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Reference intervals for putative biomarkers of drug-induced liver injury and liver regeneration in healthy human volunteers
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  • Andrea Jorgensen,
  • Samantha Korver,
  • Amy Schofield,
  • Lawrence Howell,
  • Joanna Clarke,
  • Lauren Walker,
  • Nathalie Brillant,
  • Christopher Goldring,
  • Munir Pirmohamed
Andrea Jorgensen
University of Liverpool
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Samantha Korver
University of Liverpool
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Amy Schofield
University of Liverpool
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Lawrence Howell
University of Liverpool
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Joanna Clarke
University of Liverpool
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Lauren Walker
University of Liverpool
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Nathalie Brillant
University of Liverpool
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Christopher Goldring
University of Liverpool
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Munir Pirmohamed
University of Liverpool

Corresponding Author:[email protected]

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Abstract

Background & Aims: The potential of mechanistic biomarkers to improve prediction of drug-induced liver injury (DILI) and hepatic regeneration is widely acknowledged. We sought to determine reference intervals for new biomarkers of DILI and regeneration, as well as to characterize their natural variability and impact of diurnal variation. Methods: Serum samples from 227 healthy volunteers were recruited as part of a cross-sectional study; of these, 25 subjects had weekly serial sampling over 3 weeks, while 23 had intensive blood sampling over a 24h period. Alanine aminotransferase (ALT), MicroRNA-122 (miR-122), High Mobility Group Box-1 (HMGB1), total Keratin-18 (K18), caspase-cleaved Keratin-18 (ccK18), Glutamate Dehydrogenase (GLDH) and Macrophage Colony-Stimulating Factor-1 (CSF-1) were assayed. Results: Reference intervals were established for each biomarker based on the 97.5% quantile (90% CI) following the assessment of fixed effects in univariate and multivariable models. Intra-individual variability was found to be non-significant, and there was no significant impact of diurnal variation. Conclusions: Reference intervals for novel DILI biomarkers have been described. An upper limit of a reference range might represent the most appropriate mechanism to utilize these data. These data can now be used to interpret data from exploratory clinical DILI studies and to assist their further qualification as required by regulatory authorities.
12 Jun 2024Submitted to British Journal of Clinical Pharmacology
13 Jun 2024Submission Checks Completed
13 Jun 2024Assigned to Editor
13 Jun 2024Review(s) Completed, Editorial Evaluation Pending
16 Jun 2024Reviewer(s) Assigned
07 Oct 20241st Revision Received
09 Oct 2024Submission Checks Completed
09 Oct 2024Assigned to Editor
09 Oct 2024Review(s) Completed, Editorial Evaluation Pending
12 Oct 2024Reviewer(s) Assigned
29 Oct 2024Editorial Decision: Revise Minor