Importance of Drug Pharmacokinetics at the Site of Action

Ml, Rizk; Zou, Ling; Savić, Radoslav; Dooley, KE

doi:10.1111/cts.12448

Cited by 98 publications

(74 citation statements)

References 102 publications

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“…PK/PD studies determine drug absorption, dosage and half-life of BSAAs. Toxicological studies determine if the drugs have any adverse effects on the tissues and organs of the animals and defining the dosage of adverse effects (Alabaster V. and In Vivo Pharmacology Training Group, 2002;Parasuraman, 2011;Rizk et al, 2017). Studying the efficacy of BSAAs is generally done by treating the animal with the drug or vehicle and infecting it with a virus of interest.…”

Section: Evaluation Of Bsaas In Animal Modelsmentioning

confidence: 99%

Discovery and development of safe-in-man broad-spectrum antiviral agents

Andersen

Ianevski

Lysvand

et al. 2020

International Journal of Infectious Diseases

190

108

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# Contributed equally J o u r n a l P r e -p r o o f Highlights  We reviewed discovery and development process of broad-spectrum antiviral agents.  We summarized the information on 119 safe-in-man agents in freely accessible database.  Further studies will increase the number of broad-spectrum antivirals, expand spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections. Abstract: Viral diseases are one of the leading causes of morbidity and mortality in the world. Virus-specific vaccines and antiviral drugs are the most powerful tools to combat viral diseases. However, broad-spectrum antiviral agents (BSAAs, i.e. compounds targeting viruses belonging to two or more viral families) could provide additional protection of general population from emerging and reemerging viral diseases reinforcing the arsenal of available antiviral options. Here, we reviewed discovery and development of BSAAs and summarized the information on 119 safe-in-man agents in freely accessible database (https://drugvirus.info/). Future and ongoing pre-clinical and clinical studies will increase the number of BSAAs, expand spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections as well as co-infections. J o u r n a l P r e -p r o o f 2015). Antiviral drugs and vaccines are used to fight viral infections in human (De Clercq and Li, 2016; Marston et al., 2014). Previously, there has been a focus on "one drug, one virus" dogma, which relied on targeting virus-specific factors. A counterpoint to this is "one drug, multiple viruses" paradigm, which came with the discovery of broad-spectrum antiviral agents (BSAAs), small-molecules that inhibit a wide range of human viruses (Bekerman and Einav, 2015; de Clercq and Montgomery, 1983; Debing et al., 2015; Ianevski et al., 2019; Rada and Dragun, 1977; Sidwell et al., 1972). This paradigm was based on the observation that different viruses utilize similar pathways and host factors to replicate inside a cell (Bosl et al., 2019). Although the concept of BSAAs has been around for almost 50 years, the field received a new impetus with recent outbreaks of Ebola, Zika, Dengue, influenza and other viral infections, the discovery of novel host-directed agents as well as development of drug repositioning methodology. Drug repurposing, also called repositioning, redirecting, reprofiling, is a strategy for generating additional value from an existing drug by targeting disease other than that for which it was originally intended (Nishimura and Hara, 2018; Pushpakom et al., 2019). This has significant advantages over new drug discovery since chemical synthesis steps, manufacturing processes, reliable safety, and pharmacokinetic properties in pre-clinical (animal model) and early clinical developmental phases (phase 0, I and IIa) are already available (Figure 1). Therefore, repositioning of launched or even failed drugs to viral diseases provides unique translational opportunities, includi...

