TAK-994 Mechanistic Investigation into Drug-Induced Liver Injury.

The frequency of drug-induced liver injury (DILI) in clinical trials remains a challenge for drug developers despite advances in human hepatotoxicity models and improvements in reducing liver-related attrition in preclinical species. TAK-994, an oral orexin receptor 2 agonist, was withdrawn from phase II clinical trials due to the appearance of severe DILI. Here, we investigate the likely mechanism of TAK-994 DILI in hepatic cell culture systems examined cytotoxicity, mitochondrial toxicity, impact on drug transporter proteins, and covalent binding.

Personalized predictions of Glioblastoma infiltration: Mathematical models, Physics-Informed Neural Networks and multimodal scans.

Predicting the infiltration of Glioblastoma (GBM) from medical MRI scans is crucial for understanding tumor growth dynamics and designing personalized radiotherapy treatment plans. Mathematical models of GBM growth can complement the data in the prediction of spatial distributions of tumor cells. However, this requires estimating patient-specific parameters of the model from clinical data, which is a challenging inverse problem due to limited temporal data and the limited time between imaging and diagnosis.

Physician Posttraumatic Stress Disorder During COVID-19: A Systematic Review and Meta-Analysis.

Importance: The COVID-19 pandemic placed many physicians in situations of increased stress and challenging resource allocation decisions. Insight into the prevalence of posttraumatic stress disorder in physicians and its risk factors during the COVID-19 pandemic will guide interventions to prevent its development.

Objective: To determine the prevalence of posttraumatic stress disorder (PTSD) among physicians during the COVID-19 pandemic and examine variations based on factors, such as sex, age, medical specialty, and career stage.

A quantitative systems pharmacology model of plasma kallikrein-kinin system dysregulation in hereditary angioedema.

Hereditary angioedema (HAE) due to C1-inhibitor deficiency is a rare, debilitating, genetic disorder characterized by recurrent, unpredictable, attacks of edema. The clinical symptoms of HAE arise from excess bradykinin generation due to dysregulation of the plasma kallikrein-kinin system (KKS). A quantitative systems pharmacology (QSP) model that mechanistically describes the KKS and its role in HAE pathophysiology was developed based on HAE attacks being triggered by autoactivation of factor XII (FXII) to activated FXII (FXIIa), resulting in kallikrein production from prekallikrein.

Personalized Predictions of Glioblastoma Infiltration: Mathematical Models, Physics-Informed Neural Networks and Multimodal Scans.

Predicting the infiltration of Glioblastoma (GBM) from medical MRI scans is crucial for understanding tumor growth dynamics and designing personalized radiotherapy treatment plans.Mathematical models of GBM growth can complement the data in the prediction of spatial distributions of tumor cells. However, this requires estimating patient-specific parameters of the model from clinical data, which is a challenging inverse problem due to limited temporal data and the limited time between imaging and diagnosis.

Leveraging a physiologically-based quantitative translational modeling platform for designing B cell maturation antigen-targeting bispecific T cell engagers for treatment of multiple myeloma.

Bispecific T cell engagers (TCEs) are an emerging anti-cancer modality that redirects cytotoxic T cells to tumor cells expressing tumor-associated antigens (TAAs), thereby forming immune synapses to exert anti-tumor effects. Designing pharmacokinetically acceptable TCEs and optimizing their size presents a considerable protein engineering challenge, particularly given the complexity of intercellular bridging between T cells and tumor cells. Therefore, a physiologically-relevant and clinically-verified computational modeling framework is of crucial importance to understand the protein engineering trade-offs.

Applications of Quantitative System Pharmacology Modeling to Model-Informed Drug Development.

Significant advances in analytical technologies have dramatically improved our ability to deconvolute disease biology at molecular, cellular, and tissue levels. Quantitative system pharmacology (QSP) modeling is a computational framework to systematically integrate pharmaceutical properties of a drug candidate with scientific understanding of that deeper disease etiology, target expression, genetic variability, and human physiological processes, thus enabling more insightful drug development decisions related to efficacy and safety. In this chapter, we discuss the key attributes of QSP models in comparison to traditional models.

Does sex alter the relationship between CYP2B6 variation, hydroxybupropion concentration and bupropion-aided smoking cessation in African Americans? A moderated mediation analysis.

