Tacrolimus

A complete drug profile of Tacrolimus an immunosuppressant used for organ transplant. It consist of PK/PD, MOA, Indication & Uses, Contraindications, Warnings & Precautions, Drug-interaction, Doses & Administration, Dosage forms, Chemical Formula, Side-Effects, Adverse Drug Reactions, Therapeutic Drug Monitoring (TDM).

1. Tacrolimus Asish Kumar Saha, PharmD

2. Introduction Tacrolimus, a macrolide immunosuppressant produced by Streptomyces tsukubaensis . Chemically, tacrolimus is designated as [3 S [3 R *[ E (1 S *,3 S *,4 S *)],4 S *,5 R *,8 S *,9 E ,12 R *,14 R *,15 S *,16 R *,18 S *,19 S *,26a R *]]5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10, 12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1- c ][ 1,4]oxaazacyclotricosine-1,7,20,21(4H,23H) tetrone,monohydrate . Tacrolimus has an empirical formula of C44H69NO12•H2O and a formula weight of 822.03.

3. Indications & Uses Tacrolimus is a calcineurin-inhibitor immunosuppressant indicated for Prophylaxis of organ rejection in patients receiving allogeneic liver, kidney or heart transplants Use concomitantly with adrenal corticosteroids; in kidney and heart transplant, use in conjunction with azathioprine or mycophenolate mofetil (MMF)

4. Limitations of Use Do not use simultaneously with cyclosporine Intravenous use reserved for patients who can not tolerate capsules orally Use with sirolimus is not recommended in liver and heart transplant; use with sirolimus in kidney transplant has not been established

5. Pharmacokinetics

6. Absorption Tacrolimus, orally administrated, has a large variability in the rate of absorption and absolute bioavailability which implies that the mean bioavailability is approximately 25% but can range from 5% to 93% Oral doses of tacrolimus should be 3 to 4 times higher than intravenous doses to achieve comparable drug exposure after oral and intravenous administration. In most patients tacrolimus is absorbed rapidly with peak plasma/blood concentrations obtained in 0.5-1 hour32 however a lag time of 0 to 2 hours has also been reported in some liver transplant recipients37 or an extended lag time or secondary peaks

7. Distribution Transplant recipients have significantly higher blood tacrolimus concentrations (mean 15 times; range 4 to 114 times) than the corresponding plasma concentrations due to the extensive binding of tacrolimus to the red blood cells. The maximum amount of tacrolimus bound to red blood cells ( bmax ) is 418 ± 258 μg /l with an apparent dissociation constant ( kd ) of 3.8 ± 4.7 μg /l in transplant patients while bmax is 1127 μg /l and KD of 13.5 μg /l in healthy volunteers.

8. Metabolism Tacrolimus undergoes O-demethylation, hydroxylation and/or oxidative metabolic reactions, predominantly by CYP3A4 and CYP3A5 in the liver and intestinal wall, with <0.5% of the parent drug appearing unchanged in the urine or faeces. Several metabolites are the product of a two-step reaction: oxidation by cytochrome P450 3A enzymes destabilising the macrolide ring and followed by its rearrangement.

9. Elimination The metabolites of tacrolimus are for more than 95% eliminated by the biliary route. Urinary excretion accounts for, on average, 2.4% of tacrolimus elimination. Biliary obstruction is reported to increase the concentration of tacrolimus metabolites in the blood .

10. Mechanism of Action It binds to an intracellular receptor and subsequently binds to calcineurin and inhibits the calcineurin pathway that stimulates the nuclear factor, NFAT. The action resembles that of cyclosporine (both drugs are calcineurin inhibitors), although the cellular receptors differ. By inhibiting the action of NFAT, tacrolimus decreases synthesis of inflammatory cytokines. In particular, synthesis of interleukin-2 (IL-2) is inhibited, which results in decreased activation of T-lymphocytes. It is 10-100 times more potent than cyclosporine. Tacrolimus inhibits release of mast cell and basophil mediators and decreases inflammatory mediator expression.

