Tacrolimus


Article Author:
Ayesha Araya


Article Editor:
Yasar Tasnif


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
7/30/2019 11:08:09 PM

Indications

Tacrolimus is an immunosuppressive agent used for prophylaxis of organ rejection post-transplant. Tacrolimus use is in combination with one or, most commonly, two other immunosuppressive medications. It has an application as an agent for as prevention or treatment for certain autoimmune diseases. 

In solid organ transplantation, it serves as the treatment of organ rejection in kidney, liver, and heart allogeneic transplants. There is also an off-label indication for the prevention of rejection in lung transplant patients.

Other off-label indications include:

  • Crohn disease
  • Graft-versus-host disease (GVHD)
  • Myasthenia gravis
  • Rheumatoid arthritis

Tacrolimus indications also include topical use in moderate to severe atopic dermatitis, as well as other off-label dermatologic disease states.[1]

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 transplant 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 in combination 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.

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 tacrolimus' pathway of metabolism, 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 in SCr. 

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

Enhancing Healthcare Team Outcomes

Management of post-transplant patients is multidisciplinary. A combination of the skills and knowledge of each profession contributes to the successful longevity of the transplanted organ, as well as a higher quality of life for the patient. As per the CMS guidelines, a multidisciplinary 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 V]


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Tacrolimus - Questions

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A 16-year-old female kidney transplant recipient (living donor from sister) presents to the clinic for a routine monthly follow-up. She underwent kidney transplant a year ago due to advanced glomerulonephritis. Her current immunosuppressant medications include cyclosporine 50mg by mouth twice daily and mycophenolate mofetil 750mg by mouth twice daily. Other medications include magnesium 400mg by mouth daily, and vitamin D3 1,000 IU by mouth daily. Her current labs are: white blood cell count: 6.8 × 10^9/L, hemoglobin: 11 gm/dL, hematocrit: 33.3 %, platelet count: 350 × 10^9/L sodium: 139 mmol/L, potassium: 5 mmol/L, chloride: 104 mmol/L, carbon dioxide: 25 mmol/L, creatinine: 0.9 mg/dL, blood urea nitrogen: 15 mg/dL, glucose: 110 mg/dL, calcium: 8.9 mg/dL, magnesium: 2.2 mg/dL, phosphorus: 3.4 mg/dL cyclosporine trough level: 100 ng/mL. The patient's main complaint at this visit is excessive facial hair growth, which started a few months after transplant. She is frustrated and wants to stop all her medications. Considering her current medications, labs, and complaint, why would switching her from cyclosporine to tacrolimus be an option in this case?



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What is the one major benefit of using tacrolimus over cyclosporine?



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A 35-year-old female patient is 24-hours post-living-donor-kidney transplant. Her last dialysis session was just prior to the transplant. Renal failure was due to hypertension and diabetes type 2. The patient will receive a dose of thymoglobulin today and convert to oral mycophenolate mofetil and steroids. The patient seems to be doing exceptionally well, demonstrated by the strong appetite and a good report from physical therapy. The incision site is clean, and the nurse reports no complaints of pain, as well as urine output of 100 mL in the past hour. Her systolic blood pressure has held around 140-150 mmHg. Based on physical examination and the following labs, the team decides she is stable enough to start oral tacrolimus IR. Na 135 mEq/L K 4.1 mEq/L Cl 100 mEq/L CO2 25 mEq/ L BUN 30 mg/dL SCr 3.1 mg/dL (Prior to transplant 6.2 mg/dL) Glucose 167 mg/dL What is the mechanism of action for tacrolimus?



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A 40-year-old male patient presents to the outpatient clinic for follow-up. He is seven months status post deceased donor kidney transplant, and reports that hand tremors and headaches from the last two visits have not subsided. The patient's tacrolimus (FK) levels have been stable at a range of 5-6 ng/mL. His serum creatinine ranges between 1.3 and 1.7 mg/dL. The patient confirms adherence to his current dosage of tacrolimus 2 mg twice daily, which has not changed for the last four months. What change should be made, if any, for this patient?



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A 40-year old female patient presents to the physician's office with oral thrush. She is 3-months post-transplant. She is given clotrimazole lozenges to be taken for 14 days. Her current anti-rejection regimen is tacrolimus 2 mg q12h, mycophenolate mofetil 500mg q12h, and prednisone 10 mg daily. What changes to her tacrolimus level should be expected, if any at all?



