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Development of an Enantioselective and Biomarker-Informed Translational Population Pharmacokinetic/Pharmacodynamic Model for Etodolac

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Abstract

Cyclooxygenase-2 (COX-2) isoform has a critical role in the development of pain. Inhibition of COX-2 in vitro serves as a biomarker for nonsteroidal anti-inflammatory drugs (NSAIDs). The NSAID concentrations yielding 80% COX-2 inhibition (IC80) correlate with therapeutic doses to achieve analgesia across multiple COX-2 inhibitors. However, there are no time-course models relating COX-2 inhibition with decreased pain. This study aimed to characterize the relationship between NSAID concentrations, in vitro COX-2 inhibition, and acute pain decrease in humans over time by a translational approach using clinical pharmacokinetic and literature reported in vitro and clinical pharmacodynamic data. In a two-way cross-over study, eight healthy volunteers received 300 and 400 mg racemic etodolac, a preferential COX-2 inhibitor. R- and S-etodolac were determined by LC-MS/MS and simultaneously modeled. Literature in vitro IC50 data for COX-2 inhibition by S-etodolac were used to fit adjusted pain score profiles from dental patients receiving etodolac. External model qualification was performed using published ibuprofen data. Etodolac absorption was highly variable due to gastric transit kinetics and low aqueous solubility. The disposition parameters differed substantially between enantiomers with a total clearance of 2.21 L/h for R-etodolac and 26.8 L/h for S-etodolac. Volume of distribution at steady-state was 14.6 L for R-etodolac and 45.8 L for S-etodolac. Inhibition of COX-2 by 78.1% caused a half-maximal pain decrease. The time-course of pain decrease following ibuprofen was successfully predicted via the developed translational model. This proposed enantioselective pharmacodynamic-informed approach presents the first quantitative time-course model for COX-2 induced pain inhibition in patients.

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References

  1. Benish M, Bartal I, Goldfarb Y, Levi B, Avraham R, Raz A, et al. Perioperative use of beta-blockers and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis. Ann Surg Oncol. 2008;15(7):2042–52. https://doi.org/10.1245/s10434-008-9890-5.

    Article  PubMed  Google Scholar 

  2. Okamoto A, Shirakawa T, Bito T, Shigemura K, Hamada K, Gotoh A, et al. Etodolac, a selective cyclooxygenase-2 inhibitor, induces upregulation of E-cadherin and has antitumor effect on human bladder cancer cells in vitro and in vivo. Urology. 2008;71(1):156–60. https://doi.org/10.1016/j.urology.2007.09.061.

    Article  PubMed  Google Scholar 

  3. de Souza TL, da Costa ES, Lopes DV, Borojevic R. Racemic etodolac is cytotoxic and cytostatic for B-cell precursor acute lymphoblastic leukemia cells. Biomed Pharmacother. 2009;63(7):548–51. https://doi.org/10.1016/j.biopha.2008.09.009.

    Article  Google Scholar 

  4. Kapadia GJ, Azuine MA, Shigeta Y, Suzuki N, Tokuda H. Chemopreventive activities of etodolac and oxyphenbutazone against mouse skin carcinogenesis. Bioorg Med Chem Lett. 2010;20(8):2546–8. https://doi.org/10.1016/j.bmcl.2010.02.093.

    Article  CAS  PubMed  Google Scholar 

  5. Hasegawa K, Torii Y, Ishii R, Oe S, Kato R, Udagawa Y. Effects of a selective COX-2 inhibitor in patients with uterine endometrial cancers. Arch Gynecol Obstet. 2011;284(6):1515–21. https://doi.org/10.1007/s00404-011-1883-0.

    Article  CAS  PubMed  Google Scholar 

  6. Weideman RA, Kelly KC, Kazi S, Cung A, Roberts KW, Smith HJ, et al. Risks of clinically significant upper gastrointestinal events with etodolac and naproxen: a historical cohort analysis. Gastroenterology. 2004;127(5):1322–8. https://doi.org/10.1053/j.gastro.2004.08.016.

    Article  CAS  PubMed  Google Scholar 

  7. Colebatch AN, Marks JL, van der Heijde DM, Edwards CJ. Safety of nonsteroidal antiinflammatory drugs and/or paracetamol in people receiving methotrexate for inflammatory arthritis: a Cochrane systematic review. J Rheumatol Suppl. 2012;90:62–73. https://doi.org/10.3899/jrheum.120345.

