Tacrolimus

Mechanism of Action

Tacrolimus is a calcineurin inhibitor (CNI). It inhibits T-cell proliferation by binding to FK506 binding protein (FKBP).[2]

The following are pharmacologic parameters of tacrolimus[3][4][5][6]:

• Metabolism: CYP3A4, CYP3A5, P-glycoprotein (PGP)/ABCB1
• Metabolites: Fifteen possible; chief breakdown metabolite: 13-O-dimethyl-tacrolimus
• Enzymes Inhibited: CYP3A4
• Half-Life: 4 to 41 h (about 12 h on average)
• The volume of Distribution (using plasma separated at 37 degrees C): approximately 30 L/kg
• Clearance (using plasma separated at 37 degrees C): 1.69 +/- 0.57 L/h/kg
• Excretion: Biliary route (approximately 95%), urinary excretion (approximately 2.4% as unchanged drug)

Administration

Tacrolimus can administration can be by oral, sublingual, topical, or intravenous (IV) route. Oral tacrolimus is available in immediate-release (IR) and extended-release (ER: XR and XL) formulations. The various formulations have different pharmacokinetic parameters and are not interchangeable. Doses should be titrated to target trough concentrations.

Prevention of Post-Organ Transplant Rejection (Adult Dosing)

Liver Transplant:

• Oral[7]:
  • IR: Initially 0.1 to 0.15 mg/kg/day in two divided doses in combination
  • ER: 0.1 to 0.2 mg/kg once daily in combination with corticosteroid. Please note that the XL formulation is not approved for liver transplants in the US due to increased mortality in female liver transplants receiving the XL formulation.
• IV: Initially 0.03 to 0.05 mg/kg/day as a continuous infusion

Heart Transplant: In combination with an antimetabolite

• Oral: IR: Initially 0.075 mg/kg/day in two divided doses, given every 12 hours
• IV:  Initially 0.01 mg/kg/day as a continuous infusion

Kidney Transplant: Use in combination with an antimetabolite agent

• Oral:
  • IR: Initially, 0.2 mg/kg/day in combination with azathioprine or 0.1 mg/kg/day combined with mycophenolate mofetil.
  • ER:
    • XL: 0.15 to 0.2 mg/kg/day with basiliximab induction; 0.2mg/kg/day without basiliximab induction.
    • XR:  Initially 0.14 mg/kg/day
• IV: 0.03 to 0.05 mg/kg/day as a continuous infusion

IV tacrolimus use is not common due to increased nephrotoxic adverse effects.[8][9]

Tacrolimus can be administered with or without food but may occur with food in the presence of GI intolerance. IR doses should be 12 hours apart. Dose rounding should be to a whole number that is feasible with the available strengths. For example, IR tacrolimus comes in 0.5 mg, 1mg, and 5 mg strengths.[10]

When converting from IR to ER formulations, utilize the following factors [7][11]:

• IR to XL: 1 to 1
• IR to XR: 1 to 0.8

Sublingual to oral conversion rates have varied from 1 to 1 to 1 to 3, but 1 to 2 has recently been the most commonly suggested in studies. There has been no optimally established dosing.[12][13]

Adverse Effects

Adverse effects include, but are not limited to:[14][15]

• Cardiovascular: Angina pectoris, cardiac arrhythmias, hypertension
• Central nervous system: Abnormal dreams, headaches, insomnia, tremors
• Dermatologic: Acne vulgaris, alopecia, pruritis, rash
• Endocrine and metabolic: Decreased serum bicarbonate, decreased serum iron, new-onset diabetes mellitus after transplant (NODAT), hypercalcemia, hyperkalemia, hyperlipidemia, hyperphosphatemia, hypertriglyceridemia, hyperuricemia, hypervolemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, metabolic acidosis, weight gain
• Gastrointestinal: Abdominal pain, nausea, vomiting, diarrhea
• Genitourinary: Urinary tract infection
• Hepatic: Abnormal hepatic function tests
• Infection: Bacterial infection, BK virus, candidiasis, cytomegalovirus, Epstein-Barr infection, herpes simplex infection, herpes zoster infection, other opportunistic infection
• Neuromuscular and skeletal: Arthralgia, muscle cramps
• Ophthalmic: Blurred vision, visual disturbance
• Otic: Otalgia, otitis media, tinnitus
• Renal: Acute renal failure, increased blood urea nitrogen (BUN), increase serum creatinine (SCr), renal failure syndrome, renal tubular necrosis, decreased GFR, nephrotoxicity

Infection may be secondary to immunosuppression and highlights the importance of reducing target doses with careful monitoring to balance the risk of rejection.

