Eptinezumab is a recombinant humanized immunoglobulin G1 (IgG1) antibody that binds to α- and β-forms of human calcitonin gene-related peptide (CGRP) ligand with low picomolar affinity (4 and 3 pM Kd, respectively). Eptinezumab prevents the activation of the CGRP receptors and hence the downstream cascade of physiological events linked to initiation of migraine attacks.
Eptinezumab inhibits α- and β-CGRP-mediated neurogenic inflammation and vasodilation.
Eptinezumab is highly selective (>100,000-fold vs related neuropeptides amylin, calcitonin, adrenomedullin and intermedin).
As eptinezumab is administered intravenously, it is 100% bioavailable. Eptinezumab exhibits linear pharmacokinetics and exposure increases proportionally with doses from 10 to 1000 mg. Steady-state is attained after the first-dose during a once every 12 weeks dosing schedule. Median time to maximum concentration (Cmax) is 30 minutes (end-of-infusion), and the average terminal elimination half-life is 27 days. The mean accumulation ratios based on Cmax and AUC0-tau are 1.08 and 1.15, respectively.
Eptinezumab is administered by intravenous infusion which bypasses extravascular absorption and is 100% bioavailable. Median time to peak concentration was attained at the end of infusion (30 minutes).
The central volume of distribution (Vc) for eptinezumab was approximately 3.7 litres.
Eptinezumab is expected to be degraded by proteolytic enzymes into small peptides and amino acids.
Eptinezumab apparent clearance was 0.15 L/day, and the terminal elimination half-life was approximately 27 days.
A population pharmacokinetic analysis including 2 123 subjects explored the effect of age, gender, ethnicity and body weight on the pharmacokinetics of eptinezumab. Relative to a 70 kg subject, steady state exposure of eptinezumab in a 190 kg subject was up to 52% lower, whereas is would be up to 50% higher in a 39 kg subject. However, from the exposure-response evaluation, there was no effect of body weight on the clinical efficacy. No dose adjustment is required based on body weight. The pharmacokinetics of eptinezumab were not affected by age (18-71), gender or race based on population pharmacokinetics. Therefore, no dose adjustment is needed.
No dedicated hepatic or renal impairment studies were conducted to assess the effects of hepatic and renal impairment upon the pharmacokinetics of eptinezumab. Population pharmacokinetic analysis of integrated data from the eptinezumab clinical studies did not reveal any differences in patients with renal or hepatic impairment that would require dose adjustment. No data for patients with severe renal impairment are available.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, juvenile toxicity, or toxicity to reproduction and development.
As eptinezumab is unlikely to interact directly with DNA or other chromosomal material, evaluations for potential genotoxicity were considered unnecessary and not performed.
As no carcinogenicity risk has been identified by extensive evaluation of the literature related to inhibition of CGRP and as no eptinezumab-related proliferative findings were observed in long term studies in monkeys, carcinogenicity testing was considered unnecessary and not performed.
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