Selection and interpretation of clinical pathology indicators of hepatic injury in preclinical studies L. Boone, D. Meyer, P. Cusick, D. Ennulat, A. Provencher Bolliger, N. Everds, V. Meador, G. Elliott, D. Honor, D. Bounous, H. Jordan, for the Regulatory Affairs Committee of the American Society for Veterinary Clinical Pathology Abstract: This position paper delineates the expert recommendations of the Regulatory Affairs Committee of the American Society for Veterinary Clinical Pathology for the use of preclinical, clinical pathology endpoints in assessment of the potential for drug- induced hepatic injury in animals and humans. Development of these guidelines has been based on current recommendations in the relevant preclinical and human clinical trial literature; they are intended to provide a method for consistent and rigorous interpretation of liver-specific data for the identification of hepatic injury in preclinical studies and potential liability for hepatic injury in human patients. (Vet Clin Pathol. 2005;34:182–188) Ó2005 American Society for Veterinary Clinical Pathology Key Words: ALT, hepatic injury, hepatotoxicity, liver, preclinical safety assessment u I. Introduction .................................... 182 II. Objective ....................................... 183 III. Previously Published Recommendations for Clinical Pathology Testing in Toxicity and Safety Studies ........ 183 IV. Updated Recommendations for Clinical Pathology Parameters of Hepatic Injury in Preclinical Studies ...... 183 A. Indicators of hepatocellular injury: ALT and AST .... 184 B. Supplemental indicators of hepatocellular injury: SDH and GDH................................ 184 C. Indicators of hepatobiliary injury: ALP and TBILI .... 184 D. Supplemental indicator of hepatobiliary injury: GGT. . 184 E. Supplemental indicators of hepatic synthetic function ..................................... 185 F. Hepatic parameters not routinely assessed in preclinical studies .............................. 185 G. Novel bioassays and biomarkers ................. 185 V. Recommendations for the Interpretation of Clinical Pathology Data in the Identification of Hepatic Injury in Preclinical Studies in Rats, Dogs, and Non-human Primates ............................. 185 A. Terminology of effect level ...................... 185 B. General guidelines for clinical pathology data interpretation .................................... 186 C. Guidelines for interpreting changes in the values of specific hepatic parameters .................... 186 1. Serum ALT activity .......................... 187 2. Serum TBILI concentration .................... 187 3. Serum ALP and GGT activities ................. 187 VI. Summary ...................................... 187 VII. References ...................................... 187 Detection of potential human hepatic injury is a major challenge in preclinical pharmaceutical research and can pre- sent a severe impediment to the development of novel, effica- cious, and safe drugs. The majority of drugs that cause hepatic injury in preclinical studies do not progress to clinical trials or are developed with substantial patient monitoring. 1,2 Inte- grated evaluation of all study data, including the results of alanine aminotransferase (ALT) measurement and liver his- tology, has been shown to be crucial for the identification of hepatic injury in preclinical studies as an indicator of potential liability for hepatic injury in humans. However, a retrospective review of 548 compounds marketed between 1975 and 1999 indicated that 10.2% were withdrawn or acquired a black box warning, 3 with hepatic injury cited as a predominant reason for withdrawal or addition of a warning to the label. Growing concerns about adverse hepatic drug reactions have led to commentaries 4 concerning the adequacy of current practices for evaluating hepatic injury in preclinical studies. Similar concerns have resulted in the release of draft position papers regarding the detection of drug-induced liver injury from agencies responsible for the investigation of the safety and efficacy of human health products within the United States (Federal Drug Administration, FDA) 5 and Canada (Health Canada). 6 Recently, the agency responsible for evaluation of human health products in Europe, the European Medicines Agency (EMEA), also indicated their intent to draft a guidance paper for detection of drug-induced liver injury for human health products. 7 Position Paper The authors are Diplomates of the American College of Veterinary Pathologists in Clinical Pathology (Boone, Meyer, Cusick, Ennulat, Bolliger, Everds, Meador, Elliott, Honor, Bounous, and Jordan) and Anatomic Pathology (Cusick, Ennulat, Meador); the American College of Veterinary Internal Medicine (Meyer); and the American Board of Toxicology (Cusick). The Regulatory Affairs Committee is a standing committee of the American Society for Veterinary Clinical Pathology (ASVCP), Madison, WI, USA. An earlier but not substantively different version of this paper was submitted to the European Medicines Agency (EMEA) to provide guidance in the preparation of recommendations for the detection of drug-induced liver injury for human health products in Europe. Corresponding author: Laura I. Boone, DVM, PhD (boone_laura_I@lilly.com). ª2005 American Society for Veterinary Clinical Pathology Page 182 Veterinary Clinical Pathology Vol. 34 / No. 3 / 2005