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• W2128680329 abstract "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. 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. The coxibs, selective inhibitors of cyclooxygenase (COX)-2, were designed to inhibit the major enzymatic source of the prostaglandins (PGs), which mediate pain, inflammation, and, perhaps, tumorigenesis, while sparing COX-1-derived PGs, which contribute dominantly to gastric cytoprotection.1FitzGerald G.A. Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2.N Engl J Med. 2001; 345: 433-442Crossref PubMed Scopus (1407) Google Scholar Two coxibs, rofecoxib2Bombardier C. Laine L. Reicin A. Shapiro D. Burgos-Vargas R. Davis B. Day R. Ferraz M.B. Hawkey C.J. Hochberg M.C. Kvien T.K. Schnitzer T.J. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group.N Engl J Med. 2000; 343: 1520-1530Crossref PubMed Scopus (3706) Google Scholar and lumiracoxib,3Schnitzer T.J. Burmester G.R. Mysler E. Hochberg M.C. Doherty M. Ehrsam E. Gitton X. Krammer G. Mellein B. Matchaba P. Gimona A. Hawkey C.J. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications randomised controlled trial.Lancet. 2004; 364: 665-674Abstract Full Text Full Text PDF PubMed Scopus (630) Google Scholar have been shown in controlled trials to reduce the incidence of serious gastrointestinal (GI) adverse effects when compared with traditional nonsteroidal anti-inflammatory drugs (tNSAIDs). Celecoxib reduced the number of colorectal polyps compared with placebo in patients with familial adenomatous polyposis in a controlled clinical trial.4Steinbach G. Lynch P.M. Phillips R.K. Wallace M.H. Hawk E. Gordon G.B. Wakabayashi N. Saunders B. Shen Y. Fujimura T. Su L.K. Levin B. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis.N Engl J Med. 2000; 342: 1946-1952Crossref PubMed Scopus (2265) Google Scholar However, 3 structurally distinct coxibs, rofecoxib, valdecoxib, and celecoxib, increased the incidence of myocardial infarction and stroke in randomized controlled trials,2Bombardier C. Laine L. Reicin A. Shapiro D. Burgos-Vargas R. Davis B. Day R. Ferraz M.B. Hawkey C.J. Hochberg M.C. Kvien T.K. Schnitzer T.J. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group.N Engl J Med. 2000; 343: 1520-1530Crossref PubMed Scopus (3706) Google Scholar, 5Ott E. Nussmeier N.A. Duke P.C. Feneck R.O. Alston R.P. Snabes M.C. Hubbard R.C. Hsu P.H. Saidman L.J. Mangano D.T. Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery.J Thorac Cardiovasc Surg. 2003; 125: 1481-1492Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar, 6Solomon S.D. McMurray J.J. Pfeffer M.A. Wittes J. Fowler R. Finn P. Anderson W.F. Zauber A. Hawk E. Bertagnolli M. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention.N Engl J Med. 2005; 352: 1071-1080Crossref PubMed Scopus (1891) Google Scholar, 7Bresalier R.S. Sandler R.S. Quan H. Bolognese J.A. Oxenius B. Horgan K. Lines C. Riddell R. Morton D. Lanas A. Konstam M.A. Baron J.A. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.N Engl J Med. 2005; 352: 1092-1102Crossref PubMed Scopus (2287) Google Scholar, 8Nussmeier N.A. Whelton A.A. Brown M.T. Langford R.M. Hoeft A. Parlow J.L. Boyce S.W. Verburg K.M. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery.N Engl J Med. 2005; 352: 1081-1091Crossref PubMed Scopus (961) Google Scholar suggesting that selectivity for inhibition of COX-2 may confer a cardiovascular hazard. Rofecoxib and valdecoxib have recently been withdrawn from the market. Both compounds are more selective for COX-2 than celecoxib in vitro.9Tacconelli S. Capone M.L. Sciulli M.G. Ricciotti E. Patrignani P. The biochemical selectivity of novel COX-2 inhibitors in whole blood assays of COX-isozyme activity.Curr Med Res Opin. 2002; 18: 503-511Crossref PubMed Scopus (87) Google Scholar Despite such differences, all of the coxibs depress substantially prostacyclin (PGI2), leaving platelet COX-1-derived thromboxane (Tx) A2 unaffected, in contrast to aspirin or tNSAIDs, which inhibit both COX-1 and COX-2.10McAdam B.F. Catella-Lawson F. Mardini I.A. Kapoor S. Lawson J.A. FitzGerald G.A. