Establishing reference ranges for circulating biomarkers of drug-induced liver injury in healthy human volunteers1

Jorgensen, AL ORCID: 0000-0002-6977-9337, Korver, S ORCID: 0000-0001-7670-3093, Schofield, A, Howell, L, Clarke, JI, Walker, LE, Brillant, N, Goldring, CEP ORCID: 0000-0002-8951-2226 and Pirmohamed, M ORCID: 0000-0002-7534-7266 (2025) Establishing reference ranges for circulating biomarkers of drug-induced liver injury in healthy human volunteers1 British Journal of Clinical Pharmacology, 91 (5). pp. 1361-1369. ISSN 0306-5251, 1365-2125

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Abstract

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. Conclusion: 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.

Item Type:	Article
Uncontrolled Keywords:	biomarker, drug-induced liver injury, qualification, validation
Divisions:	Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	20 Dec 2024 16:16
Last Modified:	28 Feb 2026 15:48
DOI:	10.1111/bcp.16371
Open Access URL:	https://doi.org/10.1111/bcp.16371
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3189396
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