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DILIsym 包含的機(jī)制

DILIsym基于以下的理念進(jìn)行開發(fā)，通過化合物(母藥和/或代謝產(chǎn)物)在肝臟中的暴露從而引起各自內(nèi)在的毒性機(jī)制來(lái)描述可能產(chǎn)生的DILI。目前包括的機(jī)制有：

這些機(jī)制單獨(dú)或聯(lián)合作用可導(dǎo)致肝細(xì)胞凋亡或壞死。肝細(xì)胞壞死釋放損傷相關(guān)分子模式(DAMP)分子，能夠激活先天免疫細(xì)胞(如Kupffer細(xì)胞)?；罨拿庖呒?xì)胞將產(chǎn)生介質(zhì)，可用于擴(kuò)增正在進(jìn)行損傷的細(xì)胞和/或促進(jìn)肝臟的再生。免疫細(xì)胞也可能由于持續(xù)的炎癥過程而積累。此外，上述因素可能也會(huì)為適應(yīng)性免疫反應(yīng)的發(fā)展提供環(huán)境。

DILIsym還包括多個(gè)導(dǎo)致DILI的機(jī)制，包括受化合物的暴露影響的細(xì)胞內(nèi)生化系統(tǒng)（如線粒體、膽汁酸、活性氮/氧）、肝細(xì)胞和膽管細(xì)胞生命周期、先天免疫反應(yīng)的激活。DILIsym可以輸出包括細(xì)胞死亡時(shí)肝細(xì)胞釋放的生物標(biāo)志物及總膽紅素的增加，以反映由于肝細(xì)胞損失或直接的膽紅素的作用酶/轉(zhuǎn)運(yùn)體復(fù)合效應(yīng)導(dǎo)致的肝功能損傷。還可輸出新興生物標(biāo)志物(如GLDH, miR-122, CK-18)，開展新的機(jī)制研究。SimPops模型可考察個(gè)體間變異性對(duì)DILI的影響。

線粒體毒性機(jī)制

由于線粒體負(fù)責(zé)細(xì)胞ATP的大部分合成，線粒體功能的損傷在DILI中可發(fā)揮重要的作用。破壞任何ATP的合成都會(huì)導(dǎo)致ATP水平降低，引發(fā)其它細(xì)胞生化過程的紊亂，最終導(dǎo)致細(xì)胞壞死。母藥及其代謝物可能以多種方式破壞ATP的產(chǎn)生，最常見的是通過解偶聯(lián)減少線粒體蛋白濃度梯度，抑制電子傳輸鏈通量，或直接抑制ATP的合成?；钚匝?氮(ROS/RNS)產(chǎn)生的增加也能減少ATP的合成。

此外，還開發(fā)了體外線粒體呼吸和ATP生成模型(MITOsym^?)，該模型可以與體外線粒體試驗(yàn)檢測(cè)結(jié)果直接比較。用于確定MITOsym的細(xì)胞參數(shù)包括耗氧率(OCR)和細(xì)胞外酸化率(ECAR)，ETC活性和糖酵解功能的變化。

膽汁酸機(jī)制

膽汁酸是調(diào)節(jié)脂質(zhì)平衡和細(xì)胞功能的重要調(diào)節(jié)分子。然而，當(dāng)它們?cè)诟渭?xì)胞中淤積時(shí)，會(huì)產(chǎn)生毒性作用。抑制肝臟外排轉(zhuǎn)運(yùn)體，如BSEP、MRP3或MRP4，可能會(huì)導(dǎo)致膽汁酸超出生理濃度，進(jìn)而導(dǎo)致肝臟毒性。該模型中膽汁酸生物化學(xué)包括與肝臟毒性有關(guān)的特定膽汁酸的動(dòng)態(tài)變化，包含了膽汁酸的合成、吸收、再循環(huán)和流出。藥物介導(dǎo)的膽汁酸的動(dòng)態(tài)變化可以增加細(xì)胞內(nèi)的膽汁酸，繼而產(chǎn)生肝臟毒性。并對(duì)波生坦等典型化合物進(jìn)行了模擬，以完善該模型，確保膽汁酸毒性的模型表現(xiàn)與現(xiàn)有數(shù)據(jù)一致。