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2 the human pharmacology of a selective inhibitor of COX-2.Proc Natl Acad Sci U S A. 1999; 96: 272-277Crossref PubMed Scopus (1185) Google Scholar, 11Catella-Lawson F. McAdam B. Morrison B.W. Kapoor S. Kujubu D. Antes L. Lasseter K.C. Quan H. Gertz B.J. FitzGerald G.A. Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids.J Pharmacol Exp Ther. 1999; 289: 735-741PubMed Google Scholar PGI2 acts as a constraint on all agonists, which elevate blood pressure, activate platelets, and stimulate atherogenesis.12Cheng Y. Austin S.C. Rocca B. Koller B.H. Coffman T.M. Grosser T. Lawson J.A. FitzGerald G.A. Role of prostacyclin in the cardiovascular response to thromboxane A2.Science. 2002; 296: 539-541Crossref PubMed Scopus (722) Google Scholar, 13Qi Z. Hao C.M. Langenbach R.I. Breyer R.M. Redha R. Morrow J.D. Breyer M.D. Opposite effects of cyclooxygenase-1 and -2 activity on the pressor response to angiotensin II.J Clin Invest. 2002; 110: 61-69Crossref PubMed Scopus (242) Google Scholar, 14Kobayashi T. Tahara Y. Matsumoto M. Iguchi M. Sano H. Murayama T. Arai H. Oida H. Yurugi-Kobayashi T. Yamashita J.K. Katagiri H. Majima M. Yokode M. Kita T. Narumiya S. Roles of thromboxane A2 and prostacyclin in the development of atherosclerosis in apoE-deficient mice.J Clin Invest. 2004; 114: 784-794Crossref PubMed Scopus (332) Google Scholar Thus, drug selectivity for inhibition of COX-2 is thought to contribute to the likelihood of hypertension, myocardial infarction, and stroke resulting from treatment with coxibs.15FitzGerald G.A. COX-2 and beyond approaches to prostaglandin inhibition in human disease.Nat Rev Drug Discov. 2003; 2: 879-890Crossref PubMed Scopus (464) Google Scholar, 16FitzGerald G.A. Coxibs and cardiovascular disease.N Engl J Med. 2004; 351: 1709-1711Crossref PubMed Scopus (832) Google Scholar The detection of cardiovascular complications attributable to coxibs relates in patients to their underlying risk of cardiovascular disease.17Furberg C.D. Psaty B.M. FitzGerald G.A. Parecoxib, valdecoxib, and cardiovascular risk.Circulation. 2005; 111: 249Crossref PubMed Scopus (100) Google Scholar Thus, it seems rational that patients with identifiable cardiovascular risk factors will be excluded from treatment with selective COX-2 inhibitors. However, cardiovascular adverse events attributable to the coxibs also occurred in patients who were apparently at low initial risk of cardiovascular disease,6Solomon S.D. McMurray J.J. Pfeffer M.A. Wittes J. Fowler R. Finn P. Anderson W.F. Zauber A. Hawk E. Bertagnolli M. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention.N Engl J Med. 2005; 352: 1071-1080Crossref PubMed Scopus (1891) Google Scholar, 7Bresalier R.S. Sandler R.S. Quan H. Bolognese J.A. Oxenius B. Horgan K. Lines C. Riddell R. Morton D. Lanas A. Konstam M.A. Baron J.A. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.N Engl J Med. 2005; 352: 1092-1102Crossref PubMed Scopus (2287) Google Scholar suggesting that both rofecoxib and celecoxib caused a risk transformation during extended treatment of these individuals. The emerging hazard would be expected to relate to multiple factors, including the degree of selectivity for inhibition of COX-2 actually attained within an individual, plasma concentrations, and half-life and duration of drug action.15FitzGerald G.A. COX-2 and beyond approaches to prostaglandin inhibition in human disease.Nat Rev Drug Discov. 2003; 2: 879-890Crossref PubMed Scopus (464) Google Scholar, 16FitzGerald G.A. Coxibs and cardiovascular disease.N Engl J Med. 2004; 351: 1709-1711Crossref PubMed Scopus (832) Google Scholar Such pharmacokinetic and pharmacodynamic characteristics have been increasingly associated with both drug safety and efficacy and may be successfully exploited to individualize therapy18Israel E. Chinchilli V.M. Ford J.G. Boushey H.A. Cherniack R. Craig T.J. Deykin A. Fagan J.K. Fahy J.V. Fish J. Kraft M. Kunselman S.J. Lazarus S.C. Lemanske Jr, R.F. Liggett S.B. Martin R.J. Mitra N. Peters S.P. Silverman E. Sorkness C.A. Szefler S.J. Wechsler M.E. Weiss S.T. Drazen J.M. Use of regularly scheduled albuterol treatment in asthma genotype-stratified, randomised, placebo-controlled cross-over trial.Lancet. 