Cristin-resultat-ID: 1915213
Sist endret: 3. desember 2021, 11:37
NVI-rapporteringsår: 2021
Resultat
Vitenskapelig oversiktsartikkel/review
2021

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

Bidragsytere:
  • Hubert Dirven
  • Gunn Elisabeth Vist
  • Sricharan Bandhakavi
  • Jyotsna Mehta
  • Seneca E. Fitch
  • Pandora Pound
  • mfl.

Tidsskrift

Scientific Reports
ISSN 2045-2322
e-ISSN 2045-2322
NVI-nivå 1

Om resultatet

Vitenskapelig oversiktsartikkel/review
Publiseringsår: 2021
Publisert online: 2021
Volum: 11
Artikkelnummer: 6403
Open Access

Importkilder

Scopus-ID: 2-s2.0-85102745097

Beskrivelse Beskrivelse

Tittel

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

Sammendrag

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human DILI using two anti‑diabetic drugs from the same class, but with different toxicological profiles: troglitazone (withdrawn from US market due to DILI) and rosiglitazone (remains on US market).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.

Bidragsytere

Hubert Dirven

  • Tilknyttet:
    Forfatter
    ved Avdeling for miljø og helse ved Folkehelseinstituttet

Gunn Elisabeth Vist

  • Tilknyttet:
    Forfatter
    ved Avdeling for vurdering av tiltak ved Folkehelseinstituttet

Sricharan Bandhakavi

  • Tilknyttet:
    Forfatter
    ved USA

Jyotsna Mehta

  • Tilknyttet:
    Forfatter
    ved USA

Seneca E. Fitch

  • Tilknyttet:
    Forfatter
    ved USA
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