活性氮/氧機(jī)制

化合物及其穩(wěn)定或活性代謝物可通過減少細(xì)胞抗氧化劑、化合物直接介導(dǎo)或活性代謝物介導(dǎo)的相互作用等機(jī)制，導(dǎo)致肝細(xì)胞中活性氧/氮(ROS/RNS)產(chǎn)生的增加。ROS/RNS的輕微增加可觸發(fā)caspase酶的激活，引發(fā)caspase介導(dǎo)的肝細(xì)胞凋亡。ROS/RNS的大量增加可誘導(dǎo)肝細(xì)胞ATP的降低，進(jìn)而破壞其它細(xì)胞生化過程(如線粒體電子傳遞鏈活性，膽汁酸轉(zhuǎn)運(yùn))，最終導(dǎo)致肝細(xì)胞壞死。在DILIsym中，ROS/RNS可以在肝臟的任何區(qū)域產(chǎn)生并擴(kuò)散到相鄰區(qū)域

先天免疫機(jī)制

先天性免疫反應(yīng)包括巨噬細(xì)胞(Kupffer)和肝竇內(nèi)皮細(xì)胞(LSEC)群。巨噬細(xì)胞和巨噬細(xì)胞產(chǎn)生的免疫調(diào)節(jié)分子已被證明可以改變動(dòng)物模型和患者的肝毒性。

肝細(xì)胞生命周期機(jī)制

DILIsym對(duì)單個(gè)肝細(xì)胞(壞死、凋亡和有絲分裂)進(jìn)行了明確的跟蹤，可以與組織學(xué)數(shù)據(jù)進(jìn)行比較。成熟的和年輕的肝細(xì)胞被分開包括在內(nèi)，因?yàn)樗鼈兛赡苡胁煌膲乃篮偷蛲雎?，而且無(wú)生命力的細(xì)胞會(huì)以特定的半衰期被清除。

臨床生物標(biāo)志物輸出機(jī)制

DILI的主要臨床指標(biāo)包括許多生物標(biāo)志物，其中很多包含在DILIsym中。DILIsym包括經(jīng)典的血清生物標(biāo)志物，如谷丙轉(zhuǎn)氨酶(ALT)、天門冬氨酸轉(zhuǎn)氨酶(AST)、膽紅素(總、偶聯(lián)和未偶聯(lián))和凝血酶原時(shí)間。DILIsym還包含了DILI的新興生物標(biāo)志物，如HMGB1、細(xì)胞角蛋白18 (K18)、山梨醇脫氫酶(SDH)、精氨酸酶-1 (Arg-1)和micro-RNA 122 (miR-122)。

DILIsym還包括許多其他有助于評(píng)估肝損傷水平的關(guān)鍵機(jī)制的輸出，如活肝細(xì)胞的比例、肝臟中三磷酸腺苷(ATP)和谷胱甘肽(GSH)的水平，以及各種PK輸出?；罡渭?xì)胞的比例隨著時(shí)間的推移而被輸出，反映了肝細(xì)胞的凈損失和再生。結(jié)合底層模型的機(jī)制，DILIsym可以預(yù)測(cè)給定ALT曲線對(duì)應(yīng)的肝細(xì)胞損失。

群體模擬SimPops

SimPops群體模擬用于解釋個(gè)體間變異，包括影響DILI的潛在生物化學(xué)和機(jī)制因素的變異?？赏ㄟ^設(shè)置數(shù)個(gè)重要的個(gè)體間參數(shù)的變異性來(lái)考察導(dǎo)致DILI的潛在影響。包括谷胱甘肽基線水平、細(xì)胞對(duì)氧化應(yīng)激的反應(yīng)、肝細(xì)胞恢復(fù)速度、炎癥等。SimPops中的藥物特異性包括代謝和分布參數(shù)的變異性。

請(qǐng)回到該產(chǎn)品介紹頂部，查看該軟件的概述、應(yīng)用案例、專題培訓(xùn)

應(yīng)用案例1：評(píng)估候選藥物的DILI風(fēng)險(xiǎn)

