Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors.
Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors.
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DOI：
10.1093/toxsci/kfw193
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发表时间：
2017-01
期刊：
影响因子：
--
通讯作者：
Shoda LK
中科院分区：
文献类型：
--
作者：
Woodhead JL;Brock WJ;Roth SE;Shoaf SE;Brouwer KL;Church R;Grammatopoulos TN;Stiles L;Siler SQ;Howell BA;Mosedale M;Watkins PB;Shoda LK
托伐普坦是一种选择性加压素 V2 受体拮抗剂，在多个国家获批用于治疗低钠血症和常染色体显性多囊肾病 (ADPKD)。在健康受试者和非 ADPKD 适应症中，托伐普坦治疗未观察到肝损伤，但 ADPKD 临床试验显示了药物性肝损伤 (DILI) 的证据。尽管所有 DILI 事件均得到解决，但仍需要对接受托伐普坦治疗的 ADPKD 患者进行额外监测。体外测定发现胆汁酸分布的改变和线粒体呼吸的抑制是托伐普坦肝毒性的潜在机制。本报告详细介绍了 DILIsym 软件的应用，以确定这些机制是否可以解释 ADPKD 临床试验中观察到的托伐普坦的肝脏安全性。 DILIsym 模拟包括基于生理学的托伐普坦和 2 代谢物肝脏暴露的药代动力学估计，及其对肝细胞胆汁酸转运蛋白和线粒体呼吸的影响。模拟每日 90/30 毫克分次给药后，预测丙氨酸转氨酶 (ALT) 升高的频率为 7.9%，而 ADPKD 试验中临床观察到的这一比例为 4.4%。毒性是多因素的，因为胆汁酸转运蛋白和线粒体呼吸的抑制导致了模拟的 DILI。此外，模拟分析还确定了治疗前的危险因素和治疗中预测模拟 DILI 的生物标志物。模拟表明，体内肝脏暴露于托伐普坦和 DM-4103 代谢物，结合这两种毒性机制，足以解释托伐普坦介导的 DILI 的引发。假定的风险因素和潜在的新型生物标志物的识别为开发基于机制的托伐普坦风险缓解策略提供了见解。
Tolvaptan is a selective vasopressin V2 receptor antagonist, approved in several countries for the treatment of hyponatremia and autosomal dominant polycystic kidney disease (ADPKD). No liver injury has been observed with tolvaptan treatment in healthy subjects and in non-ADPKD indications, but ADPKD clinical trials showed evidence of drug-induced liver injury (DILI). Although all DILI events resolved, additional monitoring in tolvaptan-treated ADPKD patients is required. In vitro assays identified alterations in bile acid disposition and inhibition of mitochondrial respiration as potential mechanisms underlying tolvaptan hepatotoxicity. This report details the application of DILIsym software to determine whether these mechanisms could account for the liver safety profile of tolvaptan observed in ADPKD clinical trials. DILIsym simulations included physiologically based pharmacokinetic estimates of hepatic exposure for tolvaptan and2 metabolites, and their effects on hepatocyte bile acid transporters and mitochondrial respiration. The frequency of predicted alanine aminotransferase (ALT) elevations, following simulated 90/30 mg split daily dosing, was 7.9% compared with clinical observations of 4.4% in ADPKD trials. Toxicity was multifactorial as inhibition of bile acid transporters and mitochondrial respiration contributed to the simulated DILI. Furthermore, simulation analysis identified both pre-treatment risk factors and on-treatment biomarkers predictive of simulated DILI. The simulations demonstrated that in vivo hepatic exposure to tolvaptan and the DM-4103 metabolite, combined with these 2 mechanisms of toxicity, were sufficient to account for the initiation of tolvaptan-mediated DILI. Identification of putative risk-factors and potential novel biomarkers provided insight for the development of mechanism-based tolvaptan risk-mitigation strategies.
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影响因子：
3.8
作者：
Morgan, Ryan E.;Trauner, Michael;Hamadeh, Hisham K.
通讯作者：
Hamadeh, Hisham K.
DOI：
10.1002/psp4.12053
发表时间：
2016-01
期刊：
CPT: pharmacometrics & systems pharmacology
影响因子：
--
作者：
Longo DM;Yang Y;Watkins PB;Howell BA;Siler SQ
通讯作者：
Siler SQ
影响因子：
6.5
作者：
Kakiyama, Genta;Muto, Akina;Bajaj, Jasmohan S.
通讯作者：
Bajaj, Jasmohan S.
影响因子：
120.7
作者：
Lasser, KE;Allen, PD;Bor, DH
通讯作者：
Bor, DH
DOI：
10.1007/s10928-012-9266-0
发表时间：
2012-10-01
影响因子：
2.5
作者：
Howell, Brett A.;Yang, Yuching;Watkins, Paul B.
通讯作者：
Watkins, Paul B.