Clinical–alimentary tractMarked Interindividual Variability in the Response to Selective Inhibitors of Cyclooxygenase-2
Section snippets
Study Design
This randomized, double-blind, placebo-controlled protocol was approved by the Institutional Review Board of the University of Pennsylvania Health System and by the Advisory Council of the General Clinical Research Center (University of Pennsylvania, Philadelphia). Screening, enrollment, and follow-up of healthy study volunteers were performed at the General Clinical Research Center from January 2002 to January 2004. Written informed consent was obtained from all volunteers. All had an
Results
Fifty volunteers received, in random order, placebo and single therapeutic doses of rofecoxib and celecoxib to compare directly the responses to the drugs within the same subjects. Baseline levels of the drug response parameters (medians) were as follows: Serum TxB2 408 ng/mL (25%: 280 ng/mL, 75%: 557 ng/mL); LPS induced PGE2 28 ng/mL (25%: 16 ng/mL, 75%: 47 ng/mL); urine Tx-M 293 pg/mg creatinine (25%: 185 pg/mg creatinine, 75%: 439 pg/mg creatinine); urine PGI-M 81 pg/mg creatinine (25%: 55
Discussion
Variability between individuals in their response to drugs is well recognized.19 Nevertheless, the typical paradigms of drug development and approval infer a common response to a limited number of doses within a therapeutic category. Inhibitors of COX-2 are no exception. Indeed, a considerable variability in the plasma concentration/enzyme inhibition response relationships was noted as the first member of the class, celecoxib,10 entered the US market. Typically, assays in whole human blood have
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Cited by (0)
Supported by The National Heart Lung and Blood Institute (HL62250 and HL54500), the National Center for Research Resources (MO 1RR00040), the American Heart Association (Pennsylvania-Delaware Affiliate Postdoctoral Fellowship, to S.F.; Scientist Development Grant 0430148N, to T.G.), the Wellcome Trust (London, United Kingdom) (T.S.P.: Training Fellowship in Mathematical Biology to T.S.P.), Orchid Biosciences (Princeton, NJ), and the Genomics Institute of the Novartis Foundation (genotyping).
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S.F. and T.G. contributed equally to this paper.