Tacrolimus is a macrolide of fungal origin (produced by Streptomyces Tsukubaenis) with strong immunosupressive actions. Its primary target appears to be the helper T lymphocytes, with little effect on other aspects of the immune response. However, because it acts early in the process of T cell activation, it has secondary effects on other cell types that are normally activated by factors produced by the T cells.

Actions and Uses

Inhibits the production of interleukin IL-2 by helper T-cells thereby blocking T cell activation and proliferation (amplification of immune response). It is effective both in the prevention and in the treatment of ongoing acute rejection.
The current model for the mechanism of action of tacrolimus (or cyclosporine) suggests that, in the T-cell cytoplasm, tacrolimus binds to a specific binding protein called immunophilin which is actually a cis-trans isomerase. The tacro-immunophilin complex in turn binds to and blocks a phosphatase called calcineurin. The latter is required for the translocation of an activation factor (NF-ATc) from the cytosol to the nucleus, where it would normally bind to and activate enhancers/promotors of certain genes. In the presence of tacro, the cytosolic activation factor is unable to reach the nucleus, and the transcription of IL-2 (and other early activation factors) is strongly inhibited. As a result, T cells do not proliferate, secretion of gamma-interferon is inhibited, no MHC class II antigens are induced, and no further activation of the macrophages occurs.

Pharmacokinetics

Protein binding @ 77 %   (a₁-glycoprotein).
Tacrolimus is not removed by dialysis.
Blood level @ 4 x plasma level
Vd = 17 L/kg; it crosses placenta and gets into mother's milk
Oral bioavailability is variable (@30%). Absorption is reduced by food, not affected by clamping the T-tube, and is better with a closed stoma. Time to C_max= 1 - 4 hrs
Metabolized by liver (P450 3A4 ) and eliminated in bile; t_½ = 4 - 40 hrs @ 12 hrs

Contraindications and Warnings

• Increased susceptibility to infections (e.g., CMV).
  
• Increased risk of lymphoma; post-transplant lymphoprolifative disease (PTLD)
  
• Do not administer concurrently with cyclosporine, OKT3, or ATGAM.
  
• Tacro may lower the seizure threshold.
  
• Pregnancy Risk Factor = C. This drug should be used only if the potential benefits justify potential risk to the fetus.

Available As

• IV: 5 mg / mL; containing alcohol and surfactant.
  
• Oral:   0.5-mg, 1-mg and 5-mg capsules. It may also be prepared extemporaneously as an oral suspension (0.5 mg /mL in simple syrup); see details here.

Dose and Administration

• During the first 1-2 days after transplantation, tacrolimus may be administered as a continuous IV infusion (0.05 - 0.1 mg/kg/day). For this purpose a standard solution of 2.5 mg in 150 mL of D5W with a final concentration of 0.016667 mg /mL may be used. Use glass bottles and non-PVC tubing. The infusion rate is altered according to the prescribed total daily dose with the aid of a ""drip chart"". When the patient is able to take oral medications, the tacrolimus infusion is stopped and oral tacrolimus is started.
• An oral suspension of tacrolimus may be prepared extemporaneously.
• When tacrolimus suspension is administered orally, it should be separated by about 2 hours from any antacids or oral supplement of multivalent cations (Mg, Ca, Fe, etc.).

  Oral dose @ 4 x IV dose

  
  
• The oral dose is divided q 12 hrs (usually at 8 AM and 8 PM).
• Blood samples are drawn at 6-7 am for levels.
• Usual target level = 5 - 15 mg/L. The target level for a specific patient depends on a number of factors including:
  • Type of transplant (e.g., liver vs heart).
  • Level of adjuctive immunosuppressive therapy (steroids, MMF, sirolimus, etc.)
  • Risk of acute rejection (retransplant, time after transplant, high PRA, African Americans).
  • Risk of ischemic injury and primary non-function (marginal donor, prolonged cold ischemia, etc.)
  but higher levels have been used for 1-2 days to fight acute rejection; level should not be allowed to exceed 20mg/L.

Main Side Effects

• Nephrotoxicity; hyperkalemia (or hypokalemia); hypomagnesemia;
  
• Hypertension, headache, insomnia, weakness, fever, and pruritus.
  
• Nausea/vomiting, anorexia, abdominal pain, and diarrhea
  
• Diabetes (hyperglycemia), anemia, leukocytosis, abnormal LFT, ascites.
  
• Peripheral edema, pleural effusion, atelectasis, and dyspnea
  
• Tremors, paresthesia, and back pain
  

Drug Interactions

• Inhibitors and inducers of P450 3A4 (see table below) may alter rate of tacrolimus metabolism and consequently its level. Dose adjustment should be guided by measured level.
  
• Co-administration with amphotericin, aminoglycosides, or ganciclovir may enhance nephrotoxicity.
  
• Mg salts and antacids may interfere with the absorption of macrolides. Also, in vitro studies suggest that tacrolimus may be degraded in alkaline media. Therefore, we recommended that the oral administration of tacrolimus be separated from that of Mg supplements and antacids.

References

1. Prograf PI
2. Plosker GL, Foster RH. Tacrolimus: a further update of its pharmacology and therapeutic use in the management of organ transplantation. Drugs. 2000;59(2):323-89.
3. Dambrin C, Klupp J, Morris RE. Pharmacodynamics of immunosuppressive drugs. Curr Opin Immunol. 2000;12(5):557-62.
4. Venkataramanan R et al. Clinical utility of monitoring tacrolimus blood concentrations in liver transplant patients. J Clin Pharmacol. 2001;41(5):542-51.

theDrugMonitor

|

Nephrosite

|

Feedback