Xenobiotica最新文献_第4页

Use of stable isotope labeled (SIL) antibodies in cassette dosing to improve pharmacokinetics screening efficiency of ADCs with novel cytotoxic payloads. 在盒式给药中使用稳定同位素标记 (SIL) 抗体，提高带有新型细胞毒性有效载荷的 ADC 的药代动力学筛选效率。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-08-01 Epub Date: 2024-09-27 DOI: 10.1080/00498254.2024.2403029

Vineet Kumar, Alice Chin, Abbie Wong, Kristen A Cardinal, Erica McKinney, Shawna M Hengel, Hao Sun, Anthony J Lee

{"title":"Use of stable isotope labeled (SIL) antibodies in cassette dosing to improve pharmacokinetics screening efficiency of ADCs with novel cytotoxic payloads.","authors":"Vineet Kumar, Alice Chin, Abbie Wong, Kristen A Cardinal, Erica McKinney, Shawna M Hengel, Hao Sun, Anthony J Lee","doi":"10.1080/00498254.2024.2403029","DOIUrl":"10.1080/00498254.2024.2403029","url":null,"abstract":"Stable isotope labelling by amino acids in cell culture (SILAC) is an established technique used in quantitative mass spectrometry (MS)-based proteomics. SILAC is also used to generate stable isotope labelled (SIL) antibodies for internal standards (IS) used in LC-MS/MS bioassays to improve quantitative robustness.Total antibody (TAb) is measured to evaluate pharmacokinetics (PK) of antibody drug conjugate (ADC) candidates measured by either ligand binding (LBA) or LC-MS/MS. Herein, we describe an application of SILAC, where multiple SIL combinations of an antibody are used for cassette dosing and PK evaluation.Our preclinical studies demonstrate SILAC-labelled ADC therapeutics did not alter antibody PK. Furthermore, with cassette dosing SIL antibodies exhibited comparable exposure to discretely administered unlabelled test articles in rats.In addition, SIL antibodies were conjugated to cytotoxic payloads to create SIL ADCs and cassette dosed in a cynomolgus monkey PK study and SIL ADCs yielded comparable PK results to discrete dosed unlabelled ADCs.In conclusion, SIL antibodies used with a cassette dosing strategy increases PK screening throughput of ADC candidates in preclinical species. Additionally, cassette dosing strategy further facilitates the responsible use of laboratory animals to achieve the three-Rs (Replacement, Reduction, and Refinement).","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"502-510"},"PeriodicalIF":1.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142296725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A modelling approach to compare ADC deconjugation and systemic elimination rates of individual drug-load species using native ADC LC-MS data from human plasma. 利用人体血浆中的原生 ADC LC-MS 数据，采用建模方法比较单个药物载荷物种的 ADC 解结合率和全身消除率。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-08-01 Epub Date: 2024-09-27 DOI: 10.1080/00498254.2024.2340741

Shawna M Hengel, Ariel R Topletz-Erickson, Hossam Kadry, Stephen C Alley

{"title":"A modelling approach to compare ADC deconjugation and systemic elimination rates of individual drug-load species using native ADC LC-MS data from human plasma.","authors":"Shawna M Hengel, Ariel R Topletz-Erickson, Hossam Kadry, Stephen C Alley","doi":"10.1080/00498254.2024.2340741","DOIUrl":"https://doi.org/10.1080/00498254.2024.2340741","url":null,"abstract":"Native liquid chromatography mass spectrometry (LC-MS) is a commonly used approach for intact analysis of inter-chain cysteine conjugated antibody-drug conjugates (ADCs). Coupling native LC-MS with affinity capture provides a platform for intact ADC analysis from in vivo samples and characterisation of individual drug load species, specifically the impact of drug linker deconjugation, hydrolysis, and differential clearance in a biological system.This manuscript describes data generated from native LC-MS analysis of ADCs from human plasma, both in vitro incubations and clinical samples. It also details the pharmacokinetic (PK) model built to specifically characterise the disposition of individual drug load species from MMAE and MMAF interchain cysteine conjugated ADCs.In vitro deconjugation and hydrolysis rates were similar across both ADCs. Differential clearance of higher loaded species in vivo was pronounced for the MMAE conjugated ADC, while systemic elimination after accounting for deconjugation was similar across drug loads for the MMAF conjugated ADC. This is the first report of affinity capture native LC-MS analysis, and subsequent modelling of deconjugation, hydrolysis and clearance rates of individual drug load species using clinical data from cysteine conjugated ADCs.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":"54 8","pages":"492-501"},"PeriodicalIF":1.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142355176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Investigation of pharmacokinetic properties of a PEGylated bilirubin nanoparticle in male Sprague-Dawley rats using liquid chromatography-quadrupole time-of-flight mass spectrometry. 用液相色谱-四极杆飞行时间质谱法研究聚乙二醇化胆红素纳米颗粒在雄性Sprague-Dawley大鼠体内的药动学特性。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-08-01 Epub Date: 2024-09-27 DOI: 10.1080/00498254.2023.2284859

