Tool For Drug Development Research Articles

Activating Transcription Factor 5; A Potential Prognostic Molecular Biomarker for Cervical Cancer (CC)

Background: Prognostic biomarkers with high sensitivity and specificity that accurately predict disease prognosis are crucial for influencing cancer patients' treatment and disease progression choices. This research attempts to determine ATF5's cervical cancer prognostic value and find a theoretical basis for cervical cancer treatment. Method: This study began with a survival analysis, then univariate and multivariate analyses using transcriptomics, methylation, and TCGA ATF5 clinical data. Second, ATF5's role in cervical cancer development was explored using GO, KEGG, and TIMER databases. We assessed ATF5's cervical cancer treatment potential using CMap, a drug development tool. Results: After conducting several analyses, we discovered that high levels of ATF5 mRNA expression and low levels of methylation were beneficial for patients with cervical cancer prognosis. An important finding is that ATF5 may promote apoptosis in cervical carcinoma cells. In addition, we assessed the therapeutic potential of four small molecules against cervical cancer. ATF 5 function as a tumor suppressor gene in cervical cancer has been demonstrated for the first time using numerous databases and bioinformatics techniques from multiple dimensions, which is a novel aspect of this research. Moreover, the finding that ATF5 is a biomarker that can contribute to the apoptosis of cervical cancer cells and predict a favorable prognosis for the disease was an additional innovation. In the future, ATF5 can be used as a therapeutic target and to develop anti-cancer medications.

Regulatory Pathways for Qualification andAcceptance of Digital Health Technology-Derived Clinical Trial Endpoints: Considerations for Sponsors.

Despite widespread interest and substantial investment in the adoption of sensor-based digital health technologies (sDHTs) for remote data capture in drug development trials, no drug has been approved based on an sDHT-derived primary endpoint in the United States (US). One reason for this lack of advancement is the complexity of obtaining regulatory endorsement for those endpoints within current US regulatory pathways. The goal of our review is to describe the two choices currently available to pharmaceutical study Sponsors: (i) they may navigate the traditional route of compiling the evidence to support the sDHT-derived endpoint in their investigational new drug (IND) application, requiring specific expertise and substantial resources; or (ii) they may navigate the drug development tool (DDT) pathway with the goal of qualifying their sDHT-derived endpoint as a biomarker or clinical outcome assessment applicable to a broader context of use (COU), either alone or as part of a partnership or consortium. We describe the nuances of each pathway; the evidentiary requirements for supporting an sDHT-derived endpoint and the technology used to capture it; and the impact that an sDHT's regulatory status may have on a Sponsor's decision to use it for data capture. By systematically comparing the IND and DDT pathways, our over-arching goals are to support the increasing deployment of sDHTs within the clinical research setting and help advance regulatory science in the field of digital medicine.

GLI1 confers resistance to PARP inhibitors by activating the DNA damage repair pathway.

Identifying the mechanisms of action of anticancer drugs is an important step in the development of new drugs. In this study, we established a comprehensive screening platform consisting of 68 oncogenes (MANO panel), encompassing 243 genetic variants, to identify predictive markers for drug efficacy. Validation was performed using drugs that targeted EGFR, BRAF, and MAP2K1, which confirmed the utility of this functional screening panel. Screening of a BRCA2-knockout DLD1 cell line (DLD1-KO) revealed that cells expressing SMO and GLI1 were resistant to olaparib. Gene set enrichment analysis identified genes associated with DNA damage repair that were enriched in cells overexpressing SMO and GLI1. The expression of genes associated with homologous recombination repair (HR), such as the FANC family and BRCA1/2, was significantly upregulated by GLI1 expression, which is indicative of PARP inhibitor resistance. Although not all representative genes of the nucleotide excision repair (NER) pathway were upregulated, NER activity was enhanced by GLI1. The GLI1 inhibitor was effective against DLD1-KO cells overexpressing GLI1 both in vitro and in vivo. Furthermore, the combination therapy of olaparib and GLI1 inhibitor exhibited a synergistic effect on DLD1-KO, suggesting the possible clinical application of GLI1 inhibitor targeting cancer with defective DNA damage repair. This platform enables the identification of biomarkers associated with drug sensitivity, and is a useful tool for drug development.

