Dermus Ointment

Dermus Ointment 0.03% (also FK-506 or Fujimycin) is an immunosuppressive drug whose main use is after organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. It is also used in a topical preparation in the treatment of severe atopic dermatitis, severe refractory uveitis after bone marrow transplants, and the skin condition vitiligo. It was discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis. Dermus Ointment 0.03% is chemically known as a macrolide. It reduces peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This FKBP12-FK506 complex inhibits calcineurin which inhibits T-lymphocyte signal transduction and IL-2 transcription.

Dermus Ointment 0.03% is a calcineurin inhibitor used to prevent organ transplant rejection and to treat moderate to severe atopic dermatitis.

For use after allogenic organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. It was given FDA approval in 1994 for use in liver transplantation. Since then, this indication has expanded to kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea, and limb transplants. It has also been used in a topical preparation in the treatment of severe atopic dermatitis.

• Graft Versus Host Disease (GVHD)
• Heart Transplant Rejection
• Kidney Transplant Rejection
• Liver Transplant Rejection
• Oral Lichen Planus
• Psoriasis
• Pyoderma Gangrenosum
• Rheumatoid Arthritis
• Severe Atopic Dermatitis
• Vitiligo
• Moderate Atopic dermatitis
• Refractory Atopic dermatitis
• Refractory Rheumatoid arthritis
• Severe Rheumatoid arthritis

Dermus Ointment 0.03% acts by reducing peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This inhibits both T-lymphocyte signal transduction and IL-2 transcription. Dermus Ointment 0.03% has similar activity to cyclosporine but rates of rejection are lower with tacrolimus. Dermus Ointment 0.03% has also been shown to be effective in the topical treatment of eczema, particularly atopic eczema. It suppresses inflammation in a similar way to steroids, but is not as powerful. An important dermatological advantage of tacrolimus is that it can be used directly on the face; topical steroids cannot be used on the face, as they thin the skin dramatically there. On other parts of the body, topical steroid are generally a better treatment.

The mechanism of action of tacrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that tacrolimus inhibits T-lymphocyte activation by first binding 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 is inhibited. This prevents 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. Dermus Ointment 0.03% also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-, all of which are involved in the early stages of T-cell activation. Additionally, tacrolimus has been shown to inhibit the release of pre-formed mediators from skin mast cells and basophils, and to downregulate the expression of FceRI on Langerhans cells.

Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability in adult kidney transplant patients is 17±10%; in adults liver transplant patients is 22±6%; in healthy subjects is 18±5%. The absolute bioavailability in pediatric liver transplant patients was 31±24%. Dermus Ointment 0.03% maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg. When given without food, the rate and extent of absorption were the greatest. The time of the meal also affected bioavailability. When given immediately after a meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition.

• 2.6 ± 2.1 L/kg [pediatric liver transplant patients]
• 1.07 ± 0.20 L/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV]
• 3.1 ± 1.6 L/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV]
• 3.7 ± 4.7 L/kg [Mild Hepatic Impairment, 7.7 mg dose, PO]
• 3.9 ± 1.0 L/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV]
• 3.1 ± 3.4 L/kg [Severe hepatic impairment, 8 mg dose, PO]

~99% bound to human plasma protein, primarily to albumin and alpha-1-acid glycoprotein. This is independent of concentration over a range of 5-50 ng/mL.

In man, less than 1% of the dose administered is excreted unchanged in urine. When administered IV, fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1%.

The elimination half life in adult healthy volunteers, kidney transplant patients, liver transplants patients, and heart transplant patients are approximately 35, 19, 12, 24 hours, respectively. The elimination half life in pediatric liver transplant patients was 11.5±3.8 hours, in pediatric kidney transplant patients was 10.2±5.0 (range 3.4-25) hours.

• 0.040 L/hr/kg [healthy subjects, IV]
• 0.172 ± 0.088 L/hr/kg [healthy subjects, oral]
• 0.083 L/hr/kg [adult kidney transplant patients, IV]
• 0.053 L/hr/kg [adult liver transplant patients, IV]
• 0.051 L/hr/kg [adult heart transplant patients, IV]
  
• 0.138 ± 0.071 L/hr/kg [pediatric liver transplant patients]
• 0.12 ± 0.04 (range 0.06-0.17) L/hr/kg [pediatric kidney transplant patients]
• 0.038 ± 0.014 L/hr/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV]
• 0.042 ± 0.02 L/hr/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV]
• 0.034 ± 0.019 L/hr/kg [Mild Hepatic Impairment, 7.7 mg dose, PO]
• 0.017 ± 0.013 L/hr/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV]
• 0.016 ± 0.011 L/hr/kg [Severe hepatic impairment, 8 mg dose, PO]

Side effects can be severe and include blurred vision, liver and kidney problems (it is nephrotoxic), seizures, tremors, hypertension, hypomagnesemia, diabetes mellitus, hyperkalemia, itching, insomnia, confusion. LD₅₀=134-194 mg/kg (rat).

• Avoid alcohol. Consuming alcohol may increase the rate of tacrolimus release from extended-release formulations.
• Avoid grapefruit products.
• Exercise caution with St. John's Wort. This herb induces the CYP3A4 metabolism of tacrolimus; therefore, monitoring tacrolimus whole blood trough concentrations may be warranted.
• Take at the same time every day.
• Take on an empty stomach. Take at least 1 hour before or 2 hours after a meal as coadministration with food decreases the rate and extent of absorption.
• Take separate from antacids. Coadministration of tacrolimus with aluminum or magnesium hydroxide antacids may increase the serum levels of tacrolimus, which poses a risk for toxicity.