Toxicokinetics in Drug Development: An Overview of Toxicokinetic Application in the Development of PNU-101017, an Anxiolytic Drug Candidate

2000 ◽  
Vol 1 (3) ◽  
pp. 243-254 ◽  
Author(s):  
W. Zhong ◽  
M. Williams ◽  
D. Branstetter
Keyword(s):  
Drug Development ◽  
Drug Candidate ◽  
Anxiolytic Drug

scholarly journals Has molecular imaging delivered to drug development?

2017 ◽  
Vol 375 (2107) ◽  
pp. 20170112 ◽  
Author(s):  
Philip S. Murphy ◽  
Neel Patel ◽  
Timothy J. McCarthy
Keyword(s):  
Molecular Imaging ◽  
Drug Development ◽  
Clinical Studies ◽  
Pharmaceutical Research ◽  
Whole Body ◽  
Drug Candidate ◽  
Clinical Drug Development ◽  
Target Binding ◽  
The Brain ◽  
Clinical Drug

Pharmaceutical research and development requires a systematic interrogation of a candidate molecule through clinical studies. To ensure resources are spent on only the most promising molecules, early clinical studies must understand fundamental attributes of the drug candidate, including exposure at the target site, target binding and pharmacological response in disease. Molecular imaging has the potential to quantitatively characterize these properties in small, efficient clinical studies. Specific benefits of molecular imaging in this setting (compared to blood and tissue sampling) include non-invasiveness and the ability to survey the whole body temporally. These methods have been adopted primarily for neuroscience drug development, catalysed by the inability to access the brain compartment by other means. If we believe molecular imaging is a technology platform able to underpin clinical drug development, why is it not adopted further to enable earlier decisions? This article considers current drug development needs, progress towards integration of molecular imaging into studies, current impediments and proposed models to broaden use and increase impact. This article is part of the themed issue ‘Challenges for chemistry in molecular imaging’.

scholarly journals Challenges of Psychiatry Drug Development and the Role of Human Pharmacology Models in Early Development—A Drug Developer's Perspective

2021 ◽  
Vol 11 ◽  
Author(s):  
Tong Zhu
Keyword(s):  
Drug Development ◽  
Drug Exposure ◽  
Phase 1 ◽  
Drug Candidate ◽  
Phase 2 ◽  
Medical Needs ◽  
Clinical Drug Development ◽  
Human Pharmacology ◽  
Exposure Target ◽  
Target Binding

Psychiatric diseases have the lowest probability of success in clinical drug development. This presents not only an issue to address the unmet medical needs of patients, but also a hurdle for pharmaceutical and biotech industry to continue R&D in this disease area. Fundamental pharmacokinetic and pharmacodynamic principles provide an understanding of the drug exposure, target binding and pharmacological activity at the target site of action for a new drug candidate. Collectively, these principles determine the likelihood of testing the mechanism of action and enhancing the likelihood of candidate survival in Phase 2 clinical development, therefore, they are termed as the “three pillars of survival.” Human Phase 1 pharmacokinetic and pharmacodynamic studies provide evidence of the three pillars. Electroencephalogram (EEG) assessments and cognitive function tests in schizophrenia patients can provide proof of pharmacology and ensure that a pharmacological active regimen will be tested in Phase 2 proof of concept (POC) studies for the treatment of cognitive impairment associated with schizophrenia (CIAS).

scholarly journals Biomedical Graph Visualizer for Identifying Drug Candidates

2020 ◽  
Author(s):  
Ashton Teng ◽  
Blanca Villanueva ◽  
Derek Jow ◽  
Shih-Cheng (Mars) Huang ◽  
Samantha N. Piekos ◽  
...  
Keyword(s):  
Drug Development ◽  
De Novo ◽  
Drug Candidate ◽  
Knowledge Graph ◽  
Major Barrier ◽  
Drug Candidates ◽  
Novel Treatments ◽  
Computational Discovery ◽  
Complex Relationships ◽  
User Friendly

1.AbstractMillions of Americans suffer from illnesses with non-existent or ineffective drug treatment. Identifying plausible drug candidates is a major barrier to drug development due to the large amount of time and resources required; approval can take years when people are suffering now. While computational tools can expedite drug candidate discovery, these tools typically require programming expertise that many biologists lack. Though biomedical databases continue to grow, they have proven difficult to integrate and maintain, and non-programming interfaces for these data sources are scarce and limited in capability. This creates an opportunity for us to present a suite of user-friendly software tools to aid computational discovery of novel treatments through de novo discovery or repurposing. Our tools eliminate the need for researchers to acquire computational expertise by integrating multiple databases and offering an intuitive graphical interface for analyzing these publicly available data. We built a computational knowledge graph focused on biomedical concepts related to drug discovery, designed visualization tools that allow users to explore complex relationships among entities in the graph, and served these tools through a free and user-friendly web interface. We show that users can conduct complex analyses with relative ease and that our knowledge graph and algorithms recover approved repurposed drugs. Our evaluation indicates that our method provides an intuitive, easy, and effective toolkit for discovering drug candidates. We show that our toolkit makes computational analysis for drug development more accessible and efficient and ultimately plays a role in bringing effective treatments to all patients.Our application is hosted at: https://biomedical-graph-visualizer.wl.r.appspot.com/

