Absorption In healthy volunteers, as well as kidney and liver transplant patients, tacrolimus Cmax ranged from approximately 19.2 to 68.5 ng/mL, Tmax ranged from 1.5 to 3 h, AUC ranged from 203 to 3,300 ng•h/mL, t½ ranged from 11.7 to 34.8 h, and bioavailability ranged from approximately 17% to 22%.
Food effects The rate and extent of absorption were greatest under fasted conditions. The presence and composition of food decreased the rate and extent of absorption. The effect was most pronounced with a high-fat meal. Mean AUC and Cmax were decreased 37% and 77%, respectively. Tmax was lengthened 5-fold. A high-carbohydrate meal decreased mean AUC and mean Cmax 28% and 65%, respectively.
Distribution Tacrolimus Vd is about 0.85 to 1.94 L/kg. Protein binding is about 99%, mainly to albumin and alpha-1 acid glycoprotein.
Metabolism Tacrolimus is extensively metabolized by the mixed function oxidation system, primarily the CYP-450 system (CYP3A). The major metabolite identified is 13-demethyl tacrolimus.
Elimination Cl is about 0.04 to 0.083 L/h/kg. Less than 1% of an administered dose is excreted unchanged in the urine. The t½ is approximately 31.9 to 48.1 h (PO and IV).
Special Populations Hepatic Function Impairment The mean Cl was substantially lower and t½ prolonged in patients with severe hepatic function impairment.
Children Children younger than 12 yr of age need higher doses than adults to achieve similar trough concentrations.
Carbamazepine, caspofungin, phenobarbital, phenytoin, prednisolone, prednisone, rifabutin, rifampin, sirolimus, St. John's wort Tacrolimus blood concentrations may be reduced, increasing the risk of transplant rejection.
Cyclosporine Additive nephrotoxicity.
CYP3A4 inhibitors (eg, cimetidine, erythromycin, ketoconazole) Use with caution during topical administration.
Ethanol Risk of facial flushing may be increased with topical tacrolimus.
Hydantoins (eg, phenytoin) Tacrolimus plasma levels may be reduced, while hydantoin concentrations may be increased.
Mycophenolate mofetil, sildenafil, simvastatin Plasma levels may be elevated by tacrolimus, increasing the risk of adverse reactions.
Vaccination (eg, BCG, measles, mumps, oral polio, rubella, TY 21a typhoid, yellow fever) Vaccination may be less effective. Avoid use of live vaccines.
Ziprasidone Risk of life-threatening cardiac arrhythmias, including torsades de pointes, may be increased. Coadministration is contraindicated.
