Tacrolimus administration

The side effects associated with tacrolimus administration include nephro- and hepa-totoxicity, hypertension, tremors, seizures, diabetes mellitus, neuropathy, blurred vision, depression, loss of appetite andconfusion. Tacrolimus may cause opportunistic... 

Among the differential diagnoses are acute rejection, ATN, and/or cyclosporine or tacrolimus toxicity (see Chap. 46). These processes are not mutually exclusive. Definitive diagnosis is made by renal biopsy. In the presence of an elevated serum creatinine level, clinicians may reduce the dose of cyclosporine or tacrolimus to minimize the potential for drug nephrotoxicity and hasten the recovery from ATN. This practice may result in subtherapeutic immunosuppressant concentrations and hasten the occurrence of acute rejection. DGF predisposes patients to acute rejection. Induction therapy (e.g., using antibody preparations) and delaying the initiation of cyclosporine or tacrolimus administration may be useful in this setting. 

J. W., Roberts, J. P., Hebert, M. F., Tacrolimus oral bioavailability doubles with co-administration of ketoconazole, Clin. Pharmacol. Then 1997, 62, 41-49. 

S. Masuda, M. Goto, M. Okuda, Y. Ogura, F. Oike, T. Kiuchi, K. Tanaka, and K. Inui. Initial dosage adjustment for oral administration of tacrolimus using the intestinal MDR1 level in living-donor liver transplant recipients. Transplant Proc 37 1728-1729 (2005). 

Myocardial hypertrophy Myocardial hypertrophy has been reported in association with the administration of tacrolimus and generally is manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. Hypertrophy has been observed in infants, children, and adults. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. 

After oral administration the bioavailability varies widely with a maximum of some 60%. Tacrolimus can also be administered intravenously. Its concentration-time curve is biphasic. It is metabolized in the liver and is eliminated with a half-life varying from some 12 hours in patients to 20 hours in healthy subjects. 

Drug Interactions Increased prothrombin time after warfarin administration Phenytoin Cyclosporine Tolbutamide Tacrolimus Glyburide Glipizide Rifampin Cisapride Terfenadine Astemizole Theophylline ... 

Tacrolimus is given orally (twice-daily dose regimen) or as an injection. A modified release (MR) oral dosage form of tacrolimus has been developed for administration once a day to overcome noncompliance, which is the major problem in acute graft rejection in solid transplant recipients. Tacrolimus is not completely absorbed by the GI tract and its rate of absorption could vary. It binds to plasma protein at a rate of 75-99% with a half-life of approximately 12 h and is predominantly metabolized in liver by CYP3A. Some of its metabolites have immunosuppressive activity. Most of the tacrolimus is excreted in feces, and a negligible amount (< 1%) is excreted in urine without undergoing any metabolism. 

The serious side effects of sirolimus may include an allergic reaction, increased risk of infection and lymphoma. Nephrotoxicity is not a concern when the drug is not used in combination with cyclosporine or tacrolimus. Less serious side effects associated with the administration of sirolimus include stomach upset, increased cholesterol and triglyceride levels, acne, insomnia, tremor, sore or weak muscles,... 

Sirolimus is used for tissue transplantation where its major advantage over calci-neurin inhibitors is that it is not nephrotoxic. Chronic renal failure in transplant patients who have taken calcineurin inhibitors for the long term can be prevented by the administration of sirolimus. Steroid-free immunosuppression can be achieved by administering sirolimus alone or in combination with mycophenolate mofetil and cyclosporine or tacrolimus. Since impaired wound healing is one of its potential side effects, some transplant centers use sirolimus only after several weeks of surgery. 

Tacrolimus can be administered orally or intravenously. After oral administration, peak concentrations are reached after 1-4 hours. The half-life of the intravenous form is approximately 9-12 hours. Like cyclosporine, tacrolimus is metabolized primarily by P450 enzymes in the liver, and there is a potential for drug interactions. The dosage is determined by trough blood level at steady state. Its toxic effects are similar to those of cyclosporine and include nephrotoxicity, neurotoxicity, hyperglycemia, hypertension, hyperkalemia, and gastrointestinal complaints. 

Akers WS, Flynn JD, Davis GA, Green AE, Winstead PS, Strobel G. Prolonged cardiac repolarization after tacrolimus and haloperidol administration in the critically ill patient. Pharmacotherapy 2004 24 404-8. 

ST JOHN S WORT TACROLIMUS 1 tacrolimus levels Induction of CYP3A4-mediated metabolism of tacrolimus Avoid co-administration... 

CICLOSPORIN TACROLIMUS t plasma concentrations of cidosporin Tacrolimus is probably a more powerful inhibitor of CYP3A4 than cidosporin Avoid co-administration... 

The solubilization techniques for injectable formulations are similar to those in oral formulations and include pH adjustment, mixed aqueous/organic cosolvents, organic solvent mixtures, cyclodextrin com-plexation, emulsions, liposomes, polymeric gels, and combinations of techniques. " Molecules that are non-ionizable, lipophilic, and non-polar are challenging to formulate owing to their low water solubility and no effect of pH on solubility. Examples include paclitaxel, docetaxel, cyclosporin A, etoposide, loraze-pam, tacrolimus, testosterone enanthate, and halo-peridol decanoate, and they are all solubilized in non-aqueous solutions composed entirely of organic solvent(s), which are usually but not always diluted prior to administration. 

The inhibitory effect of itraconazole occurred quickly, while the time of disappearance was much longer, which is important for clinical management. Thus, during co-administration of itraconazole with tacrolimus, close... 

The interaction of tacrolimus with rifampicin has been convincingly confirmed in six healthy volunteers who took a single oral or intravenous dose of tacrolimus (112). Rifampicin 600 mg/day for 18 days produced a significant 47% increase in tacrolimus clearance after intravenous administration and a 51% reduction in its oral systemic availability, consistent with induction by rifampicin of both hepatic and intestinal metabolism of tacrolimus. 

In a patient who took tacrolimus after hver transplant, co-administration of voriconazole resulted in raised trough tacrolimus concentrations (nearly 10-fold) there were no changes in another patient, who took a placebo (123). Voriconazole inhibits the metabohsm of tacrolimus in liver microsomes by 50% in vitro. 

The nephrotoxic profile of tacrolimus is usually considered similar to that of CSA, although some authors attribute less functional nephrotoxicity to TAC [641-643]. In fact, when these drugs were administrated to healthy individuals, only the individuals receiving CSA showed decreases in GFR and RBF and blood pressure increase [644]. 

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