Background And Aims: CYP2B6, a genetically variable enzyme, converts bupropion to its active metabolite hydroxybupropion. CYP2B6 activity and bupropion-aided cessation differ between women and men. The aim of this study was to determine whether genetically normal (versus reduced) CYP2B6 activity increases bupropion-aided cessation in African American smokers via higher hydroxybupropion concentration, and whether this differs by sex.

Functional characterization of novel rare CYP2A6 variants and potential implications for clinical outcomes.

CYP2A6 activity, phenotyped by the nicotine metabolite ratio (NMR), is a predictor of several smoking behaviors, including cessation and smoking-related disease risk. The heritability of the NMR is 60-80%, yet weighted genetic risk scores (wGRSs) based on common variants explain only 30-35%. Rare variants (minor allele frequency <1%) are hypothesized to explain some of this missing heritability.

Physiologically-Based Pharmacokinetic Modeling in Renal and Hepatic Impairment Populations: A Pharmaceutical Industry Perspective.

The predictive performance of physiologically-based pharmacokinetics (PBPK) models for pharmacokinetics (PK) in renal impairment (RI) and hepatic impairment (HI) populations was evaluated using clinical data from 29 compounds with 106 organ impairment study arms were collected from 19 member companies of the International Consortium for Innovation and Quality in Pharmaceutical Development. Fifty RI and 56 HI study arms with varying degrees of organ insufficiency along with control populations were evaluated. For RI, the area under the curve (AUC) ratios of RI to healthy control were predicted within twofold of the observed ratios for > 90% (N = 47/50 arms).

Preclinical Antitumor Activity and Biodistribution of a Novel Anti-GCC Antibody-Drug Conjugate in Patient-derived Xenografts.

Guanylyl cyclase C (GCC) is a unique therapeutic target with expression restricted to the apical side of epithelial cell tight junctions thought to be only accessible by intravenously administered agents on malignant tissues where GCC expression is aberrant. In this study, we sought to evaluate the therapeutic potential of a second-generation investigational antibody-dug conjugate (ADC), TAK-164, comprised of a human anti-GCC mAb conjugated via a peptide linker to the highly cytotoxic DNA alkylator, DGN549. The binding, payload release, and activity of TAK-164 was characterized motivating evaluation.

Quantitative Systems Pharmacology Approaches for Immuno-Oncology: Adding Virtual Patients to the Development Paradigm.

Drug development in oncology commonly exploits the tools of molecular biology to gain therapeutic benefit through reprograming of cellular responses. In immuno-oncology (IO) the aim is to direct the patient's own immune system to fight cancer. After remarkable successes of antibodies targeting PD1/PD-L1 and CTLA4 receptors in targeted patient populations, the focus of further development has shifted toward combination therapies.

A Translational Physiologically Based Pharmacokinetics/Pharmacodynamics Framework of Target-Mediated Disposition, Target Inhibition and Drug-Drug Interactions of Bortezomib.

Bortezomib is a potent 20S proteasome inhibitor approved for the treatment of multiple myeloma and mantle cell lymphoma. Despite the extensive clinical use of bortezomib, the mechanism of the complex time-dependent pharmacokinetics of bortezomib has not been fully investigated in context of its pharmacodynamics (PD) and drug-drug interaction (DDI) profiles. Here, we aimed to develop a mechanistic physiologically based (PB) PK/PD model to project PK, blood target inhibition and DDI of bortezomib in patients.

A Citrulline-Based Translational Population System Toxicology Model for Gastrointestinal-Related Adverse Events Associated With Anticancer Treatments.

Gastrointestinal (GI)-related adverse events (AEs) are commonly observed in the clinic during cancer treatments. Citrulline is a potentially translatable biomarker of GI AEs. In this study, irinotecan-induced citrulline changes were studied for a range of doses and schedules in rats.

Overcoming Barriers to Hand Surgical Care in Low-Resource Settings.

There is a growing need for surgical treatment of hand injuries in low- and middle-income countries (LMICs). This rise in disease burden places more pressure on these health care systems that are already struggling to provide access to surgical care for their patients. Hand surgery outreach initiatives have increased in recent years and provide much needed care and relief to these countries.

C57BL/6 Substrain Differences in Pharmacological Effects after Acute and Repeated Nicotine Administration.

Tobacco smoking is the major cause of disability and death in the United States and around the world. In addition, tobacco dependence and addiction express themselves as complex behaviors involving an interplay of genetics, environment, and psychological state. Mouse genetic studies could potentially elucidate the novel genes and/or gene networks regulating various aspects of nicotine dependence.

