Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea.
DILIsym Services, Inc., Research Triangle Park, North Carolina, USA.
Clin Pharmacol Ther. 2019 Mar;105(3):746-753. doi: 10.1002/cpt.1254. Epub 2018 Nov 2.
It is not currently possible to rapidly estimate the extent of hepatocyte loss during drug-induced liver injury (DILI). We used a proprietary mechanistic model (DILIsym) to estimate percentage hepatocyte loss due to DILI that resulted from four different patterns of serum alanine aminotransferase (ALT) over time: rapid onset and rapid decrease in ALT levels, moderate onset and moderate decrease in ALT levels, moderate onset and extended duration (over 1 month) of ALT elevations, and an ALT profile with multiple peaks. Using these data, we derived a novel parameter, P = ALT_AUC*Peak ALT /10 ((IU/L) *h), where AUC is area under the curve, that correlated well with hepatocyte loss estimates derived by DILIsym in patients with DILI due to six different hepatotoxic drugs. Although further validation will be required, the fact that P can be derived rapidly using publicly available pharmacokinetic software may make it a useful parameter to improve the safety of drugs.
目前尚无法快速估计药物性肝损伤 (DILI) 导致的肝细胞丢失程度。我们使用专有的机制模型 (DILIsym) 来估计由于四种不同的血清丙氨酸氨基转移酶 (ALT) 随时间变化模式而导致的 DILI 引起的肝细胞丢失百分比：ALT 水平快速升高和快速下降、ALT 水平中度升高和中度下降、ALT 升高持续时间延长（超过 1 个月）和 ALT 谱呈多峰。使用这些数据，我们推导出了一个新参数，P = ALT_AUC*Peak ALT /10 ((IU/L) *h)，其中 AUC 是曲线下面积，该参数与 DILIsym 在 6 种不同肝毒性药物引起的 DILI 患者中得出的肝细胞丢失估计值相关性良好。尽管还需要进一步验证，但 P 可以使用公开的药代动力学软件快速推导出来，这一事实可能使其成为改善药物安全性的有用参数。
