Endogenous Biomarkers for SLC Transporter-Mediated Drug-Drug Interaction Evaluation

Membrane transporters play an important role in the absorption, distribution, metabolism, and excretion of xenobiotic substrates, as well as endogenous compounds. The evaluation of transporter-mediated drug-drug interactions (DDIs) is an important consideration during the drug development process and can guide the safe use of polypharmacy regimens in clinical practice. In recent years, several endogenous substrates of drug transporters have been identified as potential biomarkers for predicting changes in drug transport function and the potential for DDIs associated with drug candidates in early phases of drug development. These biomarker-driven investigations have been applied in both preclinical and clinical studies and proposed as a predictive strategy that can be supplanted in order to conduct prospective DDIs trials. Here we provide an overview of this rapidly emerging field, with particular emphasis on endogenous biomarkers recently proposed for clinically relevant uptake transporters.

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Cheminformatics techniques in antimalarial drug discovery and development from natural products 1: basic concepts

Physical Sciences Reviews ◽

10.1515/psr-2018-0130 ◽

2019 ◽

Vol 4 (7) ◽

Author(s):

Samuel Egieyeh ◽

Sarel F. Malan ◽

Alan Christoffels

Keyword(s):

Natural Products ◽

Drug Development ◽

Antimalarial Drug ◽

Drug Discovery And Development ◽

Drug Candidates ◽

Structure Activity ◽

Preclinical And Clinical Studies ◽

Research Cost

Abstract A large number of natural products, especially those used in ethnomedicine of malaria, have shown varying in vitro antiplasmodial activities. Facilitating antimalarial drug development from this wealth of natural products is an imperative and laudable mission to pursue. However, limited manpower, high research cost coupled with high failure rate during preclinical and clinical studies might militate against the pursuit of this mission. These limitations may be overcome with cheminformatic techniques. Cheminformatics involves the organization, integration, curation, standardization, simulation, mining and transformation of pharmacology data (compounds and bioactivity) into knowledge that can drive rational and viable drug development decisions. This chapter will review the application of cheminformatics techniques (including molecular diversity analysis, quantitative-structure activity/property relationships and Machine learning) to natural products with in vitro and in vivo antiplasmodial activities in order to facilitate their development into antimalarial drug candidates and design of new potential antimalarial compounds.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03300-14 ◽

2014 ◽

Vol 58 (11) ◽

pp. 6477-6483 ◽

Cited By ~ 4

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.

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Self-contained, low-cost Body-on-a-Chip systems for drug development

Experimental Biology and Medicine ◽

10.1177/1535370217694101 ◽

2017 ◽

Vol 242 (17) ◽

pp. 1701-1713 ◽

Cited By ~ 25

Author(s):

Ying I Wang ◽

Carlota Oleaga ◽

Christopher J Long ◽

Mandy B Esch ◽

Christopher W McAleer ◽

...

Keyword(s):

Drug Development ◽

Development Process ◽

Mechanical Response ◽

High Reliability ◽

Low Cost ◽

Drug Development Process ◽

Functional Responses ◽

Drug Candidates ◽

Organ Systems ◽

Microphysiological Systems

Integrated multi-organ microphysiological systems are an evolving tool for preclinical evaluation of the potential toxicity and efficacy of drug candidates. Such systems, also known as Body-on-a-Chip devices, have a great potential to increase the successful conversion of drug candidates entering clinical trials into approved drugs. Systems, to be attractive for commercial adoption, need to be inexpensive, easy to operate, and give reproducible results. Further, the ability to measure functional responses, such as electrical activity, force generation, and barrier integrity of organ surrogates, enhances the ability to monitor response to drugs. The ability to operate a system for significant periods of time (up to 28 d) will provide potential to estimate chronic as well as acute responses of the human body. Here we review progress towards a self-contained low-cost microphysiological system with functional measurements of physiological responses. Impact statement Multi-organ microphysiological systems are promising devices to improve the drug development process. The development of a pumpless system represents the ability to build multi-organ systems that are of low cost, high reliability, and self-contained. These features, coupled with the ability to measure electrical and mechanical response in addition to chemical or metabolic changes, provides an attractive system for incorporation into the drug development process. This will be the most complete review of the pumpless platform with recirculation yet written.

