The pharmacokinetics of tacrolimus after first and repeated application of 0.1% tacrolimus ointment were evaluated in 39 children, aged 6-12 y, with moderate to severe atopic dermatitis. The patients were grouped according to the size of the affected body surface area to be treated: Group 1< or =1500 cm(2); Group 2 >1500 cm(2) < or =3000 cm(2); Group 3 >3000 cm(2) < or =5000 cm(2). Serial blood samples to calculate pharmacokinetic parameters taken on Day 1 (first ointment application) and Day 14 (last application) showed minimal systemic exposure to tacrolimus. Overall, 92% of the blood samples assayed contained tacrolimus concentrations below 1 ng per mL and 17% of samples were below 0.025 ng per mL, the lower limit of quantification. Systemic exposure to tacrolimus varied between patients and tended to increase proportionally as the size of the treated body surface area increased. Absorption decreased with time as the skin lesions healed and there was no evidence of systemic accumulation. The mean apparent half-life of tacrolimus (t(1/2, z)) was 66+/-27 h (range 19-125 h). Most patients experienced substantial clinical improvement in their atopic dermatitis. There were no clinically relevant changes in laboratory values, and the most frequently reported adverse event was skin burning, which resolved quickly as the skin condition improved.
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.
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