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A 53-year old male presents four months after a deceased-donor kidney transplant. His vital signs are BP 90/60 mmHg, HR 90/min, and RR 20/min. Labs show sodium 149 mEq/L, potassium 6.3 mEq/L, chloride 97 mEq/L, bicarbonate 25 mEq/L, BUN 17 mg/dL, creatinine 1.2 mg/dL (baseline: 1.1-1.3), calcium 8.7 mg/dL, albumin 3.7 mg/dL, phosphate 3.8 mEq/L, and tacrolimus level 9 ng/mL. His current medications include tacrolimus, mycophenolate mofetil, and prednisone. Which of the following abnormalities present in the patient could be caused by the tacrolimus?



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Tacrolimus - References

References

Thomson AW,Bonham CA,Zeevi A, Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Therapeutic drug monitoring. 1995 Dec;     [PubMed]
Ruzicka T,Assmann T,Lebwohl M, Potential future dermatological indications for tacrolimus ointment. European journal of dermatology : EJD. 2003 Jul-Aug;     [PubMed]
Vicari-Christensen M,Repper S,Basile S,Young D, Tacrolimus: review of pharmacokinetics, pharmacodynamics, and pharmacogenetics to facilitate practitioners' understanding and offer strategies for educating patients and promoting adherence. Progress in transplantation (Aliso Viejo, Calif.). 2009 Sep;     [PubMed]
Doligalski CT,Liu EC,Sammons CM,Silverman A,Logan AT, Sublingual administration of tacrolimus: current trends and available evidence. Pharmacotherapy. 2014 Nov;     [PubMed]
Romero I,Jiménez C,Gil F,Escuin F,Ramirez E,Fudio S,Borobia A,Carcas A, Sublingual administration of tacrolimus in a renal transplant patient. Journal of clinical pharmacy and therapeutics. 2008 Feb;     [PubMed]
Gaïes E,Salouage I,Sahnoun R,Trabelsi S,Jebabli N,Lakhal M,Klouz A, [Interaction between azole antifugals drugs and tacrolimus in four kidney transplant patients]. Journal de mycologie medicale. 2011 Mar;     [PubMed]
Patel N,Cook A,Greenhalgh E,Rech MA,Rusinak J,Heinrich L, Overview of extended release tacrolimus in solid organ transplantation. World journal of transplantation. 2016 Mar 24;     [PubMed]
Nicolai S,Bunyavanich S, Hypersensitivity reaction to intravenous but not oral tacrolimus. Transplantation. 2012 Nov 15;     [PubMed]
Takamatsu Y,Ishizu M,Ichinose I,Ogata K,Onoue M,Kumagawa M,Suzumiya J,Tamura K, Intravenous cyclosporine and tacrolimus caused anaphylaxis but oral cyclosporine capsules were tolerated in an allogeneic bone marrow transplant recipient. Bone marrow transplantation. 2001 Aug;     [PubMed]
Bekersky I,Dressler D,Mekki Q, Effect of time of meal consumption on bioavailability of a single oral 5 mg tacrolimus dose. Journal of clinical pharmacology. 2001 Mar;     [PubMed]
Philosophe B,Leca N,West-Thielke PM,Horwedel T,Culkin-Gemmell C,Kistler K,Stevens DR, Evaluation of Flexible Tacrolimus Drug Concentration Monitoring Approach in Patients Receiving Extended-Release Once-Daily Tacrolimus Tablets. Journal of clinical pharmacology. 2018 Jul;     [PubMed]
Staatz CE,Tett SE, Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clinical pharmacokinetics. 2004     [PubMed]
Yu M,Liu M,Zhang W,Ming Y, Pharmacokinetics, Pharmacodynamics and Pharmacogenetics of Tacrolimus in Kidney Transplantation. Current drug metabolism. 2018     [PubMed]
Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. European FK506 Multicentre Liver Study Group. Lancet (London, England). 1994 Aug 13     [PubMed]
Pham PT,Pham PM,Pham SV,Pham PA,Pham PC, New onset diabetes after transplantation (NODAT): an overview. Diabetes, metabolic syndrome and obesity : targets and therapy. 2011     [PubMed]
Nankivell BJ,PʼNg CH,OʼConnell PJ,Chapman JR, Calcineurin Inhibitor Nephrotoxicity Through the Lens of Longitudinal Histology: Comparison of Cyclosporine and Tacrolimus Eras. Transplantation. 2016 Aug     [PubMed]

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