    Article  CAS  PubMed  Google Scholar 

  8. Jones RA. Etodolac: an overview of a selective COX-2 inhibitor. Inflammopharmacology. 1999;7(3):269–75. https://doi.org/10.1007/s10787-999-0010-3.

    Article  CAS  PubMed  Google Scholar 

  9. Shah KP, Gumbhir-Shah K, Brittain HG. Etodolac. In: Brittain HG, editor. Analytical profiles of drug substances and excipients. 1st ed. Cambridge: Academic Press; 2002. p. 336.

    Google Scholar 

  10. Ibrahim MM, El-Nabarawi M, El-Setouhy DA, Fadlalla MA. Polymeric surfactant based etodolac chewable tablets: formulation and in vivo evaluation. AAPS PharmSciTech. 2010;11(4):1730–7. https://doi.org/10.1208/s12249-010-9548-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tougou K, Gotou H, Ohno Y, Nakamura A. Stereoselective glucuronidation and hydroxylation of etodolac by UGT1A9 and CYP2C9 in man. Xenobiotica. 2004;34(5):449–61. https://doi.org/10.1080/00498250410001691280.

    Article  CAS  PubMed  Google Scholar 

  12. Mignot I, Presle N, Lapicque F, Monot C, Dropsy R, Netter P. Albumin binding sites for etodolac enantiomers. Chirality. 1996;8(3):271–80. https://doi.org/10.1002/(SICI)1520-636X(1996)8:3. 271, 3

    Article  CAS  PubMed  Google Scholar 

  13. Jamali F, Mehvar R, Lemko C, Eradiri O. Application of a stereospecific high-performance liquid chromatography assay to a pharmacokinetic study of etodolac enantiomers in humans. J Pharm Sci. 1988;77(11):963–6.

    Article  CAS  PubMed  Google Scholar 

  14. Hewala II, Moneeb MS, Elmongy HA, Wahbi AA. Enantioselective HPLC-DAD method for the determination of etodolac enantiomers in tablets, human plasma and application to comparative pharmacokinetic study of both enantiomers after a single oral dose to twelve healthy volunteers. Talanta. 2014;130:506–17. https://doi.org/10.1016/j.talanta.2014.07.011.

    Article  CAS  PubMed  Google Scholar 

  15. Brocks DR, Jamali F, Russell AS. Stereoselective disposition of etodolac enantiomers in synovial fluid. J Clin Pharmacol. 1991;31(8):741–6.

    Article  CAS  PubMed  Google Scholar 

  16. Brocks DR, Jamali F. Etodolac clinical pharmacokinetics. Clin Pharmacokinet. 1994;26(4):259–74. https://doi.org/10.2165/00003088-199426040-00003.

    Article  CAS  PubMed  Google Scholar 

  17. Brocks DR, Jamali F, Russell AS, Skeith KJ. The stereoselective pharmacokinetics of etodolac in young and elderly subjects, and after cholecystectomy. J Clin Pharmacol. 1992;32(11):982–9.

    Article  CAS  PubMed  Google Scholar 

  18. Center for Drug Evaluation and Research. Application Number 20-584/S003. http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018922s023lbl.pdf. Accessed Nov 2016.

  19. Humber LG, Demerson CA, Swaminathan P, Bird PH. Etodolac (1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid): a potent antiinflammatory drug. Conformation and absolute configuration of its active enantiomer. J Med Chem. 1986;29(5):871–4.

    Article  CAS  PubMed  Google Scholar 

  20. Demerson CA, Humber LG, Abraham NA, Schilling G, Martel RR, Pace-Asciak C. Resolution of etodolac and antiinflammatory and prostaglandin synthetase inhibiting properties of the enantiomers. J Med Chem. 1983;26(12):1778–80.

    Article  CAS  PubMed  Google Scholar 

  21. Inoue N, Nogawa M, Ito S, Tajima K, Kume S, Kyoi T. The enantiomers of etodolac, a racemic anti-inflammatory agent, play different roles in efficacy and gastrointestinal safety. Biol Pharm Bull. 2011;34(5):655–9.

    Article  CAS  PubMed  Google Scholar 

  22. Boni J, Korth-Bradley J, McGoldrick K, Appel A, Cooper S. Pharmacokinetic and pharmacodynamic action of etodolac in patients after oral surgery. J Clin Pharmacol. 1999;39(7):729–37.

