The right compound in the right assay at the right time: an integrated discovery DMPK strategy

Ballard, Peter; Brassil, Patrick; Bui, Khanh; Dolgos, Hugues; Petersson, Carl; Tunek, Anders; Webborn, Peter J. H.

doi:10.3109/03602532.2012.691099

Cited by 52 publications

(44 citation statements)

References 145 publications

(138 reference statements)

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“…Zhang et al [48]) available that allow estimation of pre-systemic metabolism. It has been shown before that a combination of different in vitro and in vivo methods allows a better prediction of human oral bioavailability [49,50]. This combined approach appears to be promising for common chemicals, such as pharmaceuticals, since pre-systemic metabolism is known to potentially alter the molecular structure, thereby reducing the bioavailability of the parent compound.…”

Section: Westerhout Et Almentioning

confidence: 99%

Prediction of Oral Absorption of Nanoparticles from Biorelevant Matrices Using a Combination of Physiologically Relevant In Vitro and Ex Vivo Models

Westerhout¹,

Bellmann²,

Ee³

et al. 2017

J Food Chem Nanotechol

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The application of nanoparticles (NPs) in food products is ever increasing. For consumer safety it is essential to know the human oral bioavailability of these NPs. In the present study, a combination of physiologically relevant in vitro and ex vivo models are presented, which combined are considered to predict human intestinal digestion and absorption of NPs more accurately than commonly applied animal or cellular studies.First, a computer controlled dynamic in vitro gastrointestinal model (tiny-TIM) is used for simulation of the digestive processes upon gastro-intestinal passage of non-biodegradable aminated, carboxylated, or unmodified fluorescent polystyrene NPs (PS-NPs). Then, the pretreated (digested) PS-NPs were consequently evaluated for absorption using ex vivo porcine intestinal tissue.In this study, we found that the digestion of non-biodegradable aminated, carboxylated, or unmodified fluorescent polystyrene NPs (PS-NPs) leads to different bioaccessible concentrations, with unmodified PS-NP concentrations being 3.5-and 4.5-fold lower than the aminated and carboxylated PS-NPs, respectively. In addition, we observed a reduced absorption of PS-NPs by ex vivo porcine intestinal tissue from the digestive matrix when compared to the absorption of their undigested counterparts in Krebs-Ringer Bicarbonate (KRB) buffer. The current results prove that oral absorption of PS-NPs in humans is to be expected in vivo. In the risk assessment of potential oral exposure to NPs in food products it is therefore key that the exposure and hazard assessment are performed with the NPs in physiologically relevant conditions, since this may influence the absorption and hazard properties of the NPs.

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Section: Westerhout Et Almentioning

confidence: 99%

Prediction of Oral Absorption of Nanoparticles from Biorelevant Matrices Using a Combination of Physiologically Relevant In Vitro and Ex Vivo Models

Westerhout¹,

Bellmann²,

Ee³

et al. 2017

J Food Chem Nanotechol

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“…It is a major determinant of a drugs' oral exposure as well as half-life, which in turn help define the size of dose and dosing interval. Given that there is no reliable means to predict elimination pathways in humans from in silico or in vitro methods, a combination of establishing clearance routes in pre-clinical species, and use of human in vitro systems, is required to predict human CL (5,48). In practice, confidence in the ability to make projections of human CL from in vitro data is explored during lead optimisation.…”

Section: Is Human Hepatic Clearance and First-pass Extraction Sufficimentioning

confidence: 99%

“…Animal models also provide a fuller representation of the complexities of the in vivo situation and, as detailed above, can be predictive of human F a . As such, pharmaceutical companies will continue to focus part of their prediction strategy on the ability of animal models to predict human F a (5).…”

Section: Can Human Oral Absorption Be Accurately Predicted From Pre-cmentioning

confidence: 99%

Gut Wall Metabolism. Application of Pre-Clinical Models for the Prediction of Human Drug Absorption and First-Pass Elimination

Jones

Hatley

Ungell

et al. 2016

AAPS J

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Abstract. Quantifying the multiple processes which control and modulate the extent of oral bioavailability for drug candidates is critical to accurate projection of human pharmacokinetics (PK). Understanding how gut wall metabolism and hepatic elimination factor into first-pass clearance of drugs has improved enormously. Typically, the cytochrome P450s, uridine 5′-diphosphate-glucuronosyltransferases and sulfotransferases, are the main enzyme classes responsible for drug metabolism. Knowledge of the isoforms functionally expressed within organs of first-pass clearance, their anatomical topology (e.g. zonal distribution), protein homology and relative abundances and how these differ across species is important for building models of human metabolic extraction. The focus of this manuscript is to explore the parameters influencing bioavailability and to consider how well these are predicted in human from animal models or from in vitro to in vivo extrapolation. A unique retrospective analysis of three AstraZeneca molecules progressed to first in human PK studies is used to highlight the impact that species differences in gut wall metabolism can have on predicted human PK. Compared to the liver, pharmaceutical research has further to go in terms of adopting a common approach for characterisation and quantitative prediction of intestinal metabolism. A broad strategy is needed to integrate assessment of intestinal metabolism in the context of typical DMPK activities ongoing within drug discovery programmes up until candidate drug nomination.

