title: Tissue-specific, non-invasive toxicity biomarkers: translation from preclinical safety assessment to clinical safety monitoring.
abstract: Limited sensitivity and limited target organ specificity are the major drawbacks for most peripheral clinical pathology parameters traditionally used for monitoring organ integrity both during preclinical toxicological assessment and clinical safety testing of investigational drugs. Several novel toxicity biomarkers have emerged as sensitive tools for detection, monitoring, quantification and prediction of solid organ toxicity. These tissue-specific, non-invasive biomarkers may provide valuable information for decision making during toxicological assessment and may be used for sensitive and specific target organ monitoring during clinical trials. This review critically discusses the opportunities and limitations of these biomarkers with respect to their translation into (first-in-human) clinical trials. A comprehensive overview is provided on serum- and urine-based biomarkers for hepatotoxicity, nephrotoxicity, cardiotoxicity, gonadotoxicity, pancreatic toxicity, vascular toxicity and phospholipidosis including species-specific assay availabilities and sampling regimens. In addition, the current regulatory status is presented and discussed in view of recent changes in regulatory acceptance by health authorities.
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland. patrick.mueller@novartis.com
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Muller
authors.forename: Frank
authors.initials: F
authors.lastname: Dieterle
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood* / Q000652:urine*; D002986:Clinical Trials as Topic / Q000379:methods; D017277:Drug Approval; D004353:Drug Evaluation, Preclinical / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions / Q000097:blood* / Q000652:urine*; D006801:Humans
chemical_list: D015415:Biomarkers