2004; 364: 1505-1512Abstract Full Text Full Text PDF PubMed Scopus (548) Google Scholar when heritable mechanisms or predictive host factors such as gender, race, age, or weight can be identified.19Wood A.J. Racial differences in the response to drugs—pointers to genetic differences.N Engl J Med. 2001; 344: 1394-1396Crossref PubMed Scopus (167) Google Scholar However, environmental sources of variability such as nutritional status and physical activity can mask clinically relevant associations. The relative importance of stable interindividual sources of variability in drug response—such as genetic variants—compared with less predictable, environmental sources of variability in the response to coxibs is unknown. We examined the variability, both within and between subjects, in response to celecoxib and rofecoxib, in a placebo-controlled crossover study. Our studies suggest that even healthy individuals respond quite differently to coxibs. This variance might confound the detection of cardiovascular events attributable to drug exposure. On the other hand, interindividual variability in drug response might be exploited to identify patients in whom the drug exhibits unique efficacy or in whom the evolution of cardiovascular risk is accelerated. This may permit definition of the parameters within which these drugs2Bombardier C. Laine L. Reicin A. Shapiro D. Burgos-Vargas R. Davis B. Day R. Ferraz M.B. Hawkey C.J. Hochberg M.C. Kvien T.K. Schnitzer T.J. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group.N Engl J Med. 2000; 343: 1520-1530Crossref PubMed Scopus (3706) Google Scholar, 3Schnitzer T.J. Burmester G.R. Mysler E. Hochberg M.C. Doherty M. Ehrsam E. Gitton X. Krammer G. Mellein B. Matchaba P. Gimona A. Hawkey C.J. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications randomised controlled trial.Lancet. 2004; 364: 665-674Abstract Full Text Full Text PDF PubMed Scopus (630) Google Scholar might be administered chronically to patients initially at low risk of cardiovascular disease. 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 unremarkable medical history, physical examination, and routine hematologic and biochemical screen and were within 30% of ideal body weight. Subjects were nonsmokers and abstained from the use of aspirin and tNSAIDs, as assessed by history and platelet aggregometry, for at least 2 weeks before enrollment.20Catella-Lawson F. Reilly M.P. Kapoor S.C. Cucchiara A.J. DeMarco S. Tournier B. Vyas S.N. FitzGerald G.A. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin.N Engl J Med. 2001; 345: 1809-1817Crossref PubMed Scopus (1297) Google Scholar Routine hematology, biochemistry, and urinalysis were assessed at time of screening and at 24 hours after administration of the drugs on completion of the study. Fifty healthy volunteers (Table 1), aged between 21 and 43 years, received, in random order, a single dose of placebo, celecoxib (200 mg), and rofecoxib (25 mg) under double-blind conditions, separated by washout periods of at least 2 weeks. The randomization sequence was determined by the General Clinical Research Center pharmacist by allocation of the drugs to numbered containers. Inhibition of platelet COX-1 was assessed by measurement of serum TxB2.21Patrignani P. Filabozzi P. Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects.J Clin Invest. 1982; 69: 1366-1372Crossref PubMed Scopus (784) Google Scholar COX-2 inhibition was assessed ex vivo by measurement of lipopolysaccharide-stimulated PGE2 in plasma.22Panara M.R. Renda G. Sciulli M.G. Santini G. Di Giamberardino M. Rotondo M.T. Tacconelli S. Seta F. Patrono C. Patrignani P. Dose-dependent inhibition of platelet cyclooxygenase-1 and monocyte cyclooxygenase-2 by meloxicam in healthy subjects.J Pharmacol Exp Ther. 1999; 290: 276-280PubMed Google Scholar The coefficients of variation for repeatability and reproducibility were 4.3% and 4.1%, respectively, for COX-1 inhibition and 1.9% and 4.3%, respectively, for COX-2 inhibition. Measurements were performed immediately before the administration of drug (0 hrs) and 4 hours thereafter. Urinary 2,3-dinor-6keto PGF1α (PGI-M), an index of PGI2 biosynthesis,23FitzGerald G.A. Pedersen A.K. Patrono C. Analysis of prostacyclin and thromboxane biosynthesis in cardiovascular disease.Circulation. 