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“…P-gp (MDR1) is a predominant efflux transporter in the BBB, capable of limiting the penetration of a wide range of substrates into the brain. For this reason, MDCK-MDR1 cellular bidirectional transport assays are currently used in DMPK screening to assess both CNS penetrating and restricted compounds, as appropriate depending upon target profile [4]. Differences in transporter expression and passive permeability have been shown in 2D static co-culture models (described above).…”

Section: Neuhaus Et Almentioning

confidence: 99%

“…These DMPK properties are optimized within drug discovery so that an NCE has the right clinical profile, e.g. ideally a high oral bioavailability, an elimination half-life that enables a once daily dosing regimen, sufficient exposure at the target tissue and an absence of drug-drug interaction (DDI) potential [4]. In vitro 2D cell based models are routinely used within pharmaceutical research to investigate the DMPK properties of absorption (Caco-2, derived from human colon carcinoma cells), distribution (MDCKII-MDR1, derived from canine kidney cells) and metabolism/excretion (hepatocytes) for NCEs.…”

Section: …………………………………………………………………………………………………………………………………………mentioning

confidence: 99%

The use of bioreactors as in vitro models in pharmaceutical research

Ginai

Elsby

Hewitt

et al. 2013

Drug Discovery Today

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Word TeaserThe development of dynamic 3D bioreactor based systems as in vitro models for use in DMPK studies. Author BiographiesMaaria Ginai graduated with a first Class Bachelors degree with honours in Biomedical Science from the University of Kent (UK) in 2010. She is currently studying a BBSRC CASEfunded PhD at the Centre for Biological Engineering at Loughborough University in the area of bioartificial device progression to in vitro models for use in the pharmaceutical industry. This project is supported by AstraZeneca.Christopher J. Hewitt has a first Class Bachelors degree in Biology from Royal Holloway College, University of London (UK) and a PhD in Chemical Engineering from the University of Birmingham (UK). He is Director of the £7.3M EPSRC Doctoral Training Centre in Regenerative Medicine and co-founder of the £2M Centre for Biological Engineering at Loughborough University (UK). He also leads the Cell Technologies research group whose work spans the Engineering/Life science interface seeking to understand the interaction of the organism with the engineering environment within such diverse areas as microbial fermentation, bio-transformation, cell culture and mostly recently regenerative medicine bioprocessing.Karen Coopman has a first Class Bachelors degree in Pharmacology from the University of Bristol (UK) and a PhD from the Department of Pharmacy and Pharmacology at the University of Bath (UK). She was appointed to a lectureship at Loughborough University, where she is the Operations Manager of the EPSRC-funded Doctoral Training Centre in Regenerative Medicine. She co-leads the Cell Technologies research group within University's Centre for Biological Engineering and is currently a member of the EPSRC's Early Career Forum in Manufacturing Research. The overarching themes of Karen's research are the manufacture of cellular therapies and the use of cells in the drug discovery process. AbstractBringing a new drug to market is costly in terms of capital and time investments, and any development issues encountered in late stage clinical trials may often be due to in vitro -in vivo extrapolations (IVIVE) not accurately reflecting clinical outcome. In the discipline of drug metabolism and pharmacokinetics (DMPK), current in vitro cellular methods do not provide the 3D structure and function of organs found in vivo, so new dynamic methods need to be established to aid improvement of IVIVE. This review will highlight the importance of model progression into dynamic systems for use within drug development, focussing on devices developed currently in the areas of the liver and blood-brain barrier, and the potential to develop models for other organ systems such as the kidney.

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The right compound in the right assay at the right time: an integrated discovery DMPK strategy

Cited by 52 publications

References 145 publications

Prediction of Oral Absorption of Nanoparticles from Biorelevant Matrices Using a Combination of Physiologically Relevant In Vitro and Ex Vivo Models

Prediction of Oral Absorption of Nanoparticles from Biorelevant Matrices Using a Combination of Physiologically Relevant In Vitro and Ex Vivo Models

Gut Wall Metabolism. Application of Pre-Clinical Models for the Prediction of Human Drug Absorption and First-Pass Elimination

The use of bioreactors as in vitro models in pharmaceutical research

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