Pharmacokinetic-Pharmacodynamic Relationship of Erenumab (AMG 334) and Capsaicin-Induced Dermal Blood Flow in Healthy and Migraine Subjects

• Published in: Pharmaceutical research Vol. 34; no. 9; pp. 1784 - 1795
• Main Authors: Vu, Thuy, Ma, Peiming, Chen, Jiyun Sunny, de Hoon, Jan, Van Hecken, Anne, Yan, Lucy, Wu, Liviawati Sutjandra, Hamilton, Lisa, Vargas, Gabriel
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.09.2017; Springer; Springer Nature B.V
• Subjects: Adult; Antibodies, Monoclonal - blood; Antibodies, Monoclonal - pharmacology; Bioavailability; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Blood flow; Blood Flow Velocity - drug effects; Body weight; Calcitonin; Calcitonin gene-related peptide; Calcitonin Gene-Related Peptide - antagonists & inhibitors; Capsaicin; Capsaicin - pharmacology; Female; Headache; Homeopathy; Humans; Male; Materia medica and therapeutics; Medical Law; Migraine; Migraine Disorders - drug therapy; Migraine Disorders - physiopathology; Models, Biological; Monoclonal antibodies; Pharmacodynamics; Pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Phenols; Research Paper; Sensory System Agents - pharmacology; Skin; Skin - blood supply; Therapeutics; Young Adult; migraine; pharmacokinetics-pharmacodynamics; vasodilation; anti-CGRP receptor; dermal blood flow
• DOI: 10.1007/s11095-017-2183-6
• ISSN: 0724-8741; 1573-904X

Purpose Capsaicin-induced dermal blood flow (CIDBF) is a validated biomarker used to evaluate the target engagement of potential calcitonin gene-related peptide-blocking therapeutics for migraine. To characterize the pharmacokinetics (PK) and quantify the inhibitory effects of erenumab (AMG 334) on CIDBF, CIDBF data were pooled from a single- and a multiple-dose study in healthy and migraine subjects. Methods Repeated capsaicin challenges and DBF measurements were performed and serum erenumab concentrations determined. A population analysis was conducted using a nonlinear mixed-effects modeling approach. Effects of body weight, gender, and age on model parameters were evaluated. Results Two-compartment target-mediated drug disposition (TMDD) model assuming binding of erenumab in the central compartment best described the nonlinear PK of erenumab. Subcutaneous absorption half-life was 1.6 days and bioavailability was 74%. Erenumab produced a maximum inhibition of 89% (95% confidence interval: 87–91%). Erenumab concentrations required for 50% and 99% of maximum inhibition were 255 ng/mL and 1134 ng/mL, respectively. Increased body weight was associated with increased erenumab clearance but had no effect on the inhibitory effect on CIDBF. Conclusions Our results show that erenumab pharmacokinetics was best characterized by a TMDD model and resulted in potent inhibition of CIDBF.