title: Translational Pharmacodynamics of Calcitonin Gene-Related Peptide Monoclonal Antibody LY2951742 in a Capsaicin-Induced Dermal Blood Flow Model.
abstract: LY2951742, a monoclonal antibody targeting calcitonin gene-related peptide (CGRP), is being developed for migraine prevention and osteoarthritis pain. To support the clinical development of LY2951742, capsaicin-induced dermal blood flow (DBF) was used as a target engagement biomarker to assess CGRP activity in nonhuman primates and healthy volunteers. Inhibition of capsaicin-induced DBF in nonhuman primates, measured with laser Doppler imaging, was dose dependent and sustained for at least 29 days after a single intravenous injection of the CGRP antibody. This information was used to generate a pharmacokinetic/pharmacodynamic model, which correctly predicted inhibition of capsaicin-induced DBF in humans starting at a single subcutaneous 5-mg dose. As expected, the degree of inhibition in capsaicin-induced DBF increased with higher LY2951742 plasma concentrations. Utilization of this pharmacodynamic biomarker with pharmacokinetic data collected in phase I studies provided the dose-response relationship that assisted in dose selection for the phase II clinical development of LY2951742.
authors.affiliation: Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven and University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium (S.V., A.V.H., J.d.H.); Eli Lilly and Company, Indianapolis, Indiana (R.J.B., D.M., V.J.W., E.C.C.); and Atlas Venture, Cambridge, Massachusetts (D.G.).
authors.forename: Steve
authors.initials: S
authors.lastname: Vermeersch
authors.affiliation: Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven and University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium (S.V., A.V.H., J.d.H.); Eli Lilly and Company, Indianapolis, Indiana (R.J.B., D.M., V.J.W., E.C.C.); and Atlas Venture, Cambridge, Massachusetts (D.G.).
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Benschop
authors.affiliation: Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven and University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium (S.V., A.V.H., J.d.H.); Eli Lilly and Company, Indianapolis, Indiana (R.J.B., D.M., V.J.W., E.C.C.); and Atlas Venture, Cambridge, Massachusetts (D.G.).
authors.forename: Anne
authors.initials: A
authors.lastname: Van Hecken
authors.affiliation: Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven and University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium (S.V., A.V.H., J.d.H.); Eli Lilly and Company, Indianapolis, Indiana (R.J.B., D.M., V.J.W., E.C.C.); and Atlas Venture, Cambridge, Massachusetts (D.G.).
authors.forename: David
authors.initials: D
authors.lastname: Monteith
authors.affiliation: Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven and University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium (S.V., A.V.H., J.d.H.); Eli Lilly and Company, Indianapolis, Indiana (R.J.B., D.M., V.J.W., E.C.C.); and Atlas Venture, Cambridge, Massachusetts (D.G.).
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Wroblewski
authors.affiliation: Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven and University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium (S.V., A.V.H., J.d.H.); Eli Lilly and Company, Indianapolis, Indiana (R.J.B., D.M., V.J.W., E.C.C.); and Atlas Venture, Cambridge, Massachusetts (D.G.).
authors.forename: David
authors.initials: D
authors.lastname: Grayzel
authors.affiliation: Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven and University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium (S.V., A.V.H., J.d.H.); Eli Lilly and Company, Indianapolis, Indiana (R.J.B., D.M., V.J.W., E.C.C.); and Atlas Venture, Cambridge, Massachusetts (D.G.).
authors.forename: Jan
authors.initials: J
authors.lastname: de Hoon
authors.affiliation: Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven and University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium (S.V., A.V.H., J.d.H.); Eli Lilly and Company, Indianapolis, Indiana (R.J.B., D.M., V.J.W., E.C.C.); and Atlas Venture, Cambridge, Massachusetts (D.G.) emilycollins@lilly.com.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Collins
mesh_terms: D000279:Administration, Cutaneous; D000293:Adolescent; D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D002211:Capsaicin / Q000494:pharmacology*; D004311:Double-Blind Method; D006801:Humans; D017078:Laser-Doppler Flowmetry / Q000379:methods; D008252:Macaca fascicularis; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000188:drug therapy; D012039:Regional Blood Flow / Q000187:drug effects*; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin