Exploring the Impact of Pharmacological Target-Mediated Low Plasma Exposure in Lead Compound Selection in Drug Discovery - A Modeling Approach.
TMDD
lead compound selection
minimal PBPK model
pharmacometric model
small-molecule drug development
target-mediated low plasma exposure
Journal
The AAPS journal
ISSN: 1550-7416
Titre abrégé: AAPS J
Pays: United States
ID NLM: 101223209
Informations de publication
Date de publication:
28 Oct 2024
28 Oct 2024
Historique:
received:
11
06
2024
accepted:
16
09
2024
medline:
29
10
2024
pubmed:
29
10
2024
entrez:
29
10
2024
Statut:
epublish
Résumé
Small-molecule drug development faces the challenge of low success rate. In this paper, we propose one potential cause that may occur in the preclinical phase and has rarely been brought up before - the neglected target-mediated low plasma exposure, and the subsequent lead compound mis-selection due to conventional pharmacokinetic criteria requiring sufficient plasma exposure and desired half-life. To evaluate the concept of target-mediate low plasma exposure, we established a minimal physiologically-based pharmacokinetic (mPBPK) model to evaluate the concentration-time profiles of a group of virtual lead series analogs in plasma and in tissues with and without pharmacological target expression. Simulation results demonstrated that the candidate with the highest target binding has the lowest plasma exposure due to target-mediated tissue retention. The traditional PK criteria, such as the requirement of sufficient plasma exposure and desired half-life, may potentially result in lead compound mis-selection by discarding the appropriate and best candidate(s). The mPBPK model was partially validated using 4 tyrosine kinase inhibitors based on our in-house PK and tissue distribution data obtained in animals. The association rate constant (K
Identifiants
pubmed: 39467882
doi: 10.1208/s12248-024-00979-7
pii: 10.1208/s12248-024-00979-7
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
112Informations de copyright
© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.
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