Unveiling Novel Drug Leads: Utilizing Molecular Docking Studies for Efficient Drug Discovery

The traditional drug discovery process is often time-consuming and expensive. This review explains the basics of a computer simulation technique called molecular docking. This technique is becoming a valuable tool in drug development because it can predict how small molecules interact with important biological molecules, especially proteins. In other words, it can virtually test how well different molecules might work as drugs. First, it helps find promising starting points for drugs by virtually testing large libraries of molecules. Secondly, it can identify new targets for existing drugs. Thirdly, docking simulations can even predict hoe new compounds might work. However, docking has limitations. This study dives into the world of molecular docking and its applications in cancer. It explores the latest advancements, limitations and advantages of this technique. The focus is on how various software and docking methods can be used to discover new targets for drugs, to breathe new life into existing ones and to design entirely new candidates. Overall, the study emphasizes the value of molecular docking in cancer study, highlighting its potential to improve treatment strategies and drug development.

Scaling-law mechanical marker for liver fibrosis diagnosis and drug screening through machine learning.

Studies of cell and tissue mechanics have shown that significant changes in cell and tissue mechanics during lesions and cancers are observed, which provides new mechanical markers for disease diagnosis based on machine learning. However, due to the lack of effective mechanic markers, only elastic modulus and iconographic features are currently used as markers, which greatly limits the application of cell and tissue mechanics in disease diagnosis. Here, we develop a liver pathological state classifier through a support vector machine method, based on high dimensional viscoelastic mechanical data. Accurate diagnosis and grading of hepatic fibrosis facilitates early detection and treatment and may provide an assessment tool for drug development. To this end, we used the viscoelastic parameters obtained from the analysis of creep responses of liver tissues by a self-similar hierarchical model and built a liver state classifier based on machine learning. Using this classifier, we implemented a fast classification of healthy, diseased, and mesenchymal stem cells (MSCs)-treated fibrotic live tissues, and our results showed that the classification accuracy of healthy and diseased livers can reach 0.99, and the classification accuracy of the three liver tissues mixed also reached 0.82. Finally, we provide screening methods for markers in the context of massive data as well as high-dimensional viscoelastic variables based on feature ablation for drug development and accurate grading of liver fibrosis. We propose a novel classifier that uses the dynamical mechanical variables as input markers, which can identify healthy, diseased, and post-treatment liver tissues.

Unbiased analysis of spatial learning strategies in a modified Barnes maze using convolutional neural networks

Assessment of spatial learning abilities is central to behavioral neuroscience and a useful tool for animal model validation and drug development. However, biases introduced by the apparatus, environment, or experimentalist represent a critical challenge to the test validity. We have recently developed the Modified Barnes Maze (MBM) task, a spatial learning paradigm that overcomes inherent behavioral biases of animals in the classical Barnes maze. The specific combination of spatial strategies employed by mice is often considered representative of the level of cognitive resources used. Herein, we have developed a convolutional neural network-based classifier of exploration strategies in the MBM that can effectively provide researchers with enhanced insights into cognitive traits in mice. Following validation, we compared the learning performance of female and male C57BL/6J mice, as well as that of Ts65Dn mice, a model of Down syndrome, and 5xFAD mice, a model of Alzheimer’s disease. Male mice exhibited more effective navigation abilities than female mice, reflected in higher utilization of effective spatial search strategies. Compared to wildtype controls, Ts65Dn mice exhibited delayed usage of spatial strategies despite similar success rates in completing this spatial task. 5xFAD mice showed increased usage of non-spatial strategies such as Circling that corresponded to higher latency to reach the target and lower success rate. These data exemplify the need for deeper strategy classification tools in dissecting complex cognitive traits. In sum, we provide a machine-learning-based strategy classifier that extends our understanding of mice’s spatial learning capabilities while enabling a more accurate cognitive assessment.

Deoxynivalenol Induces Drp-1-Mediated Mitochondrial Dysfunction via Elevating Oxidative Stress.