    Article  CAS  PubMed  Google Scholar 

  23. Brune K, Patrignani P. New insights into the use of currently available non-steroidal anti-inflammatory drugs. J Pain Res. 2015;8:105–18. https://doi.org/10.2147/JPR.S75160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Huntjens DR, Danhof M, Della Pasqua OE. Pharmacokinetic-pharmacodynamic correlations and biomarkers in the development of COX-2 inhibitors. Rheumatology (Oxford). 2005;44(7):846–59. https://doi.org/10.1093/rheumatology/keh627.

    Article  CAS  Google Scholar 

  25. Patrignani P, Panara MR, Greco A, Fusco O, Natoli C, Iacobelli S, et al. Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. J Pharmacol Exp Ther. 1994;271(3):1705–12.

    CAS  PubMed  Google Scholar 

  26. Brideau C, Kargman S, Liu S, Dallob AL, Ehrich EW, Rodger IW, et al. A human whole blood assay for clinical evaluation of biochemical efficacy of cyclooxygenase inhibitors. Inflamm Res. 1996;45(2):68–74.

    Article  CAS  PubMed  Google Scholar 

  27. Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci U S A. 1999;96(13):7563–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. (CDER) CfDEaR. Guidance for industry analgesic indications: developing drug and biological products. In: U.S. Department of Health and Human Services FaDA, editor. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM384691.pdf: Office of Communications, Division of Drug Information; 2014. p. 35.

  29. Danhof M, de Jongh J, De Lange EC, Della Pasqua O, Ploeger BA, Voskuyl RA. Mechanism-based pharmacokinetic-pharmacodynamic modeling: biophase distribution, receptor theory, and dynamical systems analysis. Annu Rev Pharmacol Toxicol. 2007;47:357–400. https://doi.org/10.1146/annurev.pharmtox.47.120505.105154.

    Article  CAS  PubMed  Google Scholar 

  30. Schmidt SPT, Boroujerdi MA, van Kestern C, Ploeger BA, Della Pasqua O, Danhof M. Disease progression analysis: towards mechanism-based models. In: Kimko HC, Peck CC, editors. Clinical trial simulations applications and trends. 1st ed. New York: Springer; 2011. p. 437–59.

    Google Scholar 

  31. de Miranda SC, Rocha A, Tozatto E, da Silva LM, Donadi EA, Lanchote VL. Enantioselective analysis of etodolac in human plasma by LC-MS/MS: application to clinical pharmacokinetics. J Pharm Biomed Anal. 2016;120:120–6. https://doi.org/10.1016/j.jpba.2015.12.009.

    Article  Google Scholar 

  32. Riendeau D, Percival MD, Brideau C, Charleson S, Dube D, Ethier D, et al. Etoricoxib (MK-0663): preclinical profile and comparison with other agents that selectively inhibit cyclooxygenase-2. J Pharmacol Exp Ther. 2001;296(2):558–66.

    CAS  PubMed  Google Scholar 

  33. Neupert W, Brugger R, Euchenhofer C, Brune K, Geisslinger G. Effects of ibuprofen enantiomers and its coenzyme A thioesters on human prostaglandin endoperoxide synthases. Br J Pharmacol. 1997;122(3):487–92. https://doi.org/10.1038/sj.bjp.0701415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mazaleuskaya LL, Theken KN, Gong L, Thorn CF, FitzGerald GA, Altman RB, et al. PharmGKB summary: ibuprofen pathways. Pharmacogenet Genomics. 2015;25(2):96–106. https://doi.org/10.1097/FPC.0000000000000113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Brocks DR, Jamali F. The pharmacokinetics of etodolac enantiomers in the rat. Lack of pharmacokinetic interaction between enantiomers. Drug Metab Dispos. 1990;18(4):471–5.

    CAS  PubMed  Google Scholar 

  36. Hersh EV, Levin LM, Cooper SA, Reynolds D, Gallegos LT, McGoldrick K, et al. Conventional and extended-release etodolac for postsurgical dental pain. Clin Ther. 1999;21(8):1333–42.

    Article  CAS  PubMed  Google Scholar 

  37. Bauer RJ, Guzy S, Ng C. A survey of population analysis methods and software for complex pharmacokinetic and pharmacodynamic models with examples. AAPS J. 2007;9(1):E60–83. https://doi.org/10.1208/aapsj0901007.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Bulitta JB, Bingolbali A, Shin BS, Landersdorfer CB. Development of a new pre- and post-processing tool (SADAPT-TRAN) for nonlinear mixed-effects modeling in S-ADAPT. AAPS J. 2011;13(2):201–11. https://doi.org/10.1208/s12248-011-9257-x.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Bulitta JB, Landersdorfer CB. Performance and robustness of the Monte Carlo importance sampling algorithm using parallelized S-ADAPT for basic and complex mechanistic models. AAPS J. 2011;13(2):212–26. https://doi.org/10.1208/s12248-011-9258-9.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Holford NH, Ambros RJ, Stoeckel K. Models for describing absorption rate and estimating extent of bioavailability: application to cefetamet pivoxil. J Pharmacokinet Biopharm. 1992;20(5):421–42.