Accelerating drug development: methodology to support first-in-man pharmacokinetic studies by the use of drug candidate microdosing

2007 ◽  
Vol 68 (1) ◽  
pp. 14-22 ◽  
Author(s):  
Matthew A. McLean ◽  
Chi-Yan J. Tam ◽  
Michael T. Baratta ◽  
Christopher L. Holliman ◽  
Robert M. Ings ◽  
...  
Keyword(s):  
Drug Development ◽  
Drug Candidate ◽  
Pharmacokinetic Studies ◽  
Development Methodology

Early Drug Development: From a Drug Candidate to the Clinic

2018 ◽  
pp. 305-332
Author(s):  
Mark McAllister ◽  
Joanne Bennett ◽  
John Davis ◽  
Brian Henry ◽  
Mei Wong
Keyword(s):  
Drug Development ◽  
Drug Candidate ◽  
Early Drug

scholarly journals Use of Microdosing and Accelerator Mass Spectrometry To Evaluate the Pharmacokinetic Linearity of a Novel Tricyclic GyrB/ParE Inhibitor in Rats

2014 ◽  
Vol 58 (11) ◽  
pp. 6477-6483 ◽  
Author(s):  
Michael A. Malfatti ◽  
Victoria Lao ◽  
Courtney L. Ramos ◽  
Voon S. Ong ◽  
Kenneth W. Turteltaub
Keyword(s):  
Drug Development ◽  
Development Process ◽  
Dose Range ◽  
Area Under The Curve ◽  
Drug Candidate ◽  
Drug Development Process ◽  
Sprague Dawley ◽  
Drug Candidates ◽  
Biological Fate ◽  
Therapeutic Doses

ABSTRACTDetermining the pharmacokinetics (PKs) of drug candidates is essential for understanding their biological fate. The ability to obtain human PK information early in the drug development process can help determine if future development is warranted. Microdosing was developed to assess human PKs, at ultra-low doses, early in the drug development process. Microdosing has also been used in animals to confirm PK linearity across subpharmacological and pharmacological dose ranges. The current study assessed the PKs of a novel antimicrobial preclinical drug candidate (GP-4) in rats as a step toward human microdosing studies. Dose proportionality was determined at 3 proposed therapeutic doses (3, 10, and 30 mg/kg of body weight), and PK linearity between a microdose and a pharmacological dose was assessed in Sprague-Dawley rats. Plasma PKs over the 3 pharmacological doses were proportional. Over the 10-fold dose range, the maximum concentration in plasma and area under the curve (AUC) increased 9.5- and 15.8-fold, respectively. PKs from rats dosed with a14C-labeled microdose versus a14C-labeled pharmacological dose displayed dose linearity. In the animals receiving a microdose and the therapeutically dosed animals, the AUCs from time zero to infinity were 2.6 ng · h/ml and 1,336 ng · h/ml, respectively, and the terminal half-lives were 5.6 h and 1.4 h, respectively. When the AUC values were normalized to a dose of 1.0 mg/kg, the AUC values were 277.5 ng · h/ml for the microdose and 418.2 ng · h/ml for the pharmacological dose. This 1.5-fold difference in AUC following a 300-fold difference in dose is considered linear across the dose range. On the basis of the results, the PKs from the microdosed animals were considered to be predictive of the PKs from the therapeutically dosed animals.

scholarly journals Licofelone-DPPC Interactions: Putting Membrane Lipids on the Radar of Drug Development

Molecules ◽  
2019 ◽  
Vol 24 (3) ◽  
pp. 516 ◽  
Author(s):  
Catarina Pereira-Leite ◽  
Daniela Lopes-de-Campos ◽  
Philippe Fontaine ◽  
Iolanda Cuccovia ◽  
Cláudia Nunes ◽  
...  
Keyword(s):  
Drug Development ◽  
Membrane Lipids ◽  
Grazing Incidence ◽  
Drug Candidate ◽  
Local Order ◽  
Lipid Phase ◽  
Brewster Angle Microscopy ◽  
Pharmacological Characterization ◽  
Additional Information ◽  
Preclinical Phase