Seo-Jin Park, Jeong-Hyeon Lim, Jiyu Lee, Jeongmin Lee, Sangsoo Hwang, Hyunjin Kim, Seunghyun Jo, Duckhyang Shin, Sang Ho Ma, Myung L Kim, Young G Shin

{"title":"Investigation of pharmacokinetic properties of a PEGylated bilirubin nanoparticle in male Sprague-Dawley rats using liquid chromatography-quadrupole time-of-flight mass spectrometry.","authors":"Seo-Jin Park, Jeong-Hyeon Lim, Jiyu Lee, Jeongmin Lee, Sangsoo Hwang, Hyunjin Kim, Seunghyun Jo, Duckhyang Shin, Sang Ho Ma, Myung L Kim, Young G Shin","doi":"10.1080/00498254.2023.2284859","DOIUrl":"10.1080/00498254.2023.2284859","url":null,"abstract":"Polyethylene glycol (PEG) was introduced into synthetic bilirubin 3α and a PEGylated bilirubin 3α nanoparticle (BX-001N, Brixelle®) was developed for the first time.An in vitro microsomal stability study, in vivo PK studies with intravenous bolus (IV) and subcutaneous injection (SC), and a semi-mass balance study of BX-001N were investigated to evaluate its pharmacokinetic (PK) properties in male Sprague-Dawley (SD) rats using developed liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-qTOF/MS).Following IV administration at 10 or 30 mg/kg, BX-001N showed very low clearance (0.33-0.67 mL/min/kg) with predominant distribution in the vascular system (Vd = 51.73-83.02 mL/kg). BX-001N was also very stable in vitro liver microsomal stability study.Following SC administration at 10 or 30 mg/kg, the bioavailability of BX-001N in plasma at 10 mg/kg was around 43% and showed the less dose-proportionality at 30 mg/kg dose.BX-001N was mainly excreted via the urinary pathway (86.59-92.99% of total amount of parent drug in excreta; urine and faeces) not via the biliary one.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"563-573"},"PeriodicalIF":1.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136399457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A general perspective for the conduct of radiolabelled distribution, metabolism, and excretion studies for antibody-drug conjugates. 对抗体药物共轭物进行放射性标记分布、代谢和排泄研究的一般视角。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-08-01 Epub Date: 2024-09-27 DOI: 10.1080/00498254.2024.2336576

