Performance of preclinical models in predicting drug-induced liver injury in humans: a systematic review

Abstract

Drug-induced liver injury (DILI) causes one in three market withdrawals due to adverse drug reactions, causing preventable human suffering and massive financial loss. We applied evidence-based methods to investigate the role of preclinical studies in predicting human DILI using two anti-diabetic drugs from the same class, but with different toxicological profiles: troglitazone (withdrawn from US market due to DILI) and rosiglitazone (remains on US market). Evidence Stream 1: A systematic literature review of in vivo studies on rosiglitazone or troglitazone was conducted (PROSPERO registration CRD42018112353). Evidence Stream 2: in vitro data on troglitazone and rosiglitazone were retrieved from the US EPA ToxCast database. Evidence Stream 3: troglitazone- and rosiglitazone-related DILI cases were retrieved from WHO Vigibase. All three evidence stream analyses were conducted according to evidence-based methodologies and performed according to pre-registered protocols. Evidence Stream 1: 9288 references were identified, with 42 studies included in analysis. No reported biomarker for either drug indicated a strong hazard signal in either preclinical animal or human studies. All included studies had substantial limitations, resulting in "low" or "very low" certainty in findings. Evidence Stream 2: Troglitazone was active in twice as many in vitro assays (129) as rosiglitazone (60), indicating a strong signal for more off-target effects. Evidence Stream 3: We observed a fivefold difference in both all adverse events and liver-related adverse events reported, and an eightfold difference in fatalities for troglitazone, compared to rosiglitazone. In summary, published animal and human trials failed to predict troglitazone's potential to cause severe liver injury in a wider patient population, while in vitro data showed marked differences in the two drugs' off-target activities, offering a new paradigm for reducing drug attrition in late development and in the market. This investigation concludes that death and disability due to adverse drug reactions may be prevented if mechanistic information is deployed at early stages of drug development by pharmaceutical companies and is considered by regulators as a part of regulatory submissions.

Figure 1

PRISMA flow diagram depicting study inclusion and exclusion justification. *Results on drugs other than troglitazone and rosiglitazone will be published in forthcoming manuscripts.

Figure 2

Risk of Bias assessment of (a) animal and (b) human studies according to criteria defined in the OHAT Risk of Bial Tool for Human and Animal Studies. + +: There is direct evidence of low risk of bias practices; +: There is indirect evidence of low risk of bias practices OR it is deemed that deviations from the low risk of bias practices for these criteria during the study would not appreciably bias results;—or NR: There is indirect evidence of high risk of bias practices OR there is insufficient information (e.g., not reported or ‘NR’) provided about relevant risk of bias; There is direct evidence of high risk of bias practices; NA: Question not relevant for study type. Please note that the study of Bedoucha 2001 on mice included both troglitazone and rosiglitazone, and that the study of Anandharajan 2009 on rosiglitazone included both mice and rats.

Figure 3

Forest plots are presented separately for troglitazone and for rosiglitazone. Each outcome is sorted by species, increasing dose of the drug and increasing follow-up periods.

Figure 3

Forest plots are presented separately for troglitazone and for rosiglitazone. Each outcome is sorted by species, increasing dose of the drug and increasing follow-up periods.

Figure 4

ToxCast database analysis: workflow to identify the tests performed on the two drugs (A) and results based on the number of positive tests (B).

Figure 5

ToxCast database analysis: number of positive tests for troglitazone and rosiglitazone segmented by biological processes.

Figure 6

Definitions of Noramlized Activation Score and biological targets activation potentials.