BACKGROUND: The serum activities of ALT and AST are key indicators of liver toxicity in the drug safety evaluation of laboratory animals and patients. To ensure that the full aminotransferase activity is measured, exogenous Pyridoxyl-5-Phosphate (P5P) cofactor is included in the assay reagent. Clinical pathology laboratories make a choice to use aminotransferase assays with or without the added P5P cofactor, and the impact of assay selection on safety assessment is not well understood. OBJECTIVES: The objective of this report was to investigate the effect of aminotransferase assay selection on the detection of liver toxicity based on a literature review. METHODS: Literature in public databases was searched using combinations of the search terms alanine aminotransferase, aspartate aminotransferase, pyridoxyl-5-phosphate, holoenzyme, apoenzyme, enzyme inhibition, artifact, clinical pathology, toxicology, and safety assessment. Regulations or guidance documents published by health authorities specifying clinical pathology evaluation in nonclinical and clinical safety studies of biopharmaceuticals, chemicals, and devices were also reviewed. RESULTS: Aminotransferase testing is not standardized in safety assessment studies and consequently, laboratories use aminotransferase assays with or without P5P cofactor. Individual studies have demonstrated mean differences of approximately 10-20% in serum ALT activity in animal and human populations. The impact of aminotransferase testing without P5P on detection of toxicity and decision-making in drug development has not been systematically evaluated. CONCLUSIONS: The use of different assays for measuring aminotransferase activity contributes to the variability in data between laboratories and studies. Standardizing aminotransferase assays is an avenue for improving the diagnostic performance in drug safety evaluation.
BACKGROUND: The serum activities of ALT and AST are key indicators of liver toxicity in the drug safety evaluation of laboratory animals and patients. To ensure that the full aminotransferase activity is measured, exogenous Pyridoxyl-5-Phosphate (P5P) cofactor is included in the assay reagent. Clinical pathology laboratories make a choice to use aminotransferase assays with or without the added P5P cofactor, and the impact of assay selection on safety assessment is not well understood. OBJECTIVES: The objective of this report was to investigate the effect of aminotransferase assay selection on the detection of liver toxicity based on a literature review. METHODS: Literature in public databases was searched using combinations of the search terms alanine aminotransferase, aspartate aminotransferase, pyridoxyl-5-phosphate, holoenzyme, apoenzyme, enzyme inhibition, artifact, clinical pathology, toxicology, and safety assessment. Regulations or guidance documents published by health authorities specifying clinical pathology evaluation in nonclinical and clinical safety studies of biopharmaceuticals, chemicals, and devices were also reviewed. RESULTS: Aminotransferase testing is not standardized in safety assessment studies and consequently, laboratories use aminotransferase assays with or without P5P cofactor. Individual studies have demonstrated mean differences of approximately 10-20% in serum ALT activity in animal and human populations. The impact of aminotransferase testing without P5P on detection of toxicity and decision-making in drug development has not been systematically evaluated. CONCLUSIONS: The use of different assays for measuring aminotransferase activity contributes to the variability in data between laboratories and studies. Standardizing aminotransferase assays is an avenue for improving the diagnostic performance in drug safety evaluation.