There was no evidence based on blood concentrations that tacrolimus accumulates systemically upon intermittent topical application for periods of up to 1 year. As with other topical calcineurin inhibitors, it is not known whether tacrolimus is distributed into the lymphatic system.

Metabolism

Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.

Excretion

The mean clearance following IV administration of tacrolimus is 0.040, 0.083 and 0.053 L/hr/kg in healthy volunteers, adult kidney transplant patients and adult liver transplant patients, respectively. In man, less than 1% of the dose administered is excreted unchanged in urine.

In a mass balance study of IV administered radiolabeled tacrolimus to 6 healthy volunteers, the mean recovery of radiolabel was 77.8 ± 12.7%. Fecal elimination accounted for 92.4 ± 1.0% and the elimination half-life based on radioactivity was 48.1 ± 15.9 hours whereas it was 43.5 ± 11.6 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.029 ± 0.015 L/hr/kg and clearance of tacrolimus was 0.029 ± 0.009 L/hr/kg.

When administered PO, the mean recovery of the radiolabel was 94.9 ± 30.7%. Fecal elimination accounted for 92.6 ± 30.7%, urinary elimination accounted for 2.3 ± 1.1% and the elimination half-life based on radioactivity was 31.9 ± 10.5 hours whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and clearance of tacrolimus 0.172 ± 0.088 L/hr/kg.

Special Populations

Pediatrics

In a pharmacokinetic study of 14 pediatric atopic dermatitis patients, between the ages of 2-5 years, peak blood concentrations of tacrolimus ranged from undetectable to 14.8 ng/mL after single or multiple doses of 0.03% PROTOPIC Ointment, with 86% (12/14) of patients having peak blood concentrations below 2 ng/mL throughout the study.

The highest peak concentration was observed in one patient with 82% BSA involvement on day 1 following application of 0.03% PROTOPIC Ointment. The peak concentrations for this subject were 14.8 ng/mL on day 1 and 4.1 ng/mL on day 14. Mean peak tacrolimus blood concentrations following oral administration in pediatric liver transplant patients (n = 9) were 43.4± 27.9 ng/mL.

In a similar pharmacokinetic study with 61 enrolled pediatric patients (ages 6 -12 years) with atopic dermatitis, peak tacrolimus blood concentrations ranged from undetectable to 5.3 ng/mL after single or multiple doses of 0.1% PROTOPIC Ointment, with 91% (52/57) of evaluable patients having peak blood concentrations below 2 ng/mL throughout the study period. When detected, systemic exposure generally declined as treatment continued.

In clinical studies with periodic blood sampling, a similar distribution of tacrolimus blood levels was also observed, with 98% (509/522) of pediatric patients having a blood concentration below 2 ng/mL.

Renal Insufficiency

The effect of renal insufficiency on the pharmacokinetics of topically administered tacrolimus has not been evaluated. The mean clearance of IV administered tacrolimus in patients with renal dysfunction was similar to that of normal volunteers. On the basis of this information dose-adjustment is not expected to be needed.

Hepatic Insufficiency

The effect of hepatic insufficiency on the pharmacokinetics of topically administered tacrolimus has not been evaluated but dose-adjustment is not expected to be needed.

Clinical Studies

Three randomized, double-blind, vehicle-controlled, multi-center, phase 3 studies were conducted to evaluate PROTOPIC Ointment for the treatment of patients with moderate to severe atopic dermatitis. One (Pediatric) study included 351 patients 2-15 years of age, and the other two (Adult) studies included a total of 632 patients 15-79 years of age. Fifty-five percent (55%) of the patients were women and 27% were black. At baseline, 58% of the patients had severe disease and the mean body surface area (BSA) affected was 46%. Over 80% of patients had atopic dermatitis affecting the face and/or neck region. In these studies, patients applied either PROTOPIC Ointment 0.03%, PROTOPIC Ointment 0.1%, or vehicle ointment twice daily to 10% - 100% of their BSA for up to 12 weeks.

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