Journal article
Mechanism of hepatobiliary toxicity of the LPA(1) antagonist BMS-986020 developed to treat idiopathic pulmonary fibrosis: Contrasts with BMS-986234 and BMS-986278
Toxicology and applied pharmacology, v 438, 115885
01 Mar 2022
PMID: 35090952
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
In a Phase 2 clinical trial, BMS-986020, a lysophosphatidic acid receptor-1 (LPA 1 ) antagonist, produced hepatobiliary toxicity (increased ALT, AST, and ALP; cholecystitis) and increases in plasma bile acids (BA). Nonclinical investigations conducted to identify a potential mechanism(s) for this toxicity examined BMS-986020 and two LPA(1) antagonists structurally distinct from BMS-986020 (BMS-986234 and BMS-986278). BMS-986020 inhibited hepatic BA efflux transporters BSEP (IC50 1.8 mu M), MRP3 (IC50 22 mu M), and MRP4 (IC50 6.2 mu M) and inhibited BA canalicular efflux in human hepatocytes (68% at 10 mu M). BMS-986020 inhibited mitochondrial function (basal and maximal respiration, ATP production, and spare capacity) in human hepatocytes and cholangiocytes at >= 10 mu M and inhibited phospholipid efflux in human hepatocytes (MDR3 IC50 7.5 u mu M). A quantitative systems toxicology analysis (DILIsym (R)), considering pharmacokinetics, BA homeostasis, mitochondrial function, oxidative phosphorylation, and reactive intermediates performed for BMS-986020 recapitulated clinical findings ascribing the effects to BA transporter and mitochondrial electron transport chain inhibition. BMS-986234 and BMS-986278 minimally inhibited hepatic BA transporters (IC50 >= 20 mu M) and did not inhibit MDR3 activity (IC50 >= 100 mu M), nor did BMS-986234 inhibit BA efflux (<= 50 mu M) or mitochondrial function (<= 30 mu M) (BMS-986278 not evaluated). Multiple mechanisms may be involved in the clinical toxicity observed with BMS-986020. The data indicate that this toxicity was unrelated to LPA(1) antagonism since the mechanisms that likely influenced the adverse clinical outcome of BMS-986020 were not observed with equipotent LPA(1) antagonists BMS-986234 and BMS-986278. This conclusion is consistent with the lack of hepatobiliary toxicity in nonclinical and clinical safety studies with BMS-986278.
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Details
- Title
- Mechanism of hepatobiliary toxicity of the LPA(1) antagonist BMS-986020 developed to treat idiopathic pulmonary fibrosis: Contrasts with BMS-986234 and BMS-986278
- Creators
- Michael W. Gill - Bristol-Myers SquibbBrian J. Murphy - Bristol-Myers SquibbPeter T. W. Cheng - Bristol-Myers SquibbLakshmi Sivaraman - Bristol-Myers SquibbMyrtle Davis - Bristol-Myers SquibbLois Lehman-McKeeman - Bristol Myers Squibb, Pharmaceut Candidate Optimizat, Princeton, NJ USA
- Publication Details
- Toxicology and applied pharmacology, v 438, 115885
- Publisher
- Elsevier
- Number of pages
- 13
- Grant note
- Bristol Myers Squibb Company; Bristol-Myers Squibb
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000820972700003
- Scopus ID
- 2-s2.0-85124378025
- Other Identifier
- 991021903126304721
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- Web of Science research areas
- Pharmacology & Pharmacy
- Toxicology