Bettina Rudolph, John A Davis, Dominik Hainzl, Markus Walles

{"title":"A general perspective for the conduct of radiolabelled distribution, metabolism, and excretion studies for antibody-drug conjugates.","authors":"Bettina Rudolph, John A Davis, Dominik Hainzl, Markus Walles","doi":"10.1080/00498254.2024.2336576","DOIUrl":"https://doi.org/10.1080/00498254.2024.2336576","url":null,"abstract":"Antibody-drug conjugates (ADCs) are a class of biopharmaceuticals that combine the specificity of monoclonal antibodies (mAbs) with the cytotoxicity of small molecule drugs. 15 ADCs have been approved by regulatory authorities up to now, mainly for indications in oncology, however, this review paper will only focus on the 13 ADCs that have been approved by either the FDA or EMA.ADME (Absorption, Distribution, Metabolism, and Excretion) studies are essential for the development of small molecule drugs to evaluate their disposition properties. These studies help to select drug candidates, determine the optimal dosing regimen and help to identify potential safety concerns for the drug of interest in human. Tissue distribution studies are also important as they facilitate the understanding of the efficacy and safety for parent drug and its metabolites in preclinical and clinical studies.For biologics, ADME studies are usually not required. In this paper, we review the existing approval packages and literature for approved ADCs to determine the extent of ADME studies performed as part of ADC registration packages.We conclude that ADME studies are recommended for the development of ADCs if new linkers and payloads are used that have never been used in humans before as these studies provide valuable information on the pharmacokinetic properties, optimal dosing regimen, and potential safety concerns. However, for the development of ADCs with established linker payload combinations, radiolabelled ADME studies may not be necessary if the distribution, metabolism and excretion properties have been described before. Clinical radiolabelled ADME studies are not recommended where patients are treated for life threating diseases like for indications in oncology.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":"54 8","pages":"521-532"},"PeriodicalIF":1.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142355175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A comparison of the activity, lysosomal stability, and efficacy of legumain-cleavable and cathepsin-cleavable ADC linkers. 豆豆蛋白酶可裂解 ADC 连接体和酪蛋白酶可裂解 ADC 连接体的活性、溶酶体稳定性和功效比较。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-08-01 Epub Date: 2024-09-27 DOI: 10.1080/00498254.2024.2352051

Meghan E Gray, Karina M Zielinski, Fanny Xu, Kayla K Elder, Steven J McKay, Victor T Ojo, Samantha R Benjamin, Aiman A Yaseen, Tracy A Brooks, L Nathan Tumey

{"title":"A comparison of the activity, lysosomal stability, and efficacy of legumain-cleavable and cathepsin-cleavable ADC linkers.","authors":"Meghan E Gray, Karina M Zielinski, Fanny Xu, Kayla K Elder, Steven J McKay, Victor T Ojo, Samantha R Benjamin, Aiman A Yaseen, Tracy A Brooks, L Nathan Tumey","doi":"10.1080/00498254.2024.2352051","DOIUrl":"10.1080/00498254.2024.2352051","url":null,"abstract":"Over the past two decades, antibody-drug conjugates (ADCs) have emerged as a highly effective drug delivery technology. ADCs utilise a monoclonal antibody, a chemical linker, and a therapeutic payload to selectively deliver highly potent pharmaceutical agents to specific cell types.Challenges such as premature linker cleavage and clearance due to linker hydrophobicity have adversely impacted the stability and safety of ADCs. While there are various solutions to these challenges, our team has focused on replacement of hydrophobic ValCit linkers (cleaved by CatB) with Asn-containing linkers that are cleaved by lysosomal legumain.Legumain is abundantly present in lysosomes and is known to play a role in tumour microenvironment dynamics. Herein, we directly compare the lysosomal cleavage, cytotoxicity, plasma stability, and efficacy of a traditional cathepsin-cleavable ADC to a matched Asn-containing legumain-cleavable ADC.We demonstrate that Asn-containing linker sequences are specifically cleaved by lysosomal legumain and that Asn-linked MMAE ADCs are broadly active against a variety of tumours, even those with low legumain expression. Finally, we show that AsnAsn-linked ADCs exhibit comparable or improved efficacy to traditional ValCit-linked ADCs. Our study paves the way for replacement of the traditional ValCit linker technology with more hydrophilic Asn-containing peptide linker sequences.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"458-468"},"PeriodicalIF":1.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11436314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140912906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Preface for special issue: "Emerging strategies, technologies, and approaches for the next generation ADCs". 特刊序言："下一代 ADC 的新兴战略、技术和方法"。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-08-01 Epub Date: 2024-09-27 DOI: 10.1080/00498254.2024.2386407