11. Intracellular mode of action of tacrolimus and cyclosporine

12. DOSAGE AND ADMINISTRATION

13. Dosage in Adult Kidney, Liver, or Heart Transplant Patients

14. Dosage in Paediatric Liver Transplant Patients

15. DOSAGE FORMS AND STRENGTHS Capsules : 0.5 mg, 1 mg and 5 mg Injection : 5 mg/ mL

16. CONTRAINDICATIONS Hypersensitivity to tacrolimus or HCO-60 ( polyoxyl 60 hydrogenated castor oil )

17. WARNINGS AND PRECAUTIONS Lymphoma and Other Malignancies: Risk of lymphomas, including post transplant lymphoproliferative disorder (PLTD); appears related to intensity and duration of use. Avoid prolonged exposure to UV light and sunlight. Serious infections: Increased risk of bacterial, viral, fungal and protozoal infections, including opportunistic infections: combination immunosuppression should be used with caution. Polyoma Virus Infections: Serious, sometimes fatal outcomes, including polyoma virus-associated nephropathy (PVAN), mostly due to BK virus, and JC virus-associated progressive multifocal leukoencephalopathy (PML); consider reducing immunosuppression

18. WARNINGS AND PRECAUTIONS Cytomegalovirus (CMV) Infections: Increased risk of CMV viremia and disease; consider reducing immunosuppression . New Onset Diabetes After Transplant : Monitor blood glucose. Nephrotoxicity : Acute and/or chronic; reduce the dose; use caution with other nephrotoxic drugs Neurotoxicity : Risk of Posterior Reversible Encephalopathy Syndrome, monitor for neurologic abnormalities; reduce or discontinue Prograf and other immunosuppressants . Hyperkalemia : Monitor serum potassium levels. Careful consideration should be given prior to use of other agents also associated with hyperkalemia .

19. WARNINGS AND PRECAUTIONS Hypertension : May require antihypertensive therapy. Monitor relevant drug-drug interactions Anaphylactic Reactions with IV formulation: Observe patients receiving tacrolimus injection for signs and symptoms of anaphylaxis Use with Sirolimus : Not recommended in liver and heart transplant due to increased risk of serious adverse reactions. Myocardial Hypertrophy: Consider dosage reduction or discontinuation. Immunizations : Use of live vaccines should be avoided. Pure Red Cell Aplasia : Discontinuation should be considered.

20. DRUG INTERACTIONS Mycophenolic Acid Products: Can increase MPA exposure after crossover from cyclosporine to Prograf ; monitor for MPA-related adverse reactions and adjust MMF or MPA-dose as needed Nelfinavir and Grapefruit Juice: Increased tacrolimus concentrations via CYP3A inhibition; avoid concomitant use CYP3A Inhibitors: Increased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed with concomitant use CYP3A4 Inducers: Decreased tacrolimus concentrations; monitor concentrations and adjust tacrolimus dose as needed with concomitant use

21. USE IN SPECIFIC POPULATIONS Pregnancy : Based on animal data may cause fetal harm. Use only if the potential benefit justifies the risk. Nursing Mothers: Discontinue nursing taking into consideration importance of drug to mother. Hepatic/Renal impaired patients: Administer at the lower end of the recommended starting dose. Monitor renal function in patients with impaired renal function.

22. Therapeutic Drug Monitoring (TDM) Tacrolimus has a narrow therapeutic index and highly variable pharmacokinetic characteristics. Close monitoring of the tacrolimus concentration is required to achieve an optimal efficiency and thus minimizing the risk of subtherapeutic or toxic blood concentrations. Efficacy and side effects of tacrolimus are highly correlated with the area under the curve (AUC0-12 ) The most exact way to monitor the total tacrolimus exposure is by creating 12 hour pharmacokinetic profiles, which implicates that the tacrolimus concentration should be measured at at least 6 different time points.

23. Therapeutic Drug Monitoring (TDM) The AUC0-12 can then be calculated according to the trapezoidal rule using the tacrolimus concentrations measured at different time points. Since recording a complete 12 hour pharmacokinetic profile for every patient is not feasible in clinical practice, traditionally many transplant centres use tacrolimus trough (C0) concentrations to estimate the tacrolimus exposure. Although tacrolimus C concentrations are generally considered to be a good indication of the total systemic drug exposure its usefulness in differentiating graft rejection episodes from nephrotoxicity has been questioned.

24. Therapeutic Drug Monitoring (TDM) Based on the half-life of tacrolimus which is approximately ten hours, it is necessary to wait at least 36 hours (3.3 half-lives) to reach a steady state tacrolimus concentration after initiation of therapy or after a change in the administration regime of tacrolimus . Ideally , after starting the infusion, blood concentrations should be monitored on day 2 or 3 on average 3 to 7 times weekly during the first few weeks after transplantation, and less frequently thereafter. Special circumstances such as changes in liver function, presence of adverse effects or use of drugs that may alter tacrolimus kinetics may warrant more frequent monitoring.

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