Nonclinical pharmacokinetics and in vitro metabolism of H3B-6545, a novel selective ERα covalent antagonist (SERCA)
| Autor: | Manav Korpal, Nathalie Rioux, O'shea Morgan Welzel, Pete Smith, Sherri Smith, Markus Warmuth, Sudeep Prajapati, Zheng Guo Zhu |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Indazoles SERCA Metabolic Clearance Rate Pyridines CYP3A Drug Evaluation Preclinical Biological Availability Estrogen receptor Plasma protein binding In Vitro Techniques Pharmacology Toxicology Rats Sprague-Dawley 03 medical and health sciences Dogs 0302 clinical medicine Cytochrome P-450 Enzyme System Species Specificity Pharmacokinetics medicine Animals Cytochrome P-450 Enzyme Inhibitors Humans Tissue Distribution Pharmacology (medical) Cells Cultured Chemistry Estrogen Receptor alpha In vitro Macaca fascicularis 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Hepatocyte Hepatocytes Microsomes Liver Female Estrogen Receptor Antagonists Drug metabolism Protein Binding |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 83:151-160 |
| ISSN: | 1432-0843 0344-5704 |
| Popis: | H3B-6545, a novel selective estrogen receptor (ER)α covalent antagonist (SERCA) which inactivates both wild-type and mutant ERα, is in clinical development for the treatment of metastatic breast cancer. Preclinical studies were conducted to characterize the pharmacokinetics and metabolism of H3B-6545 in rat and monkeys. The clearance and metabolic profiles of H3B-6545 were studied using rat, monkey and human hepatocytes, and reaction phenotyping was done using recombinant human cytochrome P450 enzymes. Blood stability, protein binding, and permeability were also determined in vitro. Pharmacokinetics of H3B-6545 was assessed after both intravenous and oral dosing. A nonclinical PBPK model was developed to assess in vitro–in vivo correlation of clearance. H3B-6545 had a terminal elimination half-life of 2.4 h in rats and 4.0 h in monkeys and showed low to moderate bioavailability, in line with the in vitro permeability assessment. Plasma protein binding was similar across species, at 99.5–99.8%. Nine metabolites of H3B-6545 were identified in hepatocyte incubations, none of which were unique to humans. Formation of glutathione-related conjugate of H3B-6545 was minimal in vitro. H3B-6545, a CYP3A substrate, is expected to be mostly cleared via hepatic phase 1 metabolism. Hepatocyte clearance values were used to adequately model the time-concentration profiles in rat and monkey. We report on the absorption and metabolic fate and disposition of H3B-6545 in rats and dogs and illustrate that in vitro–in vivo correlation of clearance is possible for targeted covalent inhibitors, provided reactivity is not a predominant mechanism of clearance. |
| Databáze: | OpenAIRE |
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