Population pharmacokinetic and exposure‐response analysis of eptinezumab in the treatment of episodic and chronic migraine

Abstract

Eptinezumab is a humanized mAb that targets calcitonin gene‐related peptide and is under regulatory review for the prevention of episodic and chronic migraine (EM, CM). It is important to determine whether exposures achieved with intravenous (IV) administration of eptinezumab achieve desired pharmacologic effects. Population pharmacokinetics, including dose‐ and exposure‐response analyses, were performed using patient‐level data from the eptinezumab clinical trial program with IV doses ranging from 10 to 1000 mg in pharmacokinetic analyses or 10 to 300 mg in phase 2/3 clinical studies in patients with EM or CM. Exposure‐response analysis explored the relationship between eptinezumab exposure metrics and efficacy parameters including monthly migraine days. The pharmacokinetic profile of eptinezumab was characterized by rapid attainment of maximum plasma concentration (ie, end of IV administration) and a terminal half‐life of 27 days. Covariate analysis found that patient characteristics had no clinically significant effects on pharmacokinetic parameters and were insufficient to influence dosing. Dose‐ and exposure‐response analyses found exposure with single doses ≥100 mg was associated with greater efficacy compared with doses ≤30 mg and a plateau of effect between 100 and 300 mg. A saturable inhibitory Emax model found the exposure over 12 weeks produced by single‐dose eptinezumab 100 and 300 mg exceeded the exposure estimates required to achieve 90% of the maximal efficacy (EC90). This pharmacokinetic analysis of eptinezumab supports dosing every 12 weeks with no adjustment for patient characteristics, including exposures associated with 100‐ or 300‐mg doses producing optimal efficacy effects. The similar efficacy profiles support 100 mg as the lowest effective dose of eptinezumab.

Eptinezumab for the prevention of chronic migraine: efficacy and safety through 24 weeks of treatment in the phase 3 PROMISE-2 (Prevention of migraine via intravenous ALD403 safety and efficacy–2) study

“…Early onset and sustained response during the PROMISE-2 study may be a result of the pharmacokinetic properties of eptinezumab and its route of administration. Maximum plasma concentrations are achieved immediately upon completion of delivery of the IV administration and persist throughout the dosing interval with a terminal elimination half-life of 27 days [ 26 , 27 ].…”

Eptinezumab Demonstrated Efficacy in Sustained Prevention of Episodic and Chronic Migraine Beginning on Day 1 After Dosing

“…14 Eptinezumab is delivered by a 30-minute IV administration with rapid attainment of maximum plasma concentration by the end of IV administration. 14…”

“…By intravenous (IV) administration over 30 minutes, eptinezumab has 100% bioavailability and achieves maximum plasma concentration at the end of IV administration. 14 Pharmacokinetic results coupled with data from phase 2 studies 15,16 suggested that migraine preventive efficacy of eptinezumab may begin immediately, leading to the inclusion of the percentage of patients reporting a migraine headache on day 1 as a prespecified and alpha-controlled endpoint in pivotal phase 3 trials conducted in patients with episodic (PROMISE-1) and chronic (PROMISE-2) migraine. In both pivotal trials, the percentage of patients reporting a migraine on day 1 was reduced by more than 50% compared to baseline in eptinezumab-treated patients and by approximately 25% in placebo patients.…”

Pharmacokinetics, Pharmacodynamics and Drug–Drug Interactions of New Anti-Migraine Drugs—Lasmiditan, Gepants, and Calcitonin-Gene-Related Peptide (CGRP) Receptor Monoclonal Antibodies

“…Anti-CGRP monoclonal antibodies are less hepatotoxic than gepants, their metabolism is based on reticuloendothelial uptake. Since monoclonal antibodies are not known to be eliminated via renal pathways or metabolized in the liver, renal and hepatic impairment are not expected to impact their pharmacokinetics [111][112][113][114][115][116][117][118].…”

“…Steady-state plasma concentrations are achieved with the first dose of the once every three months dosing schedule. Eptinezumab's distribution volume is approximately 3.7 L, and biological half-life is about 27 days [117].…”