    Article  CAS  PubMed  Google Scholar 

  41. Bulitta JB, Landersdorfer CB, Kinzig M, Holzgrabe U, Sorgel F. New semiphysiological absorption model to assess the pharmacodynamic profile of cefuroxime axetil using nonparametric and parametric population pharmacokinetics. Antimicrob Agents Chemother. 2009;53(8):3462–71. https://doi.org/10.1128/AAC.00054-09.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413–20.

    Article  CAS  PubMed  Google Scholar 

  43. Dayneka NL, Garg V, Jusko WJ. Comparison of four basic models of indirect pharmacodynamic responses. J Pharmacokinet Biopharm. 1993;21(4):457–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mehlisch DR, Jasper RD, Brown P, Korn SH, McCarroll K, Murakami AA. Comparative study of ibuprofen lysine and acetaminophen in patients with postoperative dental pain. Clin Ther. 1995;17(5):852–60.

    Article  CAS  PubMed  Google Scholar 

  45. Lotsch J, Muth-Selbach U, Tegeder I, Brune K, Geisslinger G. Simultaneous fitting of R- and S-ibuprofen plasma concentrations after oral administration of the racemate. Br J Clin Pharmacol. 2001;52(4):387–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Davies NM, Takemoto JK, Brocks DR, Yanez JA. Multiple peaking phenomena in pharmacokinetic disposition. Clin Pharmacokinet. 2010;49(6):351–77. https://doi.org/10.2165/11319320-000000000-00000.

    Article  CAS  PubMed  Google Scholar 

  47. Ferdinandi ES, Sehgal SN, Demerson CA, Dubuc J, Zilber J, Dvornik D, et al. Disposition and biotransformation of 14C-etodolac in man. Xenobiotica. 1986;16(2):153–66. https://doi.org/10.3109/00498258609043518.

    Article  CAS  PubMed  Google Scholar 

  48. Davis SS, Hardy JG, Fara JW. Transit of pharmaceutical dosage forms through the small intestine. Gut. 1986;27(8):886–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Weitschies W, Blume H, Monnikes H. Magnetic marker monitoring: high resolution real-time tracking of oral solid dosage forms in the gastrointestinal tract. Eur J Pharm Biopharm. 2010;74(1):93–101. https://doi.org/10.1016/j.ejpb.2009.07.007.

    Article  CAS  PubMed  Google Scholar 

  50. Glaser K, Sung ML, O'Neill K, Belfast M, Hartman D, Carlson R, et al. Etodolac selectively inhibits human prostaglandin G/H synthase 2 (PGHS-2) versus human PGHS-1. Eur J Pharmacol. 1995;281(1):107–11.

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the São Paulo Research Foundation (FAPESP; Grant 2010/12922-1), by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and by CAPES (Coordination for the Improvement of Higher Education Personnel) Foundation, Brazil.

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Authors and Affiliations

  1. Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, 6550 Sanger Road, Orlando, Florida, 32827, USA

    Carolina de Miranda Silva, Stephan Schmidt & Jürgen B. Bulitta

  2. Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil

    Carolina de Miranda Silva, Adriana Rocha, Eduardo Tozatto & Vera Lucia Lanchote

  3. Departamento de Producao e Controle de Medicamentos, Faculdade de Farmacia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Carolina de Miranda Silva & Teresa Dalla Costa

  4. Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil

    Lucienir Maria da Silva & Eduardo Antônio Donadi

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  1. Carolina de Miranda Silva
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  2. Adriana Rocha
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  3. Eduardo Tozatto
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  4. Lucienir Maria da Silva
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  5. Eduardo Antônio Donadi
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  6. Teresa Dalla Costa
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  7. Vera Lucia Lanchote
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  8. Stephan Schmidt
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  9. Jürgen B. Bulitta
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Correspondence to Stephan Schmidt or Jürgen B. Bulitta.

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de Miranda Silva, C., Rocha, A., Tozatto, E. et al. Development of an Enantioselective and Biomarker-Informed Translational Population Pharmacokinetic/Pharmacodynamic Model for Etodolac. AAPS J 19, 1814–1825 (2017). https://doi.org/10.1208/s12248-017-0138-9

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