艾爾建公司的Ubrogepant（候選藥物）與Telcagepant（臨床上有DILI）和MK-3207（臨床上有DILI）化學(xué)結(jié)構(gòu)上很相似，申報(bào)方想考察Ubrogepant在臨床上是否有DILI風(fēng)險(xiǎn)，DILIsym評(píng)估這三種化合物引起肝毒性的可能性，涉及的機(jī)制包括線粒體功能損傷、膽汁酸穩(wěn)態(tài)的破壞和氧化應(yīng)激的定量評(píng)估，以及肝細(xì)胞和肝細(xì)胞內(nèi)劑量依賴藥物暴露的評(píng)估。DILIsym成功模擬了Telcagepant和MK-3207在臨床試驗(yàn)中使用的給藥方案下的肝毒性。相比之下，DILIsym預(yù)測(cè)在Ubrogepant治療期間不會(huì)產(chǎn)生肝毒性，即使每日給藥劑量高達(dá)1000 mg (推薦臨床給藥劑量100 mg)也是安全的。DILIsym的模擬結(jié)果作為FDA批準(zhǔn)Ubrogepant上市的科學(xué)依據(jù)之一，且藥品說明書中無(wú)藥物肝損傷的警告。此外，另一個(gè)公司Bioheavn也開展了Rimegepant和Zavegepant兩個(gè)CGRP受體拮抗劑的DILI評(píng)估，模擬結(jié)果表明這兩個(gè)候選藥物無(wú)肝毒性，后來(lái)輝瑞公司以110億美元的價(jià)格從Bioheavn公司收購(gòu)了CGRP項(xiàng)目線。

部分參考文獻(xiàn)：Mechanistic Investigations Support Liver Safety of Ubrogepant.

Brenda Smit, et al. Toxicological Sciences, Volume 177, Issue 1, September 2020, Pages 84–93.

其他應(yīng)用案例：

• 預(yù)測(cè)并比較lixivaptan（候選藥物）和tolvaptan（臨床上有DILI）的藥物性肝損傷，并將預(yù)測(cè)結(jié)果作為IND申報(bào)資料的一部分并提交給FDA。
  

• 引起remdesivir, tolvaptan, pexidartinib, TAK-875肝毒性風(fēng)險(xiǎn)的機(jī)制分析。

• 比較幾種大環(huán)內(nèi)酯類抗生素的肝臟安全機(jī)制，作為solithromycin新藥申請(qǐng)的依據(jù)。

• 鑒定Entolimod和GGF2肝臟安全性的生物標(biāo)志物分析。

• 指導(dǎo)新型抗生素候選藥物BAL30072的劑量?jī)?yōu)化。

請(qǐng)回到該產(chǎn)品介紹頂部，查看該軟件的概述、包含的機(jī)制介紹、專題培訓(xùn)

Investigating bile acid-mediated cholestatic drug-induced liver injury using a mechanistic model of multidrug resistance protein 3 (MDR3) inhibition.

Beaudoin J, Yang K, Adiwidjaja J, Taneja G, Watkins PB, Siler SQ, Howell BA, Woodhead JL. Front. Pharmacol., January 2023.

Comparing the Liver Safety Profiles of 4 Next-Generation CGRP Receptor Antagonists to the Hepatotoxic CGRP Inhibitor Telcagepant Using Quantitative Systems Toxicology Modeling.

Woodhead JL, Siler SQ, Howell BA, Watkins PB, Conway C. Toxicological Sciences, Volume 188, Issue 1, July 2022, Pages 108–116.

Quantitative Systems Toxicology Modeling Predicts that Reduced Biliary Efflux Contributes to Tolvaptan Hepatotoxicity

Beaudoin J, Brock WJ, Watkins PB, Brouwer KLR. Clinical Pharmacology & Therapeutics.Volume109， Issue2，F(xiàn)ebruary 2021，Pages 433-442

Application of the DILIsym? Quantitative Systems Toxicology drug-induced liver injury model to evaluate the carcinogenic hazard potential of acetaminophen

Authors: Eichenbaum G, Yang K, Gebremichael Y, Howell BA, Murray FJ, Jacobson-Kram D, Jaeschke H, Kuffner E, Gelotte CK, Wikoff D, Atillasoy E. Regulatory Toxicology and Pharmacology. Volume 118, December 2020, 104788

Quantitative Systems Toxicology Analysis of In Vitro Mechanistic Assays Reveals Importance of Bile Acid Accumulation and Mitochondrial Dysfunction in TAK-875-Induced Liver Injury

Longo DM, Woodhead JL, Walker P, Herédi-Szabó K, Mogyorosi K, Wolenski FS, Dragan YP, Mosedale M, Siler SQ, Watkins PB, Howell BA. TOXICOLOGICAL SCIENCES, 167(2), 2019, 458–467

Mechanistic Investigations Support Liver Safety of Ubrogepant

Smith B, Rower J, Watkins PB, Ashina M, Woodhead JL, Goadsby PJ. Toxicological Sciences, Volume 177, Issue 1, September 2020, Pages 84–93.