Mitochondrial dysfunction is often linked to neurotoxicity and neurological diseases and stems from oxidative stress, yet effective therapies are lacking. Deoxynivalenol (DON or vomitoxin) is one of the most common and hazardous type-B trichothecene mycotoxins, which contaminates crops used for food and animal feed. Despite the abundance of preliminary reports, comprehensive investigations are scarce to explore the relationship between these fungal metabolites and neurodegenerative disorders. The present study aimed to elucidate the precise role of DON in mitochondrial dynamics and cell death in neuronal cells. Excessive mitochondrial fission is associated with the pathology of several neurodegenerative diseases. Human SH-SY5Y cells were treated with different concentrations of DON (250-1000 ng/mL). Post 24 and 48 h DON treatment, the indexes were measured as follows: generation of reactive oxygen species (ROS), ATP levels, mitochondrial membrane potential, calcium levels, and cytotoxicity in SH-SY5Y cells. The results showed that cytotoxicity, intracellular calcium levels, and ROS in the DON-treated group increased, while the ATP levels and mitochondrial membrane potential decreased in a dose-dependent manner. With increasing DON concentrations, the expression levels of P-Drp-1, mitochondrial fission proteins Mff, and Fis-1 were elevated with reduced activities of MFN1, MFN2, and OPA1, further resulting in an increased expression of autophagic marker LC3 and beclin-1. The reciprocal relationship between mitochondrial damage and ROS generation is evident as ROS can instigate structural and functional deficiencies within the mitochondria. Consequently, the impaired mitochondria facilitate the release of ROS, thereby intensifying the cycle of damage and exacerbating the overall process. Using specific hydroxyl, superoxide inhibitors, and calcium chelators, our study confirmed that ROS and Ca2+-mediated signaling pathways played essential roles in DON-induced Drp1 phosphorylation. Therefore, ROS and mitochondrial fission inhibitors could provide critical research tools for drug development in mycotoxin-induced neurodegenerative diseases.

Real-time label-free three-dimensional invasion assay for anti-metastatic drug screening using impedance sensing.

Tumor metastasis presents a formidable challenge in cancer treatment, necessitating effective tools for anti-cancer drug development. Conventional 2D cell culture methods, while considered the "gold standard" for invasive studies, exhibit limitations in representing cancer hallmarks and phenotypes. This study proposes an innovative approach that combines the advantages of 3D tumor spheroid culture with impedance-based biosensing technologies to establish a high-throughput 3D cell invasion assay for anti-metastasis drug screening through multicellular tumor spheroids. In addition, the xCELLigence device is employed to monitor the time-dependent kinetics of cell behavior, including attachment and invasion out of the 3D matrix. Moreover, an iron chelator (deferoxamine) is employed to monitor the inhibition of epithelial-mesenchymal transition in 3D spheroids across different tumor cell types. The above results indicate that our integrated 3D cell invasion assay with impedance-based sensing could be a promising tool for enhancing the quality of the drug development pipeline by providing a robust platform for predicting the efficacy and safety of anti-metastatic drugs before advancing into preclinical or clinical trials.

Anticancer Potential of a Novel Benzothiazole-Derived Heterocyclic Compound: In Vitro, In Vivo, and Molecular Docking Studies

Background: Benzothiazole (BTA) is a potent organic compound with numerous biological and medicinal effects, making it a valuable tool for drug development. The purpose of the study: This study aims to produce a heterocyclic compound belonging to benzothiazoles, which are known for their great medical effectiveness, and to test their biological effectiveness against cancer cell growth. Methods: The exposure to A2 compound (1-(benzo[d]thiazol-2-yl) pyrazolidine-3,5-dione) was 72 hours, followed by adding 200 µL of crystal violet stain solution to each well and incubating at 37°C for 30 minutes. A molecular docking experiment was conducted using the crystallographic framework of the epidermal growth factor receptor (EGFR) to evaluate the binding strength of the compound to this receptor. The lethal dose (LD50) was determined using the Miller and Tainter method. Results: Even at a lower concentration of 6 µg/ml A2 compound appears to have greater cytotoxicity against SKG-T4 cells and AMGM5, while lower cytotoxicity to inhibition of rat embryo fibroblasts (REF) in exposure time at 72 h and has good affinity at the active site of EGFR due to the formation of hydrogen bonds with critical amino acids, in acute toxicity experiments, the LD50 of compound A2 was determined to be 52.31 mg/kg.Conclusion: The A2 compound, although present in a reduced amount, shows elevated cytotoxic effects on SKG-T4 cells and AMGM5, but shows decreased cytotoxicity toward REF cells after 72 hours. Furthermore, it shows a robust attraction to the active site of the EGFR.

