Pharmacological, Pharmacokinetic, Pharmacodynamic and Physicochemical Characterization of FE 205030: A Potent, Fast Acting, Injectable CGRP Receptor Antagonist for the Treatment of Acute Episodic Migraine.
J Pharm Sci
; 111(1): 247-261, 2022 01.
Article
em En
| MEDLINE
| ID: mdl-34217775
ABSTRACT
The neuropeptide calcitonin gene-related peptide (CGRP) is known to play a central role in the underlying pathophysiology of migraine. In comparison to the effective triptan class of antimigraine treatments, the CGRP antagonists possess a comparable efficacy but a superior cardiovascular safety profile in patients. This paper describes the development of selective and potent peptidic CGRP antagonist, FE 205030, that has a fast onset of action and an optimal half-life (subcutaneous Tmax ~ 60 min, and t1/2 ~ 4.4 h in 80 kg pigs, respectively), which is key to prevention of the progression of debilitating migraine symptoms. The in vivo efficacy of this agent has been established a translational pharmacodynamic model (inhibition of capsaicin-induced increase in skin blood flow) in cynomolgus monkeys and shows maximal inhibitory activity at circulating concentrations of 30-100 nM. Antagonist activity of FE 205030 was characterized on CGRP-induced vasodilation in isolated human mesenteric resistance arteries in an ex vivo isometric myograph study, and FE 205030 effectively blocked CGRP-induced vasodilation with a pA2 of 9.3 ± 0.1, mean ± standard error. Multispecies allometric scaling and modeling of subcutaneous (SC) effective concentrations indicates that a dose of 10-30 mg/day is sufficient to achieve a drug exposure/target coverage of 8h, which is useful to prevent migraine recurrence in patients. The molecule also possesses appropriate physicochemical properties that allows for a convenient dosing form factor of 1 ml injection volume with a sufficient solubility and acceptable short-term stability, optimal for treatment of acute migraine episodes in patients. Hence, FE 205030 may provide an important fast-acting injectable option for patients suffering from frequent acute migraine episodes, complementary to preventative monoclonal antibodies and oral small molecule CGRP-R antagonist therapies.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina
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Transtornos de Enxaqueca
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article