title: Setting Clinical Exposure Levels of Concern for Drug-Induced Liver Injury (DILI) Using Mechanistic in vitro Assays.
abstract: Severe drug-induced liver injury (DILI) remains a major safety issue due to its frequency of occurrence, idiosyncratic nature, poor prognosis, and diverse underlying mechanisms. Numerous experimental approaches have been published to improve human DILI prediction with modest success. A retrospective analysis of 125 drugs (70 = most-DILI, 55 = no-DILI) from the Food and Drug Administration Liver Toxicity Knowledge Base was used to investigate DILI prediction based on consideration of human exposure alone or in combination with mechanistic assays of hepatotoxic liabilities (cytotoxicity, bile salt export pump inhibition, or mitochondrial inhibition/uncoupling). Using this dataset, human plasma Cmax,total ≥ 1.1 µM alone distinguished most-DILI from no-DILI compounds with high sensitivity/specificity (80/73%). Accounting for human exposure improved the sensitivity/specificity for each assay and helped to derive predictive safety margins. Compounds with plasma Cmax,total ≥ 1.1 µM and triple liabilities had significantly higher odds ratio for DILI than those with single/dual liabilities. Using this approach, a subset of recent pharmaceuticals with evidence of liver injury during clinical development was recognized as potential hepatotoxicants. In summary, plasma Cmax,total ≥ 1.1 µM along with multiple mechanistic liabilities is a major driver for predictions of human DILI potential. In applying this approach during drug development the challenge will be generating accurate estimates of plasma Cmax,total at efficacious doses in advance of generating true exposure data from clinical studies. In the meantime, drug candidates with multiple hepatotoxic liabilities should be deprioritized, since they have the highest likelihood of causing DILI in case their efficacious plasma Cmax,total in humans is higher than anticipated.
authors.affiliation: *Worldwide Medicinal Chemistry, Pharmacokinetics, Dynamics and Metabolism and Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut 06340 falgun.shah@pfizer.com.
authors.forename: Falgun
authors.initials: F
authors.lastname: Shah
authors.affiliation: *Worldwide Medicinal Chemistry, Pharmacokinetics, Dynamics and Metabolism and Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut 06340.
authors.forename: Louis
authors.initials: L
authors.lastname: Leung
authors.affiliation: *Worldwide Medicinal Chemistry, Pharmacokinetics, Dynamics and Metabolism and Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut 06340.
authors.forename: Hugh A
authors.initials: HA
authors.lastname: Barton
authors.affiliation: *Worldwide Medicinal Chemistry, Pharmacokinetics, Dynamics and Metabolism and Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut 06340.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Will
authors.affiliation: *Worldwide Medicinal Chemistry, Pharmacokinetics, Dynamics and Metabolism and Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut 06340.
authors.forename: A David
authors.initials: AD
authors.lastname: Rodrigues
authors.affiliation: *Worldwide Medicinal Chemistry, Pharmacokinetics, Dynamics and Metabolism and Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut 06340.
authors.forename: Nigel
authors.initials: N
authors.lastname: Greene
authors.affiliation: *Worldwide Medicinal Chemistry, Pharmacokinetics, Dynamics and Metabolism and Drug Safety Research and Development, Pfizer Inc., Groton, Connecticut 06340.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Aleo
mesh_terms: D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008452:Maximum Allowable Concentration; D012189:Retrospective Studies; D018675:Toxicity Tests / Q000706:statistics & numerical data
keywords: Liver Toxicity Knowledge Base; drug-induced liver injury; plasma exposure; safety margin