Revisiting dose-finding of monoclonal antibodies in migraine
Abstract 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..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
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| Enthalten in: |
The journal of headache and pain - 24(2023), 1 vom: 09. Juni |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Al-Hassany, Linda [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| Themen: |
Dose-finding |
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| Anmerkungen: |
© The Author(s) 2023 |
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| doi: |
10.1186/s10194-023-01602-4 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
SPR051844893 |
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| 520 | |a Abstract 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. | ||
| 650 | 4 | |a Migraine |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Monoclonal antibodies |7 (dpeaa)DE-He213 | |
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| 650 | 4 | |a Early phase II clinical trials |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Karsan, Nazia |4 aut | |
| 700 | 1 | |a Lampl, Christian |4 aut | |
| 700 | 1 | |a Goadsby, Peter J. |4 aut | |
| 700 | 1 | |a MaassenVanDenBrink, Antoinette |4 aut | |
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