Structure dependence and species sensitivity of in vivo hepatobiliary toxicity with lysophosphatidic acid receptor 1 (LPA1) antagonists.
Toxicol Appl Pharmacol
; 438: 115846, 2022 03 01.
Article
em En
| MEDLINE
| ID: mdl-34974053
ABSTRACT
BMS-986020, BMS-986234 and BMS-986278, are three lysophosphatidic acid receptor 1 (LPA1) antagonists that were or are being investigated for treatment of idiopathic pulmonary fibrosis (IPF). Hepatobiliary toxicity (elevated serum AST, ALT, and ALP, plasma bile acids [BAs], and cholecystitis) was observed in a Phase 2 clinical trial with BMS-986020, and development was discontinued. In dogs and rats, the species used for the pivotal toxicology studies, there was no evidence of hepatobiliary toxicity in the dog while findings in the rat were limited to increased plasma BAs levels (6.1× control), ALT (2.9×) and bilirubin (3.4×) with no histopathologic correlates. Since neither rats nor dogs predicted clinical toxicity, follow-up studies in cynomolgus monkeys revealed hepatobiliary toxicity that included increased ALT (2.0× control) and GLDH (4.9×), bile duct hyperplasia, cholangitis, cholestasis, and cholecystitis at clinically relevant BMS-986020 exposures with no changes in plasma or liver BAs. This confirmed monkey as a relevant species for identifying hepatobiliary toxicity with BMS-986020. In order to assess whether the toxicity was compound-specific or related to LPA1 antagonism, two structurally distinct LPA1 antagonists (BMS-986234 and BMS-986278), were evaluated in rat and monkey. There were no clinical or anatomic pathology changes indicative of hepatobiliary toxicity. Mixed effects on plasma BAs in both rat and monkey has made this biomarker not a useful predictor of the hepatobiliary toxicity. In conclusion, the nonclinical data indicate the hepatobiliary toxicity observed clinically and in monkeys administered BMS-986020 is compound specific and not mediated via antagonism of LPA1.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores de Ácidos Lisofosfatídicos
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Doenças do Sistema Digestório
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Doença Hepática Induzida por Substâncias e Drogas
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Fígado
Tipo de estudo:
Diagnostic_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article