Markus Walles, Keyang Xu

{"title":"Preface for special issue: \"Emerging strategies, technologies, and approaches for the next generation ADCs\".","authors":"Markus Walles, Keyang Xu","doi":"10.1080/00498254.2024.2386407","DOIUrl":"10.1080/00498254.2024.2386407","url":null,"abstract":"1. Antibody-drug conjugates (ADCs) represent an advanced category of biotherapeutic agents, typically consisting of an antibody bound to a biologically-active cytotoxic agent. Since the first ADC, MylotargTM, was approved in 2000, there have been fifteen ADCs sanctioned to date, with thirteen receiving approval from the FDA for the treatment of a variety of cancers, including blood malignancies and solid tumors.2. In this Special Issue of Xenobiotica focusing on ADCs, our goal is to compile a collection of papers, featuring both original research and review articles authored by specialists in academia and the pharmaceutical industry, to showcase some of the historical insights gained, current progress, and future prospects to enhance comprehension and tackle obstacles in the field of ADC development for cancer therapy.3. This special issue features articles that evaluate key components of ADC development, including payload design, innovative linker chemistries, and the use of new technologies for site-specific conjugations beyond traditional engineered cysteines. It also spotlights cutting-edge ADC structures like bispecific ADCs, dual-payload ADCs, targeted nanoparticles and antibody oligonucleotide conjugates (AOCs).4. Several other papers discuss bioanalytical and ADME strategies for ADCs as well. In addition, approaches to improve the translation of pharmacokinetics, safety, and therapeutic index (TI) of ADCs are presented.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"439-441"},"PeriodicalIF":1.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141789222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Predicting routes of phase I and II metabolism based on quantum mechanics and machine learning. 基于量子力学和机器学习的第一阶段和第二阶段代谢路径预测。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-07-01 Epub Date: 2024-08-21 DOI: 10.1080/00498254.2023.2284251

Mario Öeren, Peter A Hunt, Charlotte E Wharrick, Hamed Tabatabaei Ghomi, Matthew D Segall

{"title":"Predicting routes of phase I and II metabolism based on quantum mechanics and machine learning.","authors":"Mario Öeren, Peter A Hunt, Charlotte E Wharrick, Hamed Tabatabaei Ghomi, Matthew D Segall","doi":"10.1080/00498254.2023.2284251","DOIUrl":"10.1080/00498254.2023.2284251","url":null,"abstract":"Unexpected metabolism could lead to the failure of many late-stage drug candidates or even the withdrawal of approved drugs. Thus, it is critical to predict and study the dominant routes of metabolism in the early stages of research.We describe the development and validation of a 'WhichEnzyme' model that accurately predicts the enzyme families most likely to be responsible for a drug-like molecule's metabolism. Furthermore, we combine this model with our previously published regioselectivity models for Cytochromes P450, Aldehyde Oxidases, Flavin-containing Monooxygenases, UDP-glucuronosyltransferases and Sulfotransferases - the most important Phase I and Phase II drug metabolising enzymes - and a 'WhichP450' model that predicts the Cytochrome P450 isoform(s) responsible for a compound's metabolism.The regioselectivity models are based on a mechanistic understanding of these enzymes' actions and use quantum mechanical simulations with machine learning methods to accurately predict sites of metabolism and the resulting metabolites. We train heuristics based on the outputs of the 'WhichEnzyme', 'WhichP450', and regioselectivity models to determine the most likely routes of metabolism and metabolites to be observed experimentally.Finally, we demonstrate that this combination delivers high sensitivity in identifying experimentally reported metabolites and higher precision than other methods for predicting in vivo metabolite profiles.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"379-393"},"PeriodicalIF":1.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"107592386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Application of quantitative pharmacology analysis to support early clinical development of oncology drugs: dose selection. 应用定量药理学分析支持肿瘤药物的早期临床开发：剂量选择。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-07-01 Epub Date: 2024-08-21 DOI: 10.1080/00498254.2024.2377577