Contraindications

Contraindications to tacrolimus include:

• Hypersensitivity
• Polyoxyl 60 hydrogenated castor oil (HCO-60) or other components of the formulation

Monitoring

Tacrolimus is a narrow therapeutic index drug. Therapeutic monitoring of tacrolimus in transplant patients is a valuable tool in adjusting drug levels. Since tacrolimus use is typically in combination with other immunosuppressants, target levels usually decrease as post-transplant time increases to minimize calcineurin inhibitor-mediated nephrotoxicity and adverse effects.[16] Whole blood concentrations should be used, drawn typically within 30 minutes before the next dose. Therapeutic levels range from 5 to 20 mcg/mL, though 5 to 15 mcg/mL is often employed to alleviate toxicity while preventing rejection.

Additional monitoring parameters include renal function, hepatic function, serum electrolytes (Mg, Phos, K), glucose, and blood pressure. Parameters should initially be measured two to three times a week post-operatively, gradually decreasing as time passes, achieving target levels, and patient stabilization.

The following are recommendations for tacrolimus level ranges per British Columbia Transplant Guidelines (http://www.transplant.bc.ca/health-professionals/transplant-clinical-guidelines). However, target levels vary by institution, induction protocols, and patient needs.

Adult and Kidney and Kidney/Pancreas Transplant

• Less than 1 month: 8 to 12 ng/mL
• From 1 to 3 months: 6 to 9 ng/mL
• Greater than 3 months: 4 to 8 ng/mL

Adult Liver Transplant

• Less than 1 month: 6 to 9 ng/mL
• From 1 to 3 months: 4 to 8 ng/mL
• Greater than 3 months: 4 to 6 ng/mL
• More than 12 months: 3 to 5 ng/mL

Adult Heart Transplant

• Less than 3 months: 9 to 12 ng/mL
• From 3 to 6 months: 8 to 9 ng/mL
• From 6 to 12 months: 6 to 8 ng/mL
• Over 12 months: 4 to 8 ng/mL

Adult Lung Transplant

• From 0 to 3 months: 10 to 12 ng/mL
• From 4 to 12 months: 8 to 10 ng/mL
• More than 12 months: 6 to 8 ng/mL
• Due to the metabolism pathway of tacrolimus, many drug-drug interactions exist. If starting medications that inhibit or induce the metabolism of tacrolimus, added monitoring is suggested to prevent a supra or sub-therapeutic level.

Toxicity

Tacrolimus toxicity commonly presents as acute renal failure. Close monitoring of serum creatinine, GFR, and urine output is necessary for patients on tacrolimus.       

Toxicity may also present as the development of adverse effects such as tremors, electrolyte disturbances, headaches, and increased SCr. 

No antidote exists currently to counter toxicity. Hemodialysis does not remove tacrolimus.

Enhancing Healthcare Team Outcomes

Management of post-transplant patients is an interprofessional healthcare team endeavor. A combination of the skills and knowledge of each profession contributes to the successful longevity of the transplanted organ and a higher quality of life for the patient. As per the CMS guidelines, an interprofessional team for transplant must include the following disciplines at the minimum:

• Medical/surgical (transplant physician)
• Nursing
• Clinical transplant coordinator
• Social services
• Nutritional services
• Pharmacology
• Financial coordination

Awareness of all aspects of the transplant journey, education, and support are at the core of graft longevity. Patients must receive instruction on not only the medical aspects of the transplant, but the financial needs, necessary dietary changes, and effects of the medication. This area is where specialty nursing can play a significant role and counsel the patient appropriately.

Post-transplant, the patient is closely followed by the team, both inpatient and outpatient. Nursing again will be performing the initial dosing of tacrolimus, and of course, they should coordinate with the pharmacy staff regarding proper dosing and administrator. The pharmacy will also perform medication reconciliation, both initially and as the overall drug regimen changes, to preclude drug interactions. Nursing will also be in the best position to monitor for adverse effects and report these promptly to the physician in charge of the case. Collaborative, interprofessional evaluations by nursing, medical, and pharmacy of patient's state of health and being, as well as the medication efficacy and adverse effects, allow for thorough vigilance through the eyes and expertise of various professionals. [Level 5]