TY - JOUR
T1 - Performance of preclinical models in predicting drug-induced liver injury in humans
T2 - a systematic review
AU - Dirven, Hubert
AU - Vist, Gunn E.
AU - Bandhakavi, Sricharan
AU - Mehta, Jyotsna
AU - Fitch, Seneca E.
AU - Pound, Pandora
AU - Ram, Rebecca
AU - Kincaid, Breanne
AU - Leenaars, Cathalijn H.C.
AU - Chen, Minjun
AU - Wright, Robert A.
AU - Tsaioun, Katya
N1 - Funding Information:
The study was initiated, conducted, and managed by the Evidence-based Toxicology Collaboration (EBTC) at the Johns Hopkins Bloomberg School of Public Health, which received funding from the Center for Alternatives to Animal Testing at Johns Hopkins University (CAAT), which in turn received funding from the Johns Hopkins Bloomberg School of Public Health (JHSPH), a non-profit institution. CAAT and JHSPH had no role in the study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the article for publication. The authors and contributors made their contributions in their spare time. All authors had full access to the raw data used in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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human DILI using two anti-diabetic drugs from the same class, but with different toxicological profiles: troglitazone (withdrawn from US market due to DILI) and rosiglitazone (remains on US market).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.
AB - 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.
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U2 - 10.1038/s41598-021-85708-2
DO - 10.1038/s41598-021-85708-2
M3 - Article
C2 - 33737635
AN - SCOPUS:85102745097
SN - 2045-2322
VL - 11
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 6403
ER -