Revisiting dose-finding of monoclonal antibodies in migraine

The Journal of Headache and Pain

Correspondence

Christian Lampl¹  Antoinette MaassenVanDenBrink²  Linda Al-Hassany²  Nazia Karsan³  Peter J. Goadsby³ 

[1] Department of Neurology and Stroke Unit, Koventhospital Barmherzige Brüder Linz, Linz, Austria;Headache Medical Center Linz, Linz, Austria;Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands;NIHR SLaM Clinical Research Facility, King’s College London, London, UK;Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA;

关键词: Migraine;    Monoclonal antibodies;    Dose-finding;    Dose-ranging;    Phase I Clinical Trials;    Early phase II clinical trials;   

DOI  :  10.1186/s10194-023-01602-4

 received in 2023-05-08, accepted in 2023-05-25,  发布年份 2023

来源: Springer

【 摘 要 】

Migraine is a debilitating disorder, and while the introduction of monoclonal antibodies (mAbs) has led to efficacious and tolerable responses, a substantial number of patients are so-called “non-responders”. We introduce reasons for this insufficient response, including insufficient blockade of Calcitonin Gene-Related Peptide (CGRP) or its receptor. We present a clinical case, i.e. a female migraine patient who mistakenly administered supratherapeutic (three-fold higher) doses of erenumab leading to more efficacious clinical responses without any side-effects. This example illustrates that the initial dosages might have been too low, resulting in a remaining undesired increased effect of CGRP. While a capsaicin forearm model has repeatedly been used to evaluate the pharmacokinetic-pharmacodynamic relationship of mAbs, we provide directions to revisit or reconsider dose-finding and dose-ranging of these drugs. These directions include (i) refinement and application of a capsaicin forehead model (instead of a forearm model) to study trigeminovascular activity and improve dosing, and (ii) reconsideration of trial populations. Indeed, the dose-finding studies were mainly performed in relatively young and normal-weight males, while most phase III/IV trials are marked by a high female-to-male ratio, mainly consisting of overweight to obese females. Considering these aspects in future trials could optimize healthcare for a larger proportion of migraine patients.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

Fig. 6