Abstract
Background and Objective
The chemoattractant receptor-homologous molecule expressed on T helper-2 cells (CRTH2) is a G-protein-coupled receptor for prostaglandin D2 (PGD2), a key mediator in inflammatory disorders. Two selective and potent CRTH2 antagonists currently in clinical development, ACT-453859 and setipiprant, were compared with respect to their (predicted) clinical efficacy.
Methods
Population pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to characterize how plasma concentrations (PK) of ACT-453859, its active metabolite ACT-463036 and setipiprant related to their effect on blocking PGD2-induced internalization of CRTH2 on eosinophils (PD). Simulations were used to identify doses and dosing regimens leading to 90 % of maximum blockade of CRTH2 internalization at trough.
Results
A combined concentration of ACT-453859 and its metabolite ACT-463036, with weights proportional to potency (based on an eosinophil shape change assay), enabled good characterization of the PD effect. The modelling and simulation results facilitated decision making by suggesting an ACT-453859 dose of 400 mg once daily (or 100 mg twice daily) for clinically relevant CRTH2 antagonism.
Conclusion
Pharmacometric quantification demonstrated that CRTH2 internalization is a useful new biomarker to study CRTH2 antagonism. Ninety percent of maximum blockade of CRTH2 internalization at trough is suggested as a quantitative PD target in clinical studies.
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References
Nagata K, Hirai H, Tanaka K, Ogawa K, Aso T, Sugamura K, et al. CRTH2, an orphan receptor of T-helper-2-cells, is expressed on basophils and eosinophils and responds to mast cell-derived factor(s). FEBS Lett. 1999;459(2):195–9.
Murray JJ, Tonnel AB, Brash AR, Roberts LJ 2nd, Gosset P, Workman R, et al. Release of prostaglandin D2 into human airways during acute antigen challenge. N Engl J Med. 1986;315(13):800–4. doi:10.1056/NEJM198609253151304.
Pettipher R. The roles of the prostaglandin D(2) receptors DP(1) and CRTH2 in promoting allergic responses. Br J Pharmacol. 2008;153(Suppl 1):S191–9. doi:10.1038/sj.bjp.0707488.
Choy DF, Modrek B, Abbas AR, Kummerfeld S, Clark HF, Wu LC, et al. Gene expression patterns of Th2 inflammation and intercellular communication in asthmatic airways. J Immunol. 2011;186(3):1861–9. doi:10.4049/jimmunol.1002568.
Pettipher R, Hansel TT, Armer R. Antagonism of the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases. Nat Rev Drug Discov. 2007;6(4):313–25. doi:10.1038/nrd2266.
Straumann A, Bauer M, Fischer B, Blaser K, Simon HU. Idiopathic eosinophilic esophagitis is associated with a T(H)2-type allergic inflammatory response. J Allergy Clin Immunol. 2001;108(6):954–61. doi:10.1067/mai.2001.119917.
Gervais FG, Cruz RP, Chateauneuf A, Gale S, Sawyer N, Nantel F, et al. Selective modulation of chemokinesis, degranulation, and apoptosis in eosinophils through the PGD2 receptors CRTH2 and DP. J Allergy Clin Immunol. 2001;108(6):982–8. doi:10.1067/mai.2001.119919.
Robinson DS. Th-2 cytokines in allergic disease. Br Med Bull. 2000;56(4):956–68.
Tanaka K, Hirai H, Takano S, Nakamura M, Nagata K. Effects of prostaglandin D2 on helper T cell functions. Biochem Biophys Res Commun. 2004;316(4):1009–14. doi:10.1016/j.bbrc.2004.02.151.
Xue L, Gyles SL, Wettey FR, Gazi L, Townsend E, Hunter MG, et al. Prostaglandin D2 causes preferential induction of proinflammatory Th2 cytokine production through an action on chemoattractant receptor-like molecule expressed on Th2 cells. J Immunol. 2005;175(10):6531–6.
Kostenis E, Ulven T. Emerging roles of DP and CRTH2 in allergic inflammation. Trends Mol Med. 2006;12(4):148–58. doi:10.1016/j.molmed.2006.02.005.
Sidharta PN, Diamant Z, Dingemanse J. Single- and multiple-dose tolerability and pharmacokinetics of the CRTH2 antagonist setipiprant in healthy male subjects. Fundam Clin Pharmacol. 2014;28(6):690–9. doi:10.1111/fcp.12079.
Diamant Z, Sidharta PN, Singh D, O’Connor BJ, Zuiker R, Leaker BR, et al. Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in allergic asthmatics. Clin Exp Allergy. 2014;44(8):1044–52. doi:10.1111/cea.12357.
Gehin M, Strasser DS, Zisowsky J, Farine H, Groenen PM, Dingemanse J, et al. A novel CRTH2 antagonist: single- and multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ACT-453859 in healthy subjects. J Clin Pharmacol. 2015;77(7):787–97. doi:10.1002/jcph.478.
Strasser DS, Farine H, Holdener M, Zisowsky J, Roscher R, Hoerner J, et al. Development of a decision-making biomarker for CRTH2 antagonism in clinical studies. N Horiz Transl Med. 2015;2(4–5):118–25. doi:10.1016/j.nhtm.2015.05.001.