Structure prediction of protein-ligand complexes from sequence information with Umol

Protein-ligand docking is an established tool in drug discovery and development to narrow down potential therapeutics for experimental testing. However, a high-quality protein structure is required and often the protein is treated as fully or partially rigid. Here we develop an AI system that can predict the fully flexible all-atom structure of protein-ligand complexes directly from sequence information. We find that classical docking methods are still superior, but depend upon having crystal structures of the target protein. In addition to predicting flexible all-atom structures, predicted confidence metrics (plDDT) can be used to select accurate predictions as well as to distinguish between strong and weak binders. The advances presented here suggest that the goal of AI-based drug discovery is one step closer, but there is still a way to go to grasp the complexity of protein-ligand interactions fully. Umol is available at: https://github.com/patrickbryant1/Umol.

Organoids as a new approach for improving pediatric cancer research.

A key challenge in cancer research is the meticulous development of models that faithfully emulates the intricacies of the patient scenario, with emphasis on preserving intra-tumoral heterogeneity and the dynamic milieu of the tumor microenvironment (TME). Organoids emerge as promising tool in new drug development, drug screening and precision medicine. Despite advances in the diagnoses and treatment of pediatric cancers, certain tumor subtypes persist in yielding unfavorable prognoses. Moreover, the prognosis for a significant portion of children experiencing disease relapse is dismal. To improve pediatric outcome many groups are focusing on the development of precision medicine approach. In this review, we summarize the current knowledge about using organoid system as model in preclinical and clinical solid-pediatric cancer. Since organoids retain the pivotal characteristics of primary parent tumors, they exert great potential in discovering novel tumor biomarkers, exploring drug-resistance mechanism and predicting tumor responses to chemotherapy, targeted therapy and immunotherapies. We also examine both the potential opportunities and existing challenges inherent organoids, hoping to point out the direction for future organoid development.

Unveiling the intricacies of BPA and BPS: comprehensive insights into its toxic effects using a cutting-edge microphysiological system

Concerns over Bisphenol A (BPA) and its substitute, Bisphenol S (BPS), have led to innovative exploration due to potential adverse health effects. BPS, replacing BPA in some regions to avoid toxic impacts, remains insufficiently studied. Besides this, the organ-on-a-chip technology emerges as a transformative solution in drug discovery and chemiclas toxicity testing, minimizing costs and aligning with ethical standards by reducing reliance on animal models, by integrating diverse tissues and dynamic cell environments enhances precision in predicting organ function.Here, we employ a 3-organ-on-a-chip microfluidic device with skin, intestine, and liver cultures to assess the effects of BPA and BPS via topical and oral administration. Our evaluation focused on gene markers associated with carcinogenicity, systemic toxicity, and endocrine disruption. BPA exhibited expected absorption profiles, causing liver injury and genetic modulation in related pathways. BPS, a safer alternative, induced adverse effects on gene expression, particularly in topical absorption, with distinct absorption patterns. Our findings underscore the urgency of addressing BPA and BPS toxicity concerns, highlighting the crucial role of organ-on-a-chip technology in understanding associated health risks. The study promotes the organ-on-a-chip methodology as a valuable tool for safe drug development and disease treatments, offering a novel liver toxicity screening alternative to traditional animal tests. This contributes to advancing comprehension of the biological effects of these compounds, fostering improved safety assessments in human health.

Critical View on the Qualification of Electronic Tongues Regarding Their Performance in the Development of Peroral Drug Formulations with Bitter Ingredients.

In this review, we aim to highlight the advantages, challenges, and limitations of electronic tongues (e-tongues) in pharmaceutical drug development. The authors, therefore, critically evaluated the performance of e-tongues regarding their qualification to assess peroral formulations containing bitter active pharmaceutical ingredients. A literature search using the keywords 'electronic', 'tongue', 'bitter', and 'drug' in a Web of Science search was therefore initially conducted. Reviewing the publications of the past decade, and further literature where necessary, allowed the authors to discuss whether and how e-tongues perform as expected and whether they have the potential to become a standard tool in drug development. Specifically highlighted are the expectations an e-tongue should meet. Further, a brief insight into the technologies of the utilized e-tongues is given. Reliable protocols were found that enable (i) the qualified performance of e-tongue instruments from an analytical perspective, (ii) proper taste-masking assessments, and (iii) under certain circumstances, the evaluation of bitterness.

Lipidization as a Tool for Peptide Drug Development

Peptide therapeutics are becoming increasingly important in the quest for effective compounds to treat various difficult-to-cure diseases. As potential therapeutics, peptides have many favorable chemical and pharmacological properties, ranging from their great diversity to their high affinity to various types of natural receptors. However, despite these and other advantages, they also have their pitfalls, such as a very limited stability in the organism. They have a short half-life and tend to be excreted from the body very quickly. In order to achieve a better pharmacological effect, it is desirable to find new means of modifying peptides to enable them to be used as effective drugs. There are many ways of altering the peptide structure. In this review, we summarize the approaches currently used to modify the peptide constitution with a focus on lipidization. Simultaneously this review summarizes all lipidized peptide-based therapeutics that are currently on the market.