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The Monoterpenoid Perillyl Alcohol: Anticancer Agent and Medium to Overcome Biological Barriers

Pharmaceutics ◽

10.3390/pharmaceutics13122167 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2167

Author(s):

Thomas C. Chen ◽

Clovis O. da Fonseca ◽

Daniel Levin ◽

Axel H. Schönthal

Keyword(s):

Drug Development ◽

Drug Transport ◽

Perillyl Alcohol ◽

Biological Barriers ◽

Naturally Occurring ◽

Hybrid Molecules ◽

Different Types ◽

New Chemical Entities ◽

Preclinical And Clinical Studies ◽

Pharmacologic Agents

Perillyl alcohol (POH) is a naturally occurring monoterpenoid related to limonene that is present in the essential oils of various plants. It has diverse applications and can be found in household items, including foods, cosmetics, and cleaning supplies. Over the past three decades, it has also been investigated for its potential anticancer activity. Clinical trials with an oral POH formulation administered to cancer patients failed to realize therapeutic expectations, although an intra-nasal POH formulation yielded encouraging results in malignant glioma patients. Based on its amphipathic nature, POH revealed the ability to overcome biological barriers, primarily the blood–brain barrier (BBB), but also the cytoplasmic membrane and the skin, which appear to be characteristics that critically contribute to POH’s value for drug development and delivery. In this review, we present the physicochemical properties of POH that underlie its ability to overcome the obstacles placed by different types of biological barriers and consequently shape its multifaceted promise for cancer therapy and applications in drug development. We summarized and appraised the great variety of preclinical and clinical studies that investigated the use of POH for intranasal delivery and nose-to-brain drug transport, its intra-arterial delivery for BBB opening, and its permeation-enhancing function in hybrid molecules, where POH is combined with or conjugated to other therapeutic pharmacologic agents, yielding new chemical entities with novel mechanisms of action and applications.

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Prodrug Strategies for Critical Drug Developability Issues: Part I

Current Topics in Medicinal Chemistry ◽

10.2174/156802662124211104100228 ◽

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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Intelligent Drug Development

10.1093/oso/9780199974580.001.0001 ◽

2014 ◽

Author(s):

Michael Tansey

Keyword(s):

Clinical Trials ◽

Cost Effectiveness ◽

Drug Development ◽

Clinical Research ◽

Development Process ◽

Drug Development Process ◽

Individual Trial ◽

Specific Technology

Clinical research is heavily regulated and involves coordination of numerous pharmaceutical-related disciplines. Each individual trial involves contractual, regulatory, and ethics approval at each site and in each country. Clinical trials have become so complex and government requirements so stringent that researchers often approach trials too cautiously, convinced that the process is bound to be insurmountably complicated and riddled with roadblocks. A step back is needed, an objective examination of the drug development process as a whole, and recommendations made for streamlining the process at all stages. With Intelligent Drug Development, Michael Tansey systematically addresses the key elements that affect the quality, timeliness, and cost-effectiveness of the drug-development process, and identifies steps that can be adjusted and made more efficient. Tansey uses his own experiences conducting clinical trials to create a guide that provides flexible, adaptable ways of implementing the necessary processes of development. Moreover, the processes described in the book are not dependent either on a particular company structure or on any specific technology; thus, Tansey's approach can be implemented at any company, regardless of size. The book includes specific examples that illustrate some of the ways in which the principles can be applied, as well as suggestions for providing a better context in which the changes can be implemented. The protocols for drug development and clinical research have grown increasingly complex in recent years, making Intelligent Drug Development a needed examination of the pharmaceutical process.

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Catalogue of hazards: a fundamental part for the safe design of surgical robots

Current Directions in Biomedical Engineering ◽

10.1515/cdbme-2020-0009 ◽

2020 ◽

Vol 6 (1) ◽

Author(s):

Lukas Theisgen ◽

Florian Strauch ◽

Matías de la Fuente ◽

Klaus Radermacher

Keyword(s):

Development Process ◽

New Technologies ◽

State Of The Art ◽

Hazard Identification ◽

Surgical Robots ◽

Safety Measures ◽

Fundamental Part ◽

Phases Of Development ◽

Early Phases ◽

Intended Use

AbstractRisk classes defined by MDR and FDA for state-of-the-art surgical robots based on their intended use are not suitable as indicators for their hazard potential. While there is a lack of safety regulation for an increasing degree of automation as well as the degree of invasiveness into the patient’s body, adverse events have increased in the last decade. Thus, an outright identification of hazards as part of the risk analysis over the complete development process and life cycle of a surgical robot is crucial, especially when introducing new technologies. For this reason, we present a comprehensive approach for hazard identification in early phases of development. With this multi-perspective approach, the number of hazards identified can be increased. Furthermore, a generic catalogue of hazards for surgical robots has been established by categorising the results. The catalogue serves as a data pool for risk analyses and holds the potential to reduce hazards through safety measures already in the design process before becoming risks for the patient.

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