Ningyuan Zhang, Yu Li, Wenbin Cui, Xiangqing Yu, Ying Huang

{"title":"Application of quantitative pharmacology analysis to support early clinical development of oncology drugs: dose selection.","authors":"Ningyuan Zhang, Yu Li, Wenbin Cui, Xiangqing Yu, Ying Huang","doi":"10.1080/00498254.2024.2377577","DOIUrl":"10.1080/00498254.2024.2377577","url":null,"abstract":"The selection of appropriate starting dose and suitable method to predict an efficacious dose for novel oncology drug in the early clinical development stage poses significant challenges. The traditional methods of using body surface area transformation from toxicology studies to predict the first-in human (FIH) starting dose, or simply selecting the maximum tolerated dose (MTD) or maximum administered dose (MAD) as efficacious dose or recommended phase 2 dose (RP2D), are usually inadequate and risky for novel oncology drugs.Due to the regulatory efforts aimed at improving dose optimisation in oncology drug development, clinical dose selection is now shifting away from these traditional methods towards a comprehensive benefit/risk assessment-based approach. Quantitative pharmacology analysis (QPA) plays a crucial role in this new paradigm. This mini-review summarises the use of QPA in selecting the starting dose for oncology FIH studies and potential efficacious doses for expansion or phase 2 trials. QPA allows for a more rational and scientifically based approach to dose selection by integrating information across studies and development phases.In conclusion, the application of QPA in oncology drug development has the potential to significantly enhance the success rates of clinical trials and ultimately support clinical decision-making, particularly in dose selection.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"420-423"},"PeriodicalIF":1.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141591543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Prediction of the liver safety profile of a first-in-class myeloperoxidase inhibitor using quantitative systems toxicology modeling. 利用定量系统毒理学模型预测第一类髓过氧化物酶抑制剂的肝脏安全性特征

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-07-01 Epub Date: 2024-08-21 DOI: 10.1080/00498254.2024.2361027

Jeffrey L Woodhead, Yeshi Gebremichael, Joyce Macwan, Irfan A Qureshi, Richard Bertz, Victoria Wirtz, Brett A Howell

{"title":"Prediction of the liver safety profile of a first-in-class myeloperoxidase inhibitor using quantitative systems toxicology modeling.","authors":"Jeffrey L Woodhead, Yeshi Gebremichael, Joyce Macwan, Irfan A Qureshi, Richard Bertz, Victoria Wirtz, Brett A Howell","doi":"10.1080/00498254.2024.2361027","DOIUrl":"10.1080/00498254.2024.2361027","url":null,"abstract":"The novel myeloperoxidase inhibitor verdiperstat was developed as a treatment for neuroinflammatory and neurodegenerative diseases. During development, a computational prediction of verdiperstat liver safety was performed using DILIsym v8A, a quantitative systems toxicology (QST) model of liver safety.A physiologically-based pharmacokinetic (PBPK) model of verdiperstat was constructed in GastroPlus 9.8, and outputs for liver and plasma time courses of verdiperstat were input into DILIsym. In vitro experiments measured the likelihood that verdiperstat would inhibit mitochondrial function, inhibit bile acid transporters, and generate reactive oxygen species (ROS); these results were used as inputs into DILIsym, with two alternate sets of parameters used in order to fully explore the sensitivity of model predictions. Verdiperstat dosing protocols up to 600 mg BID were simulated for up to 48 weeks using a simulated population (SimPops) in DILIsym.Verdiperstat was predicted to be safe, with only very rare, mild liver enzyme increases as a potential possibility in highly sensitive individuals. Subsequent Phase 3 clinical trials found that ALT elevations in the verdiperstat treatment group were generally similar to those in the placebo group. This validates the DILIsym simulation results and demonstrates the power of QST modelling to predict the liver safety profile of novel therapeutics.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"401-410"},"PeriodicalIF":1.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141318434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Xenobiotica Special Edition Preface. Xenobiotica 特别版序言。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-07-01 Epub Date: 2024-08-21 DOI: 10.1080/00498254.2024.2372825

Alan G E Wilson

引用次数: 0