Moving beyond Binary Predictions of Human Drug-Induced Liver Injury (DILI) toward Contrasting Relative Risk Potential

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 C max,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 On the basis of well-established clinical safety experience of marketed/withdrawn drug candidates, the background analysis consists of 200 drugs from the Liver Toxicity Knowledge Base annotated as Most-DILI-(79), Less-DILI-(56),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candidates discontinued for unacceptable incidence/magnitude of liver transaminase elevations during clinical trials or withdrawn for liver injury severity.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.

A history of the roles of cytochrome P450 enzymes in the toxicity of drugs

“…A number of in vitro approaches have been discussed in recent literature [60,[194][195][196][197][198][199][200]. Different companies have varying approaches to predicting toxicity, although many of the main elements are similar.…”

The evolution of strategies to minimise the risk of human drug-induced liver injury (DILI) in drug discovery and development

“…Supplemental Table 1 contains 1383 DILI and non-DILI reference compounds utilised from 19 publications (Aleo et al 2019;Albrecht et al 2019;Chen et al 2011Chen et al , 2016Dawson et al 2012;Garside et al 2014;Gustafsson et al 2014;Khetani et al 2012;O'Brien et al 2006;Porceddu et al 2012;Proctor et al 2017;Sakatis et al 2012;Schadt et al 2015;Tolosa et al 2012Tolosa et al , 2019Williams et al 2019). If available and/or interpretable the in vivo DILI observation has been simplified to positive (+ ve) or negative (−ve), and the assay or strategy prediction included, 422 compounds are classified in the LTKB, however, only 189 of these compounds are consistently classified as either DILI negative or positive across the publications.…”

“…This DILI classification has started to be incorporated in to more recent studies (e.g. Aleo et al 2019 and Williams et al 2019 ). A comparison of 17 publications was performed over 769 tested reference compounds, aligned with (Chen et al 2016 ), where possible (supplemental Table 1).…”

“…Pfizer recently published their latest DILI strategy using modelling approaches instead of binary endpoint analysis (Aleo et al 2019 ). The in vitro assays used were cytotoxicity in THLE or HepG2 cells, mitochondrial dysfunction (inhibition and uncoupling) using isolated mitochondria, plus the Glu/Gal assay and bile salt export pump (BSEP) inhibition, screened against a library of 200 reference drugs from the LTKB annotated as Most (79), Less (56), No (47), and Ambiguous-DILI-concern (18).…”

“…Furthermore, the incorporating of other mechanistic assays (reactive metabolite and cytotoxic metabolite generation and hepatic efflux transport inhibition, other than BSEP) to the HRM had minimal beneficial impact in DILI prediction. Using the Partition HRM hybrid scoring model successfully classified TAK-875 (liver injury in Phase 3 clinical trials) as a DILI concern and was also valuable in evaluating the relevant DILI risk for several compounds in development (Aleo et al 2019 ).…”