Tacrolimus Mechanism of Action: Preventions & Side Effects

Our immune system maintains self-tolerance. Tacrolimus, commonly available under the brand name Prograf, is an immunosuppressant medication primarily used to prevent organ rejection after transplantation (kidney, liver, heart, lung). It works by suppressing the immune system, which helps prevent the body from attacking the transplanted organ. Let’s have a look at Tacrolimus mechanism of action, some common Tacrolimus side effects and possible solutions to manage them.

Tacrolimus Mechanism of Action, Potencies, Administration Route, Warnings, Cessation,

• Mechanism of Action: Tacrolimus’s mechanism of action mainly involves inhibiting calcineurin/calcineurin phosphatase (calcium-activated serine/threonine protein phosphatase), a protein involved in the activation of T-cells, a crucial component of the immune system. By suppressing T-cell activity, tacrolimus prevents the body from recognising the transplanted organ as foreign and attacking it.
• Administration & Potencies: Tacrolimus can be administered through the intravenous route IV injected into veins), oral (usually in tablet form), topical (applied as an ointment), and sublingual (placed under the tongue).

Available in 0.5mg, 1mg, and 5mg. Tacrolimus dosing is highly individualized and requires careful monitoring by a healthcare professional. According to the dosing instruction shared by the NIH, oral and intravenous dosing varies in the case of a Heart, Liver, or Kidney transplant. The following are the adult dosing guidelines:

Heart Transplant: (Used with an antimetabolite)

Oral:

• IR: Start with 0.075 mg/kg/day, split into two doses every 12 hours.
• IV: Start with 0.01 mg/kg/day as a continuous infusion.

Liver Transplant:

Oral:

• IR (Immediate Release): Start with 0.1 to 0.15 mg/kg/day, split into two doses, combined with other medications.
• ER (Extended Release): Take 0.1 to 0.2 mg/kg once daily with a corticosteroid. (Note: The XL version is not approved in the US for liver transplants due to higher death rates in female patients.)
• IV (Intravenous): Start with 0.03 to 0.05 mg/kg/day as a continuous infusion.

Kidney Transplant: (Used with an antimetabolite)

Oral:

• IR: Start with 0.2 mg/kg/day if combined with azathioprine, or 0.1 mg/kg/day if combined with mycophenolate mofetil.

ER:

• XL: 0.15 to 0.2 mg/kg/day with basiliximab, or 0.2 mg/kg/day without it.
• XR: Start with 0.14 mg/kg/day.
• IV: 0.03 to 0.05 mg/kg/day as a continuous infusion.

Warnings:

-Serious Side Effects: Tacrolimus can cause serious side effects, including kidney problems, high blood pressure, diabetes, and an increased risk of infection.

-Cancer Risk: Some studies have suggested a possible increased risk of certain cancers in individuals taking tacrolimus long-term.

-Drug Interactions: Tacrolimus interacts with numerous medications, including many commonly used drugs.

The CYP3A4 and CYP3A5 enzymes are primarily responsible for metabolising Tacrolimus, among which CYP3A5 is the predominant one. A non-invasive PGx test by RPh LABS, by showing whether you are a normal, rapid, or poor metabolizer of CYP3A5 (genotype *3/*3) or CYP3A4 (genotype *1/*1), can help you and your doctor tailor the dose according to your metabolism. This test requires just a saliva cheek swab and gives you insights into how your body may respond to 250+ medications.

• Cessation Rules: Abruptly stopping tacrolimus can lead to severe consequences, including organ rejection. Therefore, it should always be tapered off gradually under the close supervision of a healthcare professional.
• Dose Adjustments: Tacrolimus dosing requires careful monitoring and frequent blood tests to ensure therapeutic levels and minimise side effects. Dose adjustments are often necessary based on blood levels, kidney function, and other factors.
• Active Ingredient: Considering Prograf as the most commonly used immunosuppressant. The active ingredient in Prograf is tacrolimus.
• Metabolism: Tacrolimus is primarily metabolised by the liver enzyme CYP3A5.

Can Tacrolimus (Prograf) Be Abused?

Tacrolimus is a prescription medication, and its use should be strictly as directed by a healthcare professional. Due to its potent immunosuppressive effects and potential for serious side effects, tacrolimus has a low potential for abuse. However, it can be misused if taken in higher doses than prescribed or used without medical supervision.

Side Effects of Tacrolimus (Prograf) on CYP3A5

• CYP3A5 Poor Metabolizers: Individuals who are poor metabolizers of CYP3A5 may experience higher blood levels of tacrolimus, increasing the risk of side effects.
• CYP3A5 Rapid Metabolizers: Individuals who are rapid metabolizers of CYP3A5 may require higher doses of tacrolimus to achieve the desired therapeutic effect.

How Should Tacrolimus Doses Be Personalised?

Tacrolimus dosing is highly individualised and requires careful monitoring. Factors that influence dosing include:

• Transplant type: The type of organ transplanted (e.g., kidney, liver) significantly impacts dosing requirements.
• Patient factors: Age, weight, kidney function, and liver function all play a role in determining the appropriate dose.
• Drug interactions: Concurrent medications can significantly impact tacrolimus levels.
• CYP3A5 genotype: The individual’s CYP3A5 genotype can influence tacrolimus metabolism and therefore dosing. Pharmacogenetics testing, commonly known as PGx testing, can help doctors administer dosages according to your genome (set of all DNA).

Conclusion

Tacrolimus is a powerful immunosuppressant medication administered to prevent organ rejection (by the immune system) after transplantation. While it can effectively prevent rejection, Tacrolimus side effects can be critical; hence, careful monitoring, regular blood tests, and close collaboration with the healthcare team are required to optimise treatment and minimise adverse effects. Here you can check how Pharmacogenomics testing at home works.

References:

https://pubmed.ncbi.nlm.nih.gov/12790696/
https://www.ncbi.nlm.nih.gov/books/NBK544318/
https://www.mayoclinic.org/drugs-supplements/tacrolimus-oral-route/description/drg-20068314
https://my.clevelandclinic.org/health/drugs/19932-tacrolimus-capsules

Disclaimer:

This blog post is for informational purposes only. Always consult a doctor before taking any medical action, including, but not limited to, changing your dosages or ceasing your medication.