DILIsym: Quantitative systems toxicology impacting drug development

Watkins PB. Current Opinion in Toxicology.Volumes 23–24, October–December 2020, Pages 67-73

Quantitative systems toxicology (QST) reproduces species differences in PF‐04895162 liver safety due to combined mitochondrial and bile acid toxicity

Generaux GT, Lakhani VV, Yang Y, Nadanaciva S, Qiu L, Riccardi K, Di L, Howell BA, Siler SQ, Watkins PB, Barton HA, Aleo MD, Shoda LKM. Pharmacol Res Perspect. Volume7, Issue6，December 2019

Comparison of the Hepatotoxic Potential of Two Treatments for Autosomal-Dominant Polycystic Kidney DiseaseUsing Quantitative Systems Toxicology Modeling

Woodhead JL, Pellegrini L, Shoda LKM, Howell BA. Pharmaceutical Research.37, Article number: 24 (2020) 

NDA 211-765 (ubrogepant, AGN-241688)

Freed LM. FDA NON-CLINICAL REVIEW(S). Submission date: 12/26/2018

Quantitative Systems Toxicology Approaches to Understand and Predict Drug-Induced Liver Injury

Watkins PB. Clin Liver Dis. 24 (2020) 49–60.

The DILI‐sim Initiative: Insights into Hepatotoxicity Mechanisms and Biomarker Interpretation

Watkins PB. Clin Transl Sci. Volume12, Issue2,March 2019,Pages 122-129.

Analyzing the Mechanisms Behind Macrolide Antibiotic-Induced Liver Injury Using Quantitative Systems Toxicology Modeling

Woodhead JL, Yang K, Oldach D, MacLauchlin C, Fernandes P, Watkins PB, Siler SQ, Howell BA. Pharmaceutical Research. volume 36, Article number: 48 (2019)

A Rapid Method to Estimate Hepatocyte Loss Due to Drug‐Induced Liver Injury

Chung J, Longo DM, Watkins PB. Clin Pharmacol Ther. Volume105, Issue 3,March 2019,Pages 746-753.

Can Bile Salt Export Pump Inhibition Testing in Drug Discovery and Development Reduce Liver Injury Risk? An International Transporter Consortium Perspective

Kenna JG, Taskar KS, Battista C, Brouwer KLR, Brouwer KR, Dai D, Funk C, Hafey MJ, Lai Y, Maher J, Pak YA, Pedersen JM, Polli JW, Rodrigues AD, Watkins PB, Yang K, Yucha RW. Clin Pharmacol Ther. 2018 Nov;104(5):916-932

Using Quantitative Systems Toxicology to Investigate Observed Species Differences in CKA-Mediated Hepatotoxicity

Battista C, Yang K, Stahl SH, Mettetal JT, Watkins PB, Siler SQ, Howell BA. Toxicol Sci. 2018 Nov 1;166(1):123-130

Prediction of Safety Margin and Optimization of Dosing Protocol for a Novel Antibiotic using Quantitative Systems Pharmacology Modeling

Woodhead JL, Paech F, Maurer M, Engelhardt M, Schmitt-Hoffmann AH, Spickermann J, Messner S, Wind M, Witschi AT, Kr?henbühl S, Siler SQ, Watkins PB, Howell BA. Clin Transl Sci. 2018 Sep;11(5):498-505

An Introduction to DILIsym? Software, a Mechanistic Mathematical Representation of Drug-Induced Liver Injury

Battista C, Howell BA, Siler SQ, Watkins PB. Drug-Induced Liver Toxicity. pp 101–121

In silico modeling to optimize interpretation of liver safety biomarkers in clinical trials

Church R, Watkins PB. Exp Biol Med (Maywood). 2018 Feb;243(3):300-307

Refining Liver Safety Risk Assessment: Application of Mechanistic Modeling and Serum Biomarkers to Cimaglermin Alfa (GGF2) Clinical Trials

Longo DM, Generaux GT, Howell BA, Siler SQ, Antoine DJ, Button D, Caggiano A, Eisen A, Iaci J, Stanulis R, Parry T, Mosedale M, Watkins PB. Clin Pharmacol Ther. 2017 Dec;102(6):961-969

Mechanistic Modelling of Drug-Induced Liver Injury: Investigating the Role of Innate Immune Responses

Shoda LKM, Battista C, Siler SQ. Gene Regul Syst Bio. 2017 May 30

Systems pharmacology modeling of drug-induced hyperbilirubinemia: Differentiating hepatotoxicity and inhibition of enzymes/transporters

Yang K, Battista C, Woodhead JL, Stahl SH, Mettetal JT, Watkins PB, Siler SQ, Howell BA. Clin Pharmacol Ther. 2017 Apr;101(4):501-509.

