Pharmacological Probes to Validate Biomarkers for Analgesic Drug Development.
PK/PD
analgesic
biomarkers
drug development
pain
proof of concept
proof of mechanism
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
27 Jul 2022
27 Jul 2022
Historique:
received:
16
06
2022
revised:
15
07
2022
accepted:
18
07
2022
entrez:
12
8
2022
pubmed:
13
8
2022
medline:
16
8
2022
Statut:
epublish
Résumé
There is an urgent need for analgesics with improved efficacy, especially in neuropathic and other chronic pain conditions. Unfortunately, in recent decades, many candidate analgesics have failed in clinical phase II or III trials despite promising preclinical results. Translational assessment tools to verify engagement of pharmacological targets and actions on compartments of the nociceptive system are missing in both rodents and humans. Through the Innovative Medicines Initiative of the European Union and EFPIA, a consortium of researchers from academia and the pharmaceutical industry was established to identify and validate a set of functional biomarkers to assess drug-induced effects on nociceptive processing at peripheral, spinal and supraspinal levels using electrophysiological and functional neuroimaging techniques. Here, we report the results of a systematic literature search for pharmacological probes that allow for validation of these biomarkers. Of 26 candidate substances, only 7 met the inclusion criteria: evidence for nociceptive system modulation, tolerability, availability in oral form for human use and absence of active metabolites. Based on pharmacokinetic characteristics, three were selected for a set of crossover studies in rodents and healthy humans. All currently available probes act on more than one compartment of the nociceptive system. Once validated, biomarkers of nociceptive signal processing, combined with a pharmacometric modelling, will enable a more rational approach to selecting dose ranges and verifying target engagement. Combined with advances in classification of chronic pain conditions, these biomarkers are expected to accelerate analgesic drug development.
Identifiants
pubmed: 35955432
pii: ijms23158295
doi: 10.3390/ijms23158295
pmc: PMC9368481
pii:
doi:
Substances chimiques
Analgesics
0
Biomarkers, Pharmacological
0
Types de publication
Journal Article
Systematic Review
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Innovative Medicines Initiative
ID : 777500
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