Gastroenterology

Gastroenterology

Volume 130, Issue 1, January 2006, Pages 55-64
Gastroenterology

Clinical–alimentary tract
Marked Interindividual Variability in the Response to Selective Inhibitors of Cyclooxygenase-2

https://doi.org/10.1053/j.gastro.2005.10.002Get rights and content

Background & Aims: Variability in response to drugs may influence both efficacy and safety. Cyclooxygenase (COX)-2 inhibitors pose a cardiovascular risk by potentially increasing the likelihood of thrombosis, hypertension, and atherogenesis. Differences between individuals in the response to COX-2 inhibitors would be expected to influence their susceptibility to cardiovascular complications. We examined the variability in degree and selectivity of COX-2 inhibition in humans in response to celecoxib and rofecoxib.

Methods: Fifty healthy volunteers received placebo, rofecoxib (25 mg), and celecoxib (200 mg), randomized by order. COX-1 and COX-2 inhibition was determined using ex vivo and in vivo indices of enzymatic activity. A subset of 5 individuals underwent 5 replicate studies to estimate variability in drug response both within and between subjects.

Results: Despite the higher COX-2 selectivity of rofecoxib in vitro, the average selectivity attained by 25 mg rofecoxib and 200 mg celecoxib in vivo were not different. However, there was considerable variability at an individual level in the degree of COX-2 inhibition and selectivity attained by both drugs. Approximately one third of the variability was attributable to differences between individuals, suggesting the contribution of genetic sources of variance, such as candidate polymorphisms detected in COX-1 and CYP2C9.

Conclusions: The actual degree of selectivity for inhibition of COX-2 achieved by the coxibs relates both to chemical properties of the drug and to factors within an individual that modulate drug response. These sources of variability might be exploited to identify patients uniquely susceptible to benefit or at developing risk of cardiovascular complications.

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).

    1

    S.F. and T.G. contributed equally to this paper.

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