期刊
PHARMACEUTICAL RESEARCH
卷 34, 期 9, 页码 1784-1795出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-017-2183-6
关键词
anti-CGRP receptor; dermal blood flow; migraine; pharmacokinetics-pharmacodynamics; vasodilation
资金
- Amgen Inc.
- Abide
- Amgen
- Galderma
- Genentech
- GlaxoSmithKline
- Janssen Research Development
- Lilly Chorus
- MSD
- Novartis
- Sanofi Pasteur
- UCB
- Vertex
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.
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