| アブストラクト | Drug induced liver injury during drug development is evidenced by a higher incidence of serum alanine aminotransferase (ALT) elevations in treated versus placebo populations and termed an "ALT signal". We sought to quantify whether an ALT signal in pre-marketing clinical trials predicted post-marketing hepatotoxicity. Incidence of ALT elevations (ALT >/= 3 times upper limits normal [x ULN]) for drug and placebo of new chemical entities and approved drugs associated with hepatotoxicity was calculated using the Food and Drug Administration (FDA) website. Post-marketing liver safety events were identified using the FDA Adverse Event Reporting System (AERS). The association of FDA AERS signal score (EB05 >/= 2) and excess risk of pre-marketing ALT elevation (difference in incidence of ALT >/= 3x ULN in treated versus placebo) was examined. An ALT signal of >/= 1.2% was significantly associated with a post-marketing liver safety signal (p </= 0.013) and a 71.4% positive predictive value. An absent ALT signal was associated with a high likelihood of post-marketing liver safety; negative predictive value of 89.7%. Daily drug dose information improved the prediction of post-marketing liver safety. A cut-off of 1.2% increase in ALT >/= 3x ULN in treated versus placebo groups provides an easily calculated method for predicting post-marketing liver safety. |
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| ジャーナル名 | Regulatory toxicology and pharmacology : RTP |
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| 投稿日 | 2012/06/07 |
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| 投稿者 | Moylan, Cynthia A; Suzuki, Ayako; Papay, Julie I; Yuen, Nancy A; Ames, Michael; Hunt, Christine M |
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| 組織名 | Division of Gastroenterology and Hepatology, Duke University, Durham, NC 27710,;USA. cynthia.moylan@dm.duke.edu |
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| Pubmed リンク | https://www.ncbi.nlm.nih.gov/pubmed/22668747/ |
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