1983; 67: 1174-1177Crossref PubMed Scopus (382) Google Scholar and 11-dehydro TxB2 (Tx-M),24Catella F. FitzGerald G.A. Paired analysis of urinary thromboxane B2 metabolites in humans.Thromb Res. 1987; 47: 647-656Abstract Full Text PDF PubMed Scopus (163) Google Scholar reflective of TxA2 formation in vivo, were assessed at 0 and 4 hours in spot urine samples that were collected 30 minutes after voiding. The coefficients of variation for both assays were <10%. A subset of the volunteers (n = 5) progressed through the entire protocol on 5 occasions, each separated by 2 weeks, to assess intraindividual variability in drug response in 5 replicates.Table 1Characteristics of the SubjectsFemale (n = 22)Male (n = 28)All (n = 50)Age (y) (25%, median, 75%)23.3, 26.0, 31.823.0, 29.5, 35.323.0, 27.5, 34.5Ethnicity, No. (%) White12 (54.6)17 (60.7)29 (58.0) Black7 (31.8)5 (17.9)12 (24.0) Asian3 (13.6)6 (21.4)9 (18.0)Body mass index (25%, median, 75%)21.0, 23.5, 28.223.3, 25.3, 27.821.8, 24.8, 28.0 Open table in a new tab Plasma samples were analyzed by liquid chromatography tandem mass spectrometry (Quattro Ultima, Micromass, Beverly, MA) using L755100 (Merck Frosst, Point Claire, Canada) and SC58125 (Cayman, Ann Arbor, MI) as internal standards for celecoxib and rofecoxib, respectively. Samples were chromatographed on a Luna 3μ C18 (150 × 2.0 mm) column (Phenomenex, Torrance, CA) and quantitated using negative-atmospheric-pressure ionization and selected reaction monitoring of m/z 380.2→316.1 (celecoxib), 384.2→305.1 (SC58125), 314.2→215.1 (rofecoxib), and 328.2→313.1 (L755100). The coefficients of variation for these assays were 5.4% for celecoxib and 8.6% for rofecoxib measurements. Twenty-six single nucleotide polymorphism (SNP) assays (Table 2) were performed, using the Sequenom MassARRAY system (Sequenom, San Diego, CA).25Wiltshire T. Pletcher M.T. Batalov S. Barnes S.W. Tarantino L.M. Cooke M.P. Wu H. Smylie K. Santrosyan A. Copeland N.G. Jenkins N.A. Kalush F. Mural R.J. Glynne R.J. Kay S.A. Adams M.D. Fletcher C.F. Genome-wide single-nucleotide polymorphism analysis defines haplotype patterns in mouse.Proc Natl Acad Sci U S A. 2003; 100: 3380-3385Crossref PubMed Scopus (208) Google Scholar These assays robustly detected 1083 out of 1482 genotypes. The additional 399 genotypes were determined by resequencing (ABI 3730xl; Applied Biosystems, Foster City, CA).Table 2Single Nucleotide PolymorphismsGeneDomainAccessionaAccession numbers refer to the NCBI (rs …) or the EXPASY (VAR_ …) SNP database./reference numbersPositionBase/amino acid changeAllele frequencyMajor alleleMinor alleleCOX-1Promoter(Halushka et al45Halushka M.K. Walker L.P. Halushka P.V. Genetic variation in cyclooxygenase 1 effects on response to aspirin.Clin Pharmacol Ther. 2003; 73: 122-130Crossref PubMed Scopus (266) Google Scholar)−842G/A10Signalrs12369138Trp/Arg0.960.04rs384278717Pro/Leu0.950.05EGFrs384278953Arg/His10Catalyticrs3842792185Lys/Thr0.970.03(Ulrich et al43Ulrich C.M. Bigler J. Sibert J. Greene E.A. Sparks R. Carlson C.S. Potter J.D. Cyclooxygenase 1 polymorphisms in African-American and Caucasian populations.Hum Mutat. 2002; 20: 409-410Crossref PubMed Scopus (69) Google Scholar)230Gly/Ser10rs5789237Leu/Met0.980.02(Ulrich et al43Ulrich C.M. Bigler J. Sibert J. Greene E.A. Sparks R. Carlson C.S. Potter J.D. Cyclooxygenase 1 polymorphisms in African-American and Caucasian populations.Hum Mutat. 2002; 20: 409-410Crossref PubMed Scopus (69) Google Scholar)341Lys/Arg10rs5791359Lys/Arg10rs5792443Ile/Val10rs5793467Lys/Glu10rs5794481Val/Ile0.990.01COX-2Promoter(Papatili et al44Papafili A. Hill M.R. Brull D.J. McAnulty R.J. Marshall R.P. Humphries S.E. Laurent G.J. Common promoter variant in cyclooxygenase-2 represses gene expression evidence of role in acute-phase inflammatory response.Arterioscler Thromb Vasc Biol. 2002; 22: 1631-1636Crossref PubMed Scopus (321) Google