Moving beyond Binary Predictions of Human Drug-Induced Liver Injury (DILI) toward Contrasting Relative Risk Potential.
Chem Res Toxicol
; 33(1): 223-238, 2020 01 21.
Article
en En
| MEDLINE
| ID: mdl-31532188
ABSTRACT
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 (<1, 1-10, 10-100, and >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 On the basis of well-established clinical safety experience of marketed/withdrawn drug candidates, the background analysis consists of 200 drugs from the Liver Toxicity Knowledge Base annotated as Most-DILI- (79), Less-DILI- (56), No-DILI-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candidates discontinued for unacceptable incidence/magnitude of liver transaminase elevations during clinical trials or withdrawn for liver injury severity.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.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Enfermedad Hepática Inducida por Sustancias y Drogas
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Idioma:
En
Revista:
Chem Res Toxicol
Asunto de la revista:
TOXICOLOGIA
Año:
2020
Tipo del documento:
Article