The utility of hERG channel inhibition data in the derivation of occupational exposure limits.
Regul Toxicol Pharmacol
; 134: 105224, 2022 Oct.
Article
em En
| MEDLINE
| ID: mdl-35817210
ABSTRACT
Inhibition of the human ether-à-go-go (hERG) channel may lead to QT prolongation and fatal arrhythmia. While pharmaceutical drug candidates that exhibit potent hERG channel inhibition often fail early in development, many drugs with both cardiac and non-cardiac indications proceed to market. In this study, the relationship between in vitro hERG channel inhibition and published occupational exposure limit (OEL) was evaluated. A total of 23 cardiac drugs and 44 drugs with non-cardiac indications with published hERG channel IC50 and published OELs were identified. There was an apparent relationship between hERG IC50 potency and the OEL for cardiac and non-cardiac drugs. Twenty cardiac and non-cardiac drugs were identified that had a potent hERG IC50 (≤25 µM) and a contrastingly large OEL value (≥100 µg/m3). OELs or hazard banding corresponding to ≤100 µg/m3 should be sufficiently protective of effects following occupational exposure to the majority of APIs with hERG IC50 values ≤ 100 µM. It is important to consider hERG IC50 values and possible cardiac effects when deriving OEL values for drugs, regardless of indication. These considerations may be particularly important early in the drug development process for establishing exposure control bands for drugs that do not yet have full clinical safety data.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Síndrome do QT Longo
/
Exposição Ocupacional
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article