The role of quantitative systems pharmacology modeling in the prediction and explanation of idiosyncratic drug-induced liver injury

Woodhead JL, Watkins PB, Howell BA, Siler SQ, Shoda LKM. Drug Metab Pharmacokinet. 2017 Feb;32(1):40-45.

Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors.

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 LKM. Toxicol Sci. 2017 Jan;155(1):61-74.

Sandwich-Cultured Hepatocytes as a Tool to Study Drug Disposition and Drug-Induced Liver Injury

Yang K, Guo C, Woodhead JL, St Claire RL 3rd, Watkins PB, Siler SQ, Howell BA, Brouwer KLR. J Pharm Sci. 2016 Feb;105(2):443-459

Elucidating Differences in the Hepatotoxic Potential of Tolcapone and Entacapone With DILIsym(?), a Mechanistic Model of Drug-Induced Liver Injury.

Longo DM, Yang Y, Watkins PB, Howell BA, Siler SQ. CPT Pharmacometrics Syst Pharmacol. 2016 Jan;5(1):31-9.

Exploring BSEP inhibition-mediated toxicity with a mechanistic model of drug-induced liver injury

Woodhead JL, Yang K, Siler SQ, Watkins PB, Brouwer KLR, Barton HA, Howell BA. Front Pharmacol. 2014 Nov 7;5:240. 

Systems pharmacology modeling predicts delayed presentation and species differences in bile acid-mediated troglitazone hepatotoxicity.

Yang K, Woodhead JL, Watkins PB, Howell BA, Brouwer KL. Clin Pharmacol Ther. 2014 Nov;96(5):589-98.

Mechanistic Modeling Reveals the Critical Knowledge Gaps in Bile Acid-Mediated DILI

Woodhead JL, Yang K, Brouwer KL, Siler SQ, Stahl SH, Ambroso JL, Baker D, Watkins PB, Howell BA. CPT Pharmacometrics Syst Pharmacol. 2014 Jul 9;3(7):e123. 

Use of a systems model of drug-induced liver injury (DILIsym(?)) to elucidate the mechanistic differences between acetaminophen and its less-toxic isomer, AMAP, in mice.

Howell BA, Siler SQ, Watkins PB. Toxicol Lett. 2014 Apr 21;226(2):163-72.

A mechanistic model of drug-induced liver injury AIDS the interpretation of elevated liver transaminase levels in a phase I clinical trial

Howell BA, Siler SQ, Shoda LKM, Yang Y, Woodhead JL, Watkins PB. CPT Pharmacometrics Syst Pharmacol. 2014 Feb 5;3(2):e98.

Linking physiology to toxicity using DILIsym?, a mechanistic mathematical model of drug-induced liver injury

Shoda LKM, Woodhead JL, Siler SQ, Watkins PB, Howell BA. Biopharm Drug Dispos. 2014 Jan;35(1):33-49.

Modeling drug- and chemical-induced hepatotoxicity with systems biology approaches

Bhattacharya S, Shoda LKM, Zhang Q, Woods CG, Howell BA, Siler SQ, Woodhead JL, Yang Y, McMullen P, Watkins PB, Andersen ME. Front Physiol. 2012 Dec 14;3:462.

In vitro to in vivo extrapolation and species response comparisons for drug-induced liver injury (DILI) using DILIsym?: a mechanistic, mathematical model of DILI.

Howell BA, Yang Y, Kumar R, Woodhead JL, Harrill AH, Andersen ME, Clewell HJ 3rd, Siler SQ, Watkins PB. J Pharmacokinet Pharmacodyn.  2012 Oct;39(5):527-41.

An analysis of N-acetylcysteine treatment for acetaminophen overdose using a systems model of drug-induced liver injury

Woodhead JL, Howell BA, Yang Y, Harrill AH, Clewell HJ 3rd, Andersen ME, Siler SQ, Watkins PB. J Pharmacol Exp Ther. 2012 Aug;342(2):529-40.

DILIsym宣傳手冊(cè)2023.pdf

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