PURPOSE: Efalizumab is a humanized anti-CD11a monoclonal antibody that demonstrated efficacy in the treatment of patients with psoriasis. The objective of this study was to perform a pharmacokinetic (PK)-pharmacodynamic (PD)-efficacy (E) modeling analysis with intersubject variability assessment to increase our understanding of the interaction of efalizumab with CD11a on T cells and consequent reduction in severity of disease in psoriasis patients. METHODS: A total of 6,329 samples from 240 patients in five Phase I and II clinical studies were used in the analysis. For the analysis, plasma efalizumab concentration was used as the PK measurement, the percent of predose CD11a was used as the PD measurement, and the psoriasis area and severity index was used as the measure of efficacy. A receptor-mediated PK/PD model was developed that describes the dynamic interaction of efalizumab binding with CD11a. In the efficacy model, the rate of psoriasis skin production is directly proportional to the amount of free surface CD11a on T cells, which is offset by the rate of skin healing. An additional CD11a-independent component to psoriasis skin production accounted for incomplete response to efalizumab therapy. A Monte Carlo parametric expectation maximization method implemented in the ADAPT II program was used to obtain the estimate of population parameters and inter- and intrasubject variability. RESULTS AND CONCLUSIONS: The final model described the PK/PD/E data in psoriasis patients reasonably well. In addition, simulations using the final model suggested that efalizumab administered less frequently could possibly be more convenient with similar efficacy.
PURPOSE:Efalizumab is a humanized anti-CD11a monoclonal antibody that demonstrated efficacy in the treatment of patients with psoriasis. The objective of this study was to perform a pharmacokinetic (PK)-pharmacodynamic (PD)-efficacy (E) modeling analysis with intersubject variability assessment to increase our understanding of the interaction of efalizumab with CD11a on T cells and consequent reduction in severity of disease in psoriasispatients. METHODS: A total of 6,329 samples from 240 patients in five Phase I and II clinical studies were used in the analysis. For the analysis, plasma efalizumab concentration was used as the PK measurement, the percent of predose CD11a was used as the PD measurement, and the psoriasis area and severity index was used as the measure of efficacy. A receptor-mediated PK/PD model was developed that describes the dynamic interaction of efalizumab binding with CD11a. In the efficacy model, the rate of psoriasis skin production is directly proportional to the amount of free surface CD11a on T cells, which is offset by the rate of skin healing. An additional CD11a-independent component to psoriasis skin production accounted for incomplete response to efalizumab therapy. A Monte Carlo parametric expectation maximization method implemented in the ADAPT II program was used to obtain the estimate of population parameters and inter- and intrasubject variability. RESULTS AND CONCLUSIONS: The final model described the PK/PD/E data in psoriasispatients reasonably well. In addition, simulations using the final model suggested that efalizumab administered less frequently could possibly be more convenient with similar efficacy.
Authors: D R Mould; C B Davis; E A Minthorn; D C Kwok; M J Elliott; M E Luggen; M C Totoritis Journal: Clin Pharmacol Ther Date: 1999-09 Impact factor: 6.875
Authors: Kenneth B Gordon; Kim A Papp; Tiffani K Hamilton; Patricia A Walicke; Wolfgang Dummer; Nicole Li; Brian W Bresnahan; Alan Menter Journal: JAMA Date: 2003-12-17 Impact factor: 56.272
Authors: Mark Lebwohl; Stephen K Tyring; Tiffani K Hamilton; Darryl Toth; Scott Glazer; Naji H Tawfik; Patricia Walicke; Wolfgang Dummer; Xiaolin Wang; Marvin R Garovoy; David Pariser Journal: N Engl J Med Date: 2003-11-20 Impact factor: 91.245