Pharmacokinetics of 0.1% Tacrolimus Ointment After First and Repeated Application to Adults with Moderate to Severe Atopic Dermatitis

Abstract

The systemic exposure to tacrolimus after first and repeated application of 0.1% tacrolimus ointment was investigated in 32 adults with moderate to severe atopic dermatitis. Patients were allocated to treatment groups according to the size of the affected area to be treated: Group 1</=3000 cm(2) (N=11); Group 2>3000 cm(2)</=6000 cm(2) (N=12); Group 3>6000 cm(2)</=10,000 cm(2) (N=9). Ointment was applied twice daily for 13 d and once daily on Day 14; the size of application area remained the same irrespective of healing. Blood samples were collected on Days 1 (first application), 4, and 14 (last application) and analyzed by a validated HPLC-MS/MS method. Systemic exposure to tacrolimus was generally low with 96% of blood samples assayed containing concentrations below 1 ng per mL and 23% of samples below the lower limit of quantification (0.025 ng per mL). Peak concentrations after first ointment application were </=2.8 ng per mL, and the mean area under the concentration-time curve between 0 and 12 h using the trapezoidal rule (AUC(0-12)) values were 1.1, 1.6, and 4.8 ng h per mL for Groups 1, 2, and 3, respectively. The corresponding mean values on Day 14 were similar indicating negligible systemic accumulation of tacrolimus after repeated ointment applications. Both the rate and extent of topical absorption decreased as the skin lesions healed.

Intermittent therapy for flare prevention and long-term disease control in stabilized atopic dermatitis: A randomized comparison of 3-times-weekly applications of tacrolimus ointment versus vehicle

“…4,5 Considering that even clinically normal-appearing skin in patients with AD is immunologically abnormal, 6 we hypothesized that maintenance therapy with tacrolimus ointment, a topical, nonsteroidal, calcineurin inhibitor, applied to previously involved skin might help to prevent relapse in these patients. Clinical and pharmacokinetic studies in patients with AD have shown that tacrolimus ointment is associated with minimal systemic absorption and no evidence of accumulation, [7][8][9][10][11][12] and long-term (6 months-4 years) safety and efficacy have been demonstrated in more than 10,000 patients. [13][14][15][16][17] The current prescribing information for both tacrolimus ointment and pimecrolimus cream (as revised in January 2006) states that continuous longterm use of topical calcineurin inhibitors should be avoided, and application should be limited to areas of involvement with AD.…”

Significantly Elevated Systemic Levels after Occlusive Application of Topical Tacrolimus in Atopic Dermatitis

“…Rubins et al [7] investigated pharmacokinetic parameters of topical tacrolimus. There was a trend for systemic exposure to increase proportionally as the size of the treatment area increased, but exposure was still substantially lower than for transplant patients.…”

Tacrolimus Ointment 0.03% Is Safe and Effective for the Treatment of Mild to Moderate Atopic Dermatitis in Pediatric Patients: Results From a Randomized, Double-Blind, Vehicle-Controlled Study

“…Topical applications of tacrolimus ointment result in minimal systemic absorption, do not cause a decrease in collagen synthesis or skin thickness, and have not been associated with limiting adverse events thus far. [16][17][18][19][20][21] Tacrolimus ointment (0.03% and 0.1%) has been clinically shown to reduce the extent, severity, and symptoms of moderate to severe AD in children as young as 2 years of age and to be safe and effective for long-term use for up to 4 years. [22][23][24][25][26][27] However, it has not been evaluated for treatment of mild to moderate cases.…”