Baldoni D, Mackie A, Gutierrez M, Theodor R, Dingemanse J. Setipiprant, a selective oral antagonist of human CRTH2: relative bioavailability of a capsule and a tablet formulation in healthy female and male subjects. Clin Ther. 2013;35(11):1842–8. doi:10.1016/j.clinthera.2013.09.003.
R Development Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2009.
Lixoft-Incuballiance. Monolix user guide. Edition 4.2.0. Orsay: Lixoft-Incuballiance; 2012.
Pettipher R, Hunter MG, Perkins CM, Collins LP, Lewis T, Baillet M, et al. Heightened response of eosinophilic asthmatic patients to the CRTH2 antagonist OC000459. Allergy. 2014;69(9):1223–32. doi:10.1111/all.12451.
Actelion. Study of ACT-129968 in adult patients with seasonal allergic rhinitis (SAR). http://www.ClinicalTrials.gov. 2012. https://clinicaltrials.gov/show/NCT01241214. Accessed 15 Nov 2015.
Bell S, Anderson L, Nugent C, Klopfenstein N, Eberhardt C, Carter L et al. Safety, PK and PD of ARRY-502, a CRTh2 antagonist, in healthy subjects with a history of seasonal allergies [abstract no. E3954]. European Respiratory Society Annual Congress; Barcelona; 18–22 Sep 2010.
Thomas J, Gorski K, Evangelista C, Belouski SS, Banfield C, Ferbas J. Development and implementation of a CRTH2 receptor internalization assay for assessment of target coverage by a small molecule CRTH2/DP receptor antagonist [abstract no. T.94]. 11th Annual Meeting of the Federation of Clinical Immunology Societies (FOCIS); Washington, DC; 23–26 Jun 2011.
Acknowledgments
We thank Sandrine Gioria (Actelion Pharmaceuticals Ltd) for project management, Hervé Farine (Actelion Pharmaceuticals Ltd) for PD assay development and implementation, and the staff of the PRACS Institute (previously Cetero Research, Mississauga, ON, Canada)—especially Drs Deepen Patel and Sohail Khattak—and Rakesh Nayyar (Cytoquest Corporation, Toronto ON, Canada) for their important contributions to this study.
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Funding
This study was funded by Actelion Pharmaceuticals Ltd.
Conflict of interest
Andreas Krause, Jochen Zisowsky, Daniel S. Strasser, Martine Gehin, Patricia N. Sidharta, Peter M.A. Groenen and Jasper Dingemanse were employees of Actelion Pharmaceuticals Ltd at the time when the study was conducted and may receive stock or stock options as part of their compensation.
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40262_2015_354_MOESM1_ESM.pdf
Fig. S1 Goodness-of-fit plots for a and b ACT-453859 concentration, c and d ACT-463036 concentration, and e and f percentage (perc.) of CRTH2 [chemoattractant receptor-homologous molecule expressed on T helper-2 cells] receptors on eosinophils. Graphs a, c and e show observations versus population predictions, and graphs b, d and f show observations versus individual predictions. On each graph, the pink line indicates the line of identity and the turquoise line indicates a nonlinear regression (PDF 200 kb)
40262_2015_354_MOESM2_ESM.pdf
Fig. S2 Goodness-of-fit plots for a and b setipiprant concentration, and c and d percentage (perc.) of CRTH2 [chemoattractant receptor-homologous molecule expressed on T helper-2 cells] receptors on eosinophils. Graphs a and c show observations versus population predictions, and graphs b and f show observations versus individual predictions. On each graph, the pink line indicates the line of identity and the turquoise line indicates the nonlinear regression (PDF 151 kb)
40262_2015_354_MOESM3_ESM.pdf
Fig. S3 Visual predictive checks for population pharmacokinetic/pharmacodynamic models for a, b and c ACT-453859, d, e and f ACT-463036 concentrations, and g, h and i percentage of CRTH2 [chemoattractant receptor-homologous molecule expressed on T helper-2 cells] receptors on eosinophils for doses of a, d, and g 10 mg, b, e, and h 100 mg and c, f, and i 800 mg. The blue shaded areas indicate the 90 % confidence intervals (C.I) of the 10th and 90th percentiles (prctile) of the simulated data, and the pink shaded areas indicate the medians. Data are shown as blue circles, and empirical (emp.) percentiles are shown as lines. Observed ranges outside (out.) simulated ranges are circled in red (PDF 162 kb)
40262_2015_354_MOESM4_ESM.pdf
Fig. S4 Visual predictive checks for population pharmacokinetic/pharmacodynamic models for a and b setipiprant concentration and for c and d percentage of CRTH2 [chemoattractant receptor-homologous molecule expressed on T helper-2 cells] receptors on eosinophils for doses of a and c 500 mg and b and d 1000 mg. The blue shaded areas indicate the 90 % coverage intervals (C.I) of the 10th and 90th percentiles (prctile) of the simulated data, and the pink shaded areas indicate the medians. Data are shown as blue circles, and empirical (emp.) percentiles are shown as lines. Observed ranges outside (out.) simulated ranges are circled in red (PDF 128 kb)
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Krause, A., Zisowsky, J., Strasser, D.S. et al. Pharmacokinetic/Pharmacodynamic Modelling of Receptor Internalization with CRTH2 Antagonists to Optimize Dose Selection. Clin Pharmacokinet 55, 813–821 (2016). https://doi.org/10.1007/s40262-015-0354-3
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DOI: https://doi.org/10.1007/s40262-015-0354-3