(1) Background: Membrane lipids have been disregarded in drug development throughout the years. Recently, they gained attention in drug design as targets, but they are still disregarded in the latter stages. Thus, this study aims to highlight the relevance of considering membrane lipids in the preclinical phase of drug development. (2) Methods: The interactions of a drug candidate for clinical use (licofelone) with a membrane model system made of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) were evaluated by combining Langmuir isotherms, Brewster angle microscopy (BAM), polarization-modulation infrared reflection-absorption spectroscopy (PM-IRRAS), and grazing-incidence X-ray diffraction (GIXD) measurements. (3) Results: Licofelone caused the expansion of the DPPC isotherm without changing the lipid phase transition profile. Moreover, licofelone induced the reduction of DPPC packing density, while increasing the local order of the DPPC acyl chains. (4) Conclusions: The licofelone-induced alterations in the structural organization of phosphatidylcholine monolayers may be related to its pharmacological actions. Thus, the combination of studying drug-membrane interactions with the pharmacological characterization that occurs in the preclinical stage may gather additional information about the mechanisms of action and toxicity of drug candidates. Ultimately, the addition of this innovative step shall improve the success rate of drug development.

scholarly journals Exploiting the synthetic lethality between terminal respiratory oxidases to kill Mycobacterium tuberculosis and clear host infection

2017 ◽  
Vol 114 (28) ◽  
pp. 7426-7431 ◽  
Author(s):  
Nitin P. Kalia ◽  
Erik J. Hasenoehrl ◽  
Nurlilah B. Ab Rahman ◽  
Vanessa H. Koh ◽  
Michelle L. T. Ang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Development ◽  
Synthetic Lethality ◽  
Electron Flow ◽  
Clinical Stage ◽  
Atp Synthesis ◽  
Drug Candidate ◽  
Respiratory Oxidases ◽  
Host Infection

The recent discovery of small molecules targeting the cytochrome bc1:aa3 in Mycobacterium tuberculosis triggered interest in the terminal respiratory oxidases for antituberculosis drug development. The mycobacterial cytochrome bc1:aa3 consists of a menaquinone:cytochrome c reductase (bc1) and a cytochrome aa3-type oxidase. The clinical-stage drug candidate Q203 interferes with the function of the subunit b of the menaquinone:cytochrome c reductase. Despite the affinity of Q203 for the bc1:aa3 complex, the drug is only bacteriostatic and does not kill drug-tolerant persisters. This raises the possibility that the alternate terminal bd-type oxidase (cytochrome bd oxidase) is capable of maintaining a membrane potential and menaquinol oxidation in the presence of Q203. Here, we show that the electron flow through the cytochrome bd oxidase is sufficient to maintain respiration and ATP synthesis at a level high enough to protect M. tuberculosis from Q203-induced bacterial death. Upon genetic deletion of the cytochrome bd oxidase-encoding genes cydAB, Q203 inhibited mycobacterial respiration completely, became bactericidal, killed drug-tolerant mycobacterial persisters, and rapidly cleared M. tuberculosis infection in vivo. These results indicate a synthetic lethal interaction between the two terminal respiratory oxidases that can be exploited for anti-TB drug development. Our findings should be considered in the clinical development of drugs targeting the cytochrome bc1:aa3, as well as for the development of a drug combination targeting oxidative phosphorylation in M. tuberculosis.

Prodrug Strategies for Critical Drug Developability Issues: Part I

2021 ◽  
Vol 21 (24) ◽  
pp. 2155-2156
Author(s):  
Xingyue Ji
Keyword(s):  
Drug Development ◽  
Chemical Entity ◽  
Attrition Rate ◽  
Drug Candidate ◽  
Structure Property ◽  
Drug Candidates ◽  
Fda Approval ◽  
Cns Drugs ◽  
Approved Drugs ◽  
Preclinical And Clinical Studies

Drug development is a very time, capital, and labor-intensive process. It was anticipated that bringing a novel chemical entity to market would take over a billion dollars and around 14 years [1]. In addition, drug development is characterized by a very high attrition rate both in preclinical and clinical studies. It was reported that only 40% of drug candidates with the most drug-like properties could make their way into clinical trials, and only 10% of these can eventually reach FDA approval [2]. After analyzing the data from seven UK‐based pharmaceutical companies from 1964 through 1985, Prentis et al. found that 39% of failure was attributed to poor pharmacokinetic (PK) profiles in humans, 29% was attributed to a lack of clinical efficacy, 21% was attributed to toxicity and adverse effects, and about 6% was attributed to commercial limitations [3]. When a drug candidate is identified with one of these issues (except the commercial limitations), normally, a new round of structureactivity or structure-property relationship (SAR/SPR) studies is carried out to generate a new chemical entity with improved profiles, and in most cases, such a process is time and labor-intensive. Alternatively, prodrug strategy can be leveraged to efficiently address associated drug developability issues without making enormous derivatives. Prodrug strategy has been demonstrated to be very successful and fruitful in drug development, with around 20% of approved drugs from 2008 through 2020 being clarified as prodrugs [4]. In recent years, prodrug strategy has also been leveraged to address the delivery issues associated with gasotransmitters, including NO, H2S, CO as well as SO2 [5-8]. In this thematic issue, six excellent reviews were included, focusing on varied prodrug strategies in addressing different drug developability issues associated with anticancer drugs, central nervous system (CNS) drugs, and gasotransmitters....

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