Rapid and Definitive Identification of Cyclic Peptide Soft Spots by Isotope-Labeled Reductive Dimethylation and Mass Spectrometry Fragmentation.

Cyclic peptides are an emerging therapeutic modality over the past few decades. To identify drug candidates with sufficient proteolytic stability for oral administration, it is critical to pinpoint the amide bond hydrolysis sites, or soft spots, to better understand their metabolism and provide guidance on further structure optimization. However, the unambiguous characterization of cyclic peptide soft spots remains a significant challenge during early stage discovery studies, as amide bond hydrolysis forms a linearized isobaric sequence with the addition of a water molecule, regardless of the amide hydrolysis location. In this study, an innovative strategy was developed to enable the rapid and definitive identification of cyclic peptide soft spots by isotope-labeled reductive dimethylation and mass spectrometry fragmentation. The dimethylated immonium ion with enhanced MS signal at a distinctive m/z in MS/MS fragmentation spectra reveals the N-terminal amino acid on a linearized peptide sequence definitively and, thus, significantly simplifies the soft spot identification workflow. This approach has been evaluated to demonstrate the potential of isotope-labeled dimethylation to be a powerful analytical tool in cyclic peptide drug discovery and development.

Sequence confirmation of synthetic DNA exceeding 100 nucleotides using restriction enzyme mediated digestion combined with high-resolution tandem mass spectrometry

Oligonucleotides have emerged as important therapeutic options for inherited diseases. In recent years, RNA therapeutics, especially mRNA, have been pushed to the market. Analytical methods for these molecules have been published extensively in the last few years. Notably, mass spectrometry has proven as a state-of-the-art quality control method. For RNA based therapeutics, numerous methods are available, while DNA therapeutics lack of suitable MS-based methods when it comes to molecules exceeding approximately 60 nucleotides. We present a method which combines the use of common restriction enzymes and short enzyme-directing oligonucleotides to generate DNA digestion products with the advantages of high-resolution tandem mass spectrometry. The instrumentation includes ion pair reverse phase chromatography coupled to a time-of-flight mass spectrometer with a collision induced dissociation (CID) for sequence analysis. Utilizing this approach, we increased the sequence coverage from 23.3% for a direct CID-MS/MS experiment of a 100 nucleotide DNA molecule to 100% sequence coverage using the restriction enzyme mediated approach presented in this work. This approach is suitable for research and development and quality control purposes in a regulated environment, which makes it a versatile tool for drug development.

Preclinical models for bladder cancer therapy research.

Bladder cancer (BC) is a highly heterogenous disease comprising tumours of various molecular subtypes and histologic variants. This heterogeneity represents a major challenge for the development of novel therapeutics. Preclinical models that closely mimic in vivo tumours and reflect their diverse biology are indispensable for the identification of therapies with specific activity in various BC subtypes. In this review, we summarize efforts and progress made in this context during the last 24 months. In recent years, one main focus was laid on the development of patient-derived BC models. Patient-derived organoids (PDOs) and patient-derived xenografts (PDXs) were demonstrated to widely recapitulate the molecular and histopathological characteristics, as well as the drug response profiles of the corresponding tumours of origin. These models, thus, represent promising tools for drug development and personalized medicine. Besides PDXs, syngenic in vivo models are of growing importance. Since these models are generated using immunocompetent hosts, they can, amongst others, be used to develop novel immunotherapeutics and to evaluate the impact of the immune system on drug response and resistance. In the past two years, various in vivo and in vitro models closely recapitulating the biology and heterogeneity of human bladder tumours were developed.

