Document Detail


Modeling the exposure-response relationship of etanercept in the treatment of patients with chronic moderate to severe plaque psoriasis.
MedLine Citation:
PMID:  17244775     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Modeling exposure-response relationships adds significant value to comprehending and interpreting both efficacy and safety data. An exposure-response model was developed using generalized nonlinear mixed-effects methodologies to correlate etanercept exposure with a 75% or greater reduction from baseline in the psoriasis area and severity index (PASI75). Three randomized trials of psoriasis patients were pooled for analysis. Three empirical exposure measures-cumulative dose, predicted cumulative area under the curve, and predicted trough concentration-were evaluated for their predictive capabilities. The predicted cumulative area under the curve model demonstrated the best ability via simulation to reproduce the data and was used to assess the following covariates: age, baseline psoriasis area and severity index, duration of psoriasis disease, prior systemic or phototherapy, race, sex, and weight. The final model was composed by scrutinizing the confidence intervals of a nonparametric bootstrap and included race and sex effects on baseline logit, baseline psoriasis area and severity index and prior systemic or phototherapy effects on maximum drug effect, a weight effect on apparent potency, and an age effect on the rate of drug effect. The model identified covariates predictive of data trends and adequately characterized by simulation the PASI75 over the entire clinical trial design space. In combination with a statistical subgroup analysis, the exposure-response model indicated that dose adjustment was not necessary for etanercept in any patient subpopulation with moderate to severe plaque psoriasis.
Authors:
Matthew M Hutmacher; Ivan Nestorov; Tom Ludden; Ralph Zitnik; Christopher Banfield
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of clinical pharmacology     Volume:  47     ISSN:  0091-2700     ISO Abbreviation:  J Clin Pharmacol     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-01-24     Completed Date:  2007-04-12     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0366372     Medline TA:  J Clin Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  238-48     Citation Subset:  IM    
Affiliation:
Pfizer, Inc, Ann Arbor, Michigan, USA.
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MeSH Terms
Descriptor/Qualifier:
Humans
Immunoglobulin G / blood,  therapeutic use*
Models, Biological*
Psoriasis / blood,  drug therapy*
Randomized Controlled Trials as Topic
Receptors, Tumor Necrosis Factor / blood,  therapeutic use*
Severity of Illness Index
Chemical
Reg. No./Substance:
0/Immunoglobulin G; 0/Receptors, Tumor Necrosis Factor; 185243-69-0/TNFR-Fc fusion protein

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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