10.3 3 203 ± 42 # # #
PO(0.3 mg/kg/day) 24.2 ± 15.8 1.5 288 ± 93 # # #
Liver Transplant Patients 17 IV(0.05 mg/kg/12 hr) * * 3,300 ± 2,130 11.7 ± 3.9 0.053 ± 0.017 0.85 ± 0.30
PO(0.3 mg/kg/day) 68.5 ± 30 2.3 ± 1.5 519 ± 179 # # #

Due to intersubject variability in tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. (See DOSAGE AND ADMINISTRATION). Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics.

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2020. All Rights Reserved.