Moving beyond Binary Predictions of Human Drug-Induced Liver Injury (DILI) toward Contrasting Relative Risk Potential
| Autor: | A. David Rodrigues, Louis Leung, Hugh A. Barton, Michael D. Aleo, Yvonne Will, Sarah Lazzaro, R. Scott Obach, Chester Costales, Scott W Allen, Falgun Shah, Andrea Nilson |
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| Rok vydání: | 2019 |
| Předmět: |
Drug
Oncology medicine.medical_specialty Cell Survival media_common.quotation_subject Metabolite Cmax Mitochondria Liver 010501 environmental sciences Toxicology 01 natural sciences Approved drug Risk Assessment 03 medical and health sciences chemistry.chemical_compound Drug Development Internal medicine medicine Animals Humans ATP Binding Cassette Transporter Subfamily B Member 11 030304 developmental biology 0105 earth and related environmental sciences media_common Liver injury 0303 health sciences business.industry General Medicine Hep G2 Cells medicine.disease Rats Clinical trial chemistry Relative risk Toxicity Chemical and Drug Induced Liver Injury business |
| Zdroj: | Chemical research in toxicology. 33(1) |
| ISSN: | 1520-5010 |
| Popis: | The hepatic risk matrix (HRM) was developed and used to differentiate lead clinical and back-up drug candidates against competitor/marketed drugs within the same pharmaceutical class for their potential to cause human drug-induced liver injury (DILI). The hybrid HRM scoring system blends physicochemical properties (Rule of Two Model: dose and lipophilicity or Partition Model: dose, ionization state, lipophilicity, and fractional carbon bond saturation) with common toxicity mechanisms (cytotoxicity, mitochondrial dysfunction, and bile salt export pump (BSEP) inhibition) that promote DILI. HRM scores are based on bracketed safety margins ( 100× clinical Cmax,total). On the basis of well-established clinical safety experience of marketed/withdrawn drug candidates, the background analysis consists of 200 drugs from the Liver Toxicity Knowledge Base annotated as Most-DILI- (79), Less-DILI- (56), No-DILI- (47), and Ambiguous-DILI-concern (18) drugs. Scores were generated for over 21 internal and 7 external drug candidates discontinued for unacceptable incidence/magnitude of liver transaminase elevations during clinical trials or withdrawn for liver injury severity. Both hybrid scoring systems identified 70-80% Most-DILI-concern drugs, but more importantly, stratified successful/unsuccessful drug candidates for liver safety (incidence/severity of transaminase elevations and approved drug labels). Incorporating other mechanisms (reactive metabolite and cytotoxic metabolite generation and hepatic efflux transport inhibition, other than BSEP) to the HRM had minimal beneficial impact in DILI prediction/stratification. As is, the hybrid scoring system was positioned for portfolio assessments to contrast DILI risk potential of small molecule drug candidates in early clinical development. This stratified approach for DILI prediction aided decisions regarding drug candidate progression, follow-up mechanistic work, back-up selection, clinical dose selection, and due diligence assessments in favor of compounds with less implied clinical hepatotoxicity risk. |
| Databáze: | OpenAIRE |
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