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Clinical testing of three novel transient receptor potential cation channel subfamily V member 1 antagonists in a pharmacodynamic intradermal capsaicin model
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0003-4318-6039
Swedish Orphan Biovitrum, Solna, Sweden.
Med Prod Agcy, Uppsala, Sweden.
Lundbeck AS, Valby, Denmark;Karolinska Inst, Stockholm, Sweden.
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2018 (English)In: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 22, no 7, p. 1214-1228Article in journal (Refereed) Published
Abstract [en]

Background  The transient receptor potential cation channel subfamily V 1 (TRPV1) is involved in nociception and has thus been of interest for drug developers, as a target for novel analgesics. However, several oral TRPV1 antagonists have failed in development, and novel approaches to target TRPV1 with innovative chemistry are needed. Method This work describes an intradermal microdosing approach in humans for pharmacodynamic deductions and pharmacological profiling of compounds. First, a human capsaicin model was developed, to generate pharmacodynamic translational data (Study Part A, n=24). Then, three small molecule TRPV1 antagonists (AZ11760788, AZ12048189 and AZ12099548) were investigated in healthy volunteers (Study Part B, n=36), applying the established model. Pain and flare were assessed by Visual Analogue Score and laser Doppler, respectively. Results The developed model proved useful for pharmacologic deductions; all compounds caused a dose-dependent inhibition of capsaicin-induced pain and flare responses, with a rank order potency of AZ11760788>AZ12048189 >> AZ12099548. In addition, the dose-response data showed that the minimal antagonist concentrations needed to inhibit TRPV1 was 6-7 times the equilibrium dissociation constant for each compound. Conclusion With careful design of a pharmacodynamic translational human pain model, it was possible to rank order TRPV1 efficacy among three investigational TRPV1 antagonists, and to estimate human efficacious concentrations. SignificanceThis fast and cost-effective translational approach allows for generation of human target engagement information early in drug development. This could be of value for other development programmes where pharmacological targets are expressed in peripheral sensory nerves.

Place, publisher, year, edition, pages
WILEY , 2018. Vol. 22, no 7, p. 1214-1228
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-361263DOI: 10.1002/ejp.1209ISI: 000437737300003PubMedID: 29504187OAI: oai:DiVA.org:uu-361263DiVA, id: diva2:1255156
Funder
AstraZenecaAvailable from: 2018-10-11 Created: 2018-10-11 Last updated: 2018-10-11Bibliographically approved

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