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Section: Evaluation Of Bsaas In Animal Modelsmentioning

confidence: 99%

Discovery and development of safe-in-man broad-spectrum antiviral agents

Andersen

Ianevski

Lysvand

et al. 2020

International Journal of Infectious Diseases

190

108

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“…Despite its methodological limitations, pharmacokinetic imaging is a potentially powerful approach to evaluating transporter-based strategies to improve the local delivery and/or tissue selectivity of drugs at their sites of action. Applications may not only be restricted to research in cancer therapy, but may also be extended to neurological or infectious diseases for which sanctuary sites are suspected to account for poor or incomplete therapeutic response in patients (Rizk ML et al, 2017). Moreover, radiolabeled drugs may find use in evaluating protective pharmacologic strategies to mitigate organ toxicities of certain drugs (e.g.…”

Section: Pharmacokinetic Imaging To Study the Fate Of Drugs At The Simentioning

confidence: 99%

Imaging techniques to study drug transporter function in vivo

Tournier

Stieger

Langer

2018

Pharmacology & Therapeutics

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Transporter systems involved in the permeation of drugs and solutes across biological membranes are recognized as key determinants of pharmacokinetics. Typically, the action of membrane transporters on drug exposure to tissues in living organisms is inferred from invasive procedures, which cannot be applied in humans. In recent years, imaging methods have greatly progressed in terms of instruments, synthesis of novel imaging probes as well as tools for data analysis. Imaging allows pharmacokinetic parameters in different tissues and organs to be obtained in a non-invasive or minimally invasive way. The aim of this overview is to summarize the current status in the field of molecular imaging of drug transporters. The overview is focused on human studies, both for the characterization of transport systems for imaging agents as well as for the determination of drug pharmacokinetics, and makes reference to animal studies where necessary. We conclude that despite certain methodological limitations, imaging has a great potential to study transporters at work in humans and that imaging will become an important tool, not only in drug development but also in medicine. Imaging allows the mechanistic aspects of transport proteins to be studied, as well as elucidating the influence of genetic background, pathophysiological states and drug-drug interactions on the function of transporters involved in the disposition of drugs.

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“…Drugs which act on the central nervous system are of great interest in PBPK modeling, as their activity depends on adequate levels of drug within the target tissue (e.g., brain). Because of this, clinicians often rely on surrogate markers of plasma concentration in order to determine a dose- related exposure-response relationship [15]. The blood-brain barrier consists of tight junctions between capillary endothelial cells, which restrict diffusion into the central nervous system, which even once entered can be removed by efflux pumps (e.g., P-glycoprotein or MDR1, and breast cancerresistant protein) [16,17].…”

Section: Resultsmentioning

confidence: 99%

Utilization of Physiologically Based Pharmacokinetic Modeling in Clinical Pharmacology and Therapeutics: an Overview

et al. 2020

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The purpose of this review was to assess the advancement of applications for physiologically based pharmacokinetic (PBPK) modeling in various therapeutic areas. We conducted a PubMed search, and 166 articles published between 2012 and 2018 on FDA-approved drug products were selected for further review. Qualifying publications were summarized according to therapeutic area, medication(s) studied, pharmacokinetic model type utilized, simulator program used, and the applications of that modeling. The results showed a 13-fold increase in the number of papers published from 2012 to 2018, with the largest proportion of articles dedicated to the areas of infectious diseases, oncology, and neurology, and application extensions including prediction of drug-drug interactions due to metabolism and/or transporter-mediated effects and understanding drug kinetics in special populations. In addition, we profiled several high-impact studies whose results were used to guide package insert information and formulate dose recommendations. These results show that while utilization of PBPK modeling has drastically increased over the past several years, regulatory support, lack of easy-to-use systems for clinicians, and challenges with model validation remain major challenges for the widespread adoption of this practice in institutional and ambulatory settings. However, PBPK modeling will continue to be a useful tool in the future to assess therapeutic drug monitoring and the growing field of personalized medicine.Keywords Physiologically based pharmacokinetic modeling . PBPK modeling applications . Modeling and simulation . In vitro in vivo extrapolation . Personalized medicine

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Importance of Drug Pharmacokinetics at the Site of Action

Cited by 98 publications

References 102 publications

Discovery and development of safe-in-man broad-spectrum antiviral agents

Discovery and development of safe-in-man broad-spectrum antiviral agents

Imaging techniques to study drug transporter function in vivo

Utilization of Physiologically Based Pharmacokinetic Modeling in Clinical Pharmacology and Therapeutics: an Overview

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