A Minimal Physiologically-Based Pharmacokinetic Model Demonstrates Role of the Neonatal Fc Receptor (FcRn) Competition in Drug-Disease Interactions With Antibody Therapy.

Disease trajectories following antibody therapy can have a significant impact on the pharmacokinetics of the antibody. Although this phenomenon can often be explained by reduced target-expressing cells, other mechanisms may play a role. We use a novel minimal physiologically-based pharmacokinetic model to evaluate an alternative drug-disease interaction mechanism involving competitive inhibition of neonatal Fc receptor (FcRn)-mediated Immunoglobulin G recycling by paraproteins.

Recommendations for the Design of Clinical Drug-Drug Interaction Studies With Itraconazole Using a Mechanistic Physiologically-Based Pharmacokinetic Model.

Regulatory agencies currently recommend itraconazole (ITZ) as a strong cytochrome P450 3A (CYP3A) inhibitor for clinical drug-drug interaction (DDI) studies. This work by an International Consortium for Innovation and Quality in Pharmaceutical Development working group (WG) is to develop and verify a mechanistic ITZ physiologically-based pharmacokinetic model and provide recommendations for optimal DDI study design based on model simulations. To support model development and verification, in vitro and clinical PK data for ITZ and its metabolites were collected from WG member companies.

Survival Prolongation Index as a Novel Metric to Assess Anti-Tumor Activity in Xenograft Models.

A single efficacy metric quantifying anti-tumor activity in xenograft models is useful in evaluating different tumors' drug sensitivity and dose-response of an anti-tumor agent. Commonly used metrics include the ratio of tumor volume in treated vs. control mice (T/C), tumor growth inhibition (TGI), ratio of area under the curve (AUC), and growth rate inhibition (GRI).

Application of unbound liver-to-plasma concentration ratio to quantitative projection of cytochrome P450-mediated drug-drug interactions using physiologically based pharmacokinetic modelling approach.

1. This study evaluated the prediction accuracy of cytochrome P450 (CYP)-mediated drug-drug interaction (DDI) using minimal physiologically-based pharmacokinetic (PBPK) modelling incorporating the hepatic accumulation factor of an inhibitor (i.e.

The Role of Triangular Fibrocartilage Complex in Axial Stability of the Forearm.

 The triangular fibrocartilage complex (TFCC) provides stability to the wrist and disruption of this complex can result in axial instability which can lead to ulnocarpal abutment.  This article determines the individual contributions of the volar radioulnar ligament (VRUL), dorsal radioulnar ligament (DRUL), and foveal attachment of the TFCC to longitudinal stability of the forearm under axial load.  Eighteen cadaveric specimens were randomly assigned into three groups representing the component of the TFCC to be initially transected: VRUL, DRUL, and foveal attachment.

Comparison of uptake transporter functions in hepatocytes in different species to determine the optimal model for evaluating drug transporter activities in humans.

A thorough understanding of species-dependent differences in hepatic uptake transporters is critical for predicting human pharmacokinetics (PKs) from preclinical data. In this study, the activities of organic anion transporting polypeptide (OATP/Oatp), organic cation transporter 1 (OCT1/Oct1), and sodium-taurocholate cotransporting polypeptide (NTCP/Ntcp) in cultured rat, dog, monkey and human hepatocytes were compared. The activities of hepatic uptake transporters were evaluated with respect to culture duration, substrate and species-dependent differences in hepatocytes.

The Effect of Axial Loading on Ulnar Variance.

 Forearm rotation results in change in ulnar variance. Axial loading of the wrist is required to maintain daily activities. Change in ulnar variance during axial loading has not been investigated previously.

Quantitative translational modeling to facilitate preclinical to clinical efficacy & toxicity translation in oncology.

Significant scientific advances in biomedical research have expanded our knowledge of the molecular basis of carcinogenesis, mechanisms of cancer growth, and the importance of the cancer immunity cycle. However, despite scientific advances in the understanding of cancer biology, the success rate of oncology drug development remains the lowest among all therapeutic areas. In this review, some of the key translational drug development objectives in oncology will be outlined.

Advances in Proximal Interphalangeal Joint Arthroplasty: Biomechanics and Biomaterials.

Proximal interphalangeal (PIP) joint arthritis is a debilitating condition. The complexity of the joint makes management particularly challenging. Treatment of PIP arthritis requires an understanding of the biomechanics of the joint.