Abstract LB218: Advanced ex vivo platform for drug response analysis: Evaluating the potent effects of NMC-521 mAb on mouse-and patient-derived organotypic tumor spheroids

Abstract In response to the high failure rate of new drugs in clinical trials, we have developed an innovative organotypic tumor spheroids platform, designed to mitigate the risks associated with advancing drugs to clinical stages. Utilizing patient-derived organotypic tumor spheroids (PDOTS), this platform uniquely captures both the phenotype and genotype of individual patient tumor microenvironments. This approach not only enhances the precision of preclinical models but also bridges the gap between laboratory research and clinical applicability. In this study, we assess the effectiveness of the first-in-class monoclonal antibody NMC-521 (NomoCan Pharmaceuticals, NY) using our ex vivo platform. Targeting the novel cancer-specific antigen NMC-1, NMC-521 exhibited significant growth inhibition of CT-26 tumors in syngeneic BALB/c mice, reducing tumor size by approximately 55% compared to the control. Similarly, in ex vivo settings with freshly excised CT-26 tumors (n=18), NMC-521 demonstrated a dose-dependent cytotoxic effect, achieving about a 65% reduction in tumor viability with an effective dose (ED50) of 10 µg/ml. Further insights were gained into NMC-521's mechanism of action using our ex vivo platform. The drug’s ability to induce tumor cell death in CT26 ex vivo was significantly reversed (p<0.01) when co-treated with α-NKG2D but not α-CD8, indicating a critical role for natural killer (NK) cells in its therapeutic effect. Complementing these findings, our analyses on freshly excised patient tumors (n=15) corroborated the cytotoxic effects of this drug on colorectal cancer but not to the same magnitude as in the CT-26 model. Furthermore, unlike the syngeneic murine tumor model, the response rate was (8 of 15 responsive patient tumors. Gene expression profiling indicated that NK cell-associated RNAs were elevated in NMC-521 treated PDOTS. Additionally, combination therapy studies using NMC-521 and nivolumab within our platform mirrored murine in vivo results, enhancing our understanding of the drug's potential in clinical settings. Intriguingly, an observed elevation in IL-15 levels in patient tumors treated with NMC-521 suggests an increased presence of NK cell activity when compared to treatments with nivolumab. This research underscores the potential of our organotypic tumor spheroids platform as a transformative tool in cancer drug development, offering an accurate and patient-specific method to evaluate new therapies, thereby increasing the likelihood of successful translation from the laboratory to patient care. Citation Format: Amir Aref, Alyssa Martin, Hamidreza Aboulkheyr Es, Patryk Krzesaj, Victor Adler, Kirti Khardenavis, Ehsan Sarafraz-Yazdi, Michael A. Perricone. Advanced ex vivo platform for drug response analysis: Evaluating the potent effects of NMC-521 mAb on mouse-and patient-derived organotypic tumor spheroids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB218.

Confronting the bias towards animal experimentation (animal methods bias)

Laws and policies are in place around the world to promote the replacement and reduction of nonhuman animals in science. These principles are rooted not just in ethical considerations for animals, but also in scientific considerations regarding the limitations of using nonhuman animals to model human biology, health, and disease. New nonanimal research approaches that use human biology, cells, and data to mimic complex human physiological states and therapeutic responses have become increasingly effective and accessible, replacing the use of animals in several applications, and becoming a crucial tool for biomedical research and drug development. Despite many advantages, acceptance of these new nonanimal methods has been slow, and barriers to their broader uptake remain. One such barrier is animal methods bias, the preference for animal-based methods where they are not necessary or where animal-free methods are suitable. This bias can impact research assessments and can discourage researchers from using novel nonanimal approaches. This article provides an introductory overview of animal methods bias for the general public, reviewing evidence, exploring consequences, and discussing ongoing mitigation efforts aimed at reducing barriers in the shift away from animal use in biomedical research and testing.

Individualized Pharmacotherapy Utilizing Genetic Biomarkers and Novel In Vitro Systems As Predictive Tools for Optimal Drug Development and Treatment.

In the area of drug development and clinical pharmacotherapy, a profound understanding of the pharmacokinetics and potential adverse reactions associated with the drug under investigation is paramount. Essential to this endeavor is a comprehensive understanding about interindividual variations in absorption, distribution, metabolism, and excretion (ADME) genetics and the predictive capabilities of in vitro systems, shedding light on metabolite formation and the risk of adverse drug reactions (ADRs). Both the domains of pharmacogenomics and the advancement of in vitro systems are experiencing rapid expansion. Here we present an update on these burgeoning fields, providing an overview of their current status and illuminating potential future directions. SIGNIFICANCE STATEMENT: There is very rapid development in the area of pharmacogenomics and in vitro systems for predicting drug pharmacokinetics and risk for adverse drug reactions. We provide an update of the current status of pharmacogenomics and developed in vitro systems on these aspects aimed to achieve a better personalized pharmacotherapy.