Scholar)−765G/C10Signalrs204261Met/Ile10Membraners498701161Thr/Arg10Catalyticrs3218622228Arg/His10rs4648279428Pro/Ala10rs5272488Glu/Gly10rs5273511Val/Ala0.970.03C-terminusrs3218625587Gly/Arg10CYP2C9Catalyticrs1799853bCYP2C9⁎2.144Arg/Cys0.920.08rs2256871cCYP2C9⁎9.251His/Arg0.990.01rs1057909358Tyr/Cys10rs1057910dCYP2C9⁎3.359Ile/Leu0.950.05VAR_013515eCYP2C9⁎4.359Ile/Thr10VAR_013516fCYP2C9⁎5.360Asp/Glu0.990.01a Accession numbers refer to the NCBI (rs …) or the EXPASY (VAR_ …) SNP database.b CYP2C92.c CYP2C99.d CYP2C93.e CYP2C94.f CYP2C95. Open table in a new tab The primary response variables were ex vivo COX-2 inhibition, expressed as the ratio of postdrug to predrug plasma PGE2; ex vivo COX-1 inhibition, expressed as the ratio of postdrug to predrug serum TxB2; urinary PGI-M inhibition, expressed as the ratio of concentration postdrug to postplacebo administration; urinary Tx-M inhibition, expressed as the ratio of concentration postdrug to postplacebo administration; and plasma drug concentrations 4 hours postdrug administration. Derived variables were ratios of primary measures as estimates of COX-2 selectivity. All variables were log transformed to approximate normality. Four data points (3 measurements of Tx-M and 1 plasma concentration of celecoxib) were excluded because of technical errors in the assays. Each subject in the study had either 1 or 5 replicate sets of measurements. Hence, the study followed an unbalanced hierarchical design with the repeated factor DRUG nested within measurement REPLICATE nested within study SUBJECT. However, the effects of REPLICATE grouped within SUBJECT were minimal, and a regression model was adopted in which the multivariate outcomes were grouped only by SUBJECT. These semiparametric regression models were estimated by generalized estimating equations using a robust “sandwich” variance estimator and identity link functions for the mean and scale models (geepack v0.2-10 in R 2.0-1; http://www.cran.R-project.org26Yan J. Fine J. Estimating equations for association structures.Stat Med. 2004; 23: 859-880Crossref PubMed Scopus (318) Google Scholar). The multiple measures grouped by SUBJECT were assumed to have an exchangeable correlation structure: This is equivalent to a hierarchical model with random intercepts grouped within SUBJECT. Variance components estimates were calculated using Bayesian hierarchical linear models of this type, with Markov Chain Monte Carlo estimation in winBUGS 1.4.1.27Spiegelhalter D.J. Thomas A. Best N.G. WinBUGS Version 1.2 User Manual. Technical manual. MRC Biostatistics Unit, Cambridge, UK1999Google Scholar Comparisons of the primary response variables between the treatment groups had a power in excess of 90% to detect a moderate effect size of 0.50 for 2-sided Student t test of paired observations with type I error rate of 0.05 in a study of 50 subjects. Results are graphed on logarithmic scales where error estimations were performed on log transformed data. Exploratory tests of genetic association on multiple outcome measures were conducted using multivariate analysis of variance (MANOVA), with the dependent variables averaged over replicate measurements for each subject. Analyses were conducted in 2 ways: with data points unweighted and with data points weighted by the number of replicate sets of measurements. 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 pg/mg creatinine, 75%: 117 pg/mg creatinine). Both rofecoxib and celecoxib inhibited COX-2-dependent PGE2 formation ex vivo significantly when compared with placebo (Figure 1A). Small placebo effects may be attributable to diurnal variation because predrug and postdrug measurements were performed consistently at 0800 and 1200 hours. There was no difference in the degree of COX-2 inhibition attained by the 2 drugs (rofecoxib 44.8% vs celecoxib 47.5%). Celecoxib also depressed COX-1-derived serum TxB2, but the effect was small in comparison with the inhibition of PGE2 (Figure 1B). Both drugs depressed the formation of PGI2 in vivo as assessed by urinary PGI-M excretion but not the formation of TxA2 as assessed by excretion of urinary Tx-M (Figure 1C and 1D). There was no difference between the drugs in their effects on these measures of COX-2 and COX-1 activity in vivo (Figures 1C and 1D). The degree of selectivity for COX-2 in vitro—a chemical property of a COX inhibitor—is commonly expressed as the ratio of the drug concentrations required to inhibit the enzymatic activities of COX-2 and COX-1 by 50% (Figure 2A). Based on these criteria, rofecoxib is more selective than celecoxib.1FitzGerald G.A. Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2.N Engl J Med. 2001; 345: 433-442Crossref PubMed Scopus (1407) Google Scholar However, pharmacokinetic and pharmacodynamic variations between individuals would be expected to affect the degree of COX-2 selectivity actually attained in humans, which can be described by the ratio of COX-2 inhibition vs COX-1 inhibition at any given plasma concentration (Figure 2B). When the degree of COX-2 selectivity attained in subjects was estimated using this measure, both drugs differed significantly from placebo but not from each other at this time point after dosing (Figure 2C). There was considerable variability in both ex vivo and in vivo indices of inhibition of both COX-2 and COX-1 (Figures 1E–H). However, drug response correlated poorly with plasma drug concentrations of rofecoxib (median, 215 ng/mL; range, 115–658 ng/mL) and celecoxib (median, 575 ng/mL; range, 179–1372 ng/mL) at 4 hours after dosing (data not shown). Plasma drug levels after dosing showed a trend toward lower concentrations with increasing body mass index (BMI). However, this attained significance (P < .05) only for rofecoxib: a unit increase in BMI was associated with a drop in plasma concentration of approximately 2%. We assessed intra- and interindividual variability in drug response to determine the likely contribution of random and environmental fluctuations rather than interindividual factors to variability. Thus, 5 replicate sets of measurements were performed in 5 volunteers (Figure 1I–L). The simplified model underlying this experimental design assumed that the total variability as observed in the whole population (Figure 1E-H) was composed of interindividual variability, intraindividual variability, and some portion of random variability (eg, technical variability). The replicate measurements served to determine the combination of intraindividual variability and random variability (Figure 1I–L). Thus, assessment of the total variability (Figure 1E–H) and its 2 components intraindividual and random variability (Figure 1I–L) allowed estimation of the third component, interindividual variability, using a variance component analysis. The average responses for both drugs in the replicate measurements closely approximate the observations made within the whole population. Variability within these individuals (intraindividual and random variability) was less than the variability in the population as a whole (total variability). This can be visualized by expressing for each individual the variances of the replicate measurements and comparing the average variance of measurements within the same subject with the total variance (Figure 3A–D). The replicate measurements in 3 out of 4 response variables exhibited a lower variation within individuals than in the whole population, indicating that interindividual variability, beyond that attributable to random and environmental influences, is detectable within the population. Indeed, variance component analyses suggested that up to approximately 30% of the total variability in the measures of COX-1 and COX-2 inhibition may be attributed to interindividual variability (data not shown). Genetic variability is a likely contributor to such differences in drug response between individuals. Thus, we genotyped the study population for polymorphisms in COX-1, COX-2, and cytochrome P450 (CYP) 2C9, the principal metabolizing enzyme of celecoxib, to examine their potential role in drug response (Table 2). We targ" @default.
• W2128680329 created "2016-06-24" @default.
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• W2128680329 date "2006-01-01" @default.
• W2128680329 modified "2023-10-03" @default.
• W2128680329 title "Marked Interindividual Variability in the Response to Selective Inhibitors of Cyclooxygenase-2" @default.
• W2128680329 cites W1576302979 @default.
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