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Article ; Online: Insights from mathematical modeling for convection-enhanced intraputamenal delivery of GDNF.

Belova, Elena / Shaffer, Christopher L / Trapa, Patrick E

Medical & biological engineering & computing

2017 Volume 55, Issue 12, Page(s) 2069–2077

Abstract: Glial cell line-derived neurotrophic factor (GDNF) is a potential therapy for Parkinson's disease (PD) promoting survival and functional recovery of dopaminergic neurons when delivered to the degenerated striatum. To study the aspects of intraputamenal ... ...

Abstract	Glial cell line-derived neurotrophic factor (GDNF) is a potential therapy for Parkinson's disease (PD) promoting survival and functional recovery of dopaminergic neurons when delivered to the degenerated striatum. To study the aspects of intraputamenal delivery of GDNF, a mathematical model of recombinant methionyl human GDNF (r-metHuGDNF) convection in the human putamen has been developed. The convection-enhanced delivery infusions of r-metHuGDNF were simulated at rates up to 5 μL/min. The high-rate infusions (≥1 μL/min) permit rapid and uniform distribution of drug with up to 75% of the distribution volume having a concentration within 5% of the infusate concentration. No relevant differences in distribution at infusion rates of 3 and 5 μL/min were found. The patterns of GDNF distribution were analyzed in relation to the anatomy of the posterior dorsal putamen, and a cylindrical shape was found to be preferable considering risks of target overflow. A magnetic resonance (MR) tracer Gd-DTPA (Magnevist®) was evaluated as a surrogate in clinical studies, and the most accurate prediction of GDNF distribution was calculated immediately after infusion. The clearance of GDNF from the striatum is confirmed to be slow, with a half-life of ca. 19 h.
MeSH term(s)	Computer Simulation ; Corpus Striatum/diagnostic imaging ; Corpus Striatum/metabolism ; Gadolinium DTPA/administration & dosage ; Gadolinium DTPA/pharmacokinetics ; Glial Cell Line-Derived Neurotrophic Factor/administration & dosage ; Glial Cell Line-Derived Neurotrophic Factor/pharmacokinetics ; Humans ; Models, Biological ; Putamen/diagnostic imaging ; Putamen/metabolism ; Recombinant Proteins/administration & dosage ; Recombinant Proteins/pharmacokinetics
Chemical Substances	GDNF protein, human ; Glial Cell Line-Derived Neurotrophic Factor ; Recombinant Proteins ; Gadolinium DTPA (K2I13DR72L)
Language	English
Publishing date	2017-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	282327-5
ISSN	1741-0444 ; 0025-696X ; 0140-0118
ISSN (online)	1741-0444
ISSN	0025-696X ; 0140-0118
DOI	10.1007/s11517-017-1650-x
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Article ; Online: Harnessing Preclinical Data as a Predictive Tool for Human Brain Tissue Targeting.

Patel, Nandini C / Feng, Bo / Hou, Xinjun / West, Mark A / Trapa, Patrick E / Sciabola, Simone / Verhoest, Patrick / Liras, Jennifer L / Maurer, Tristan S / Wager, Travis T

ACS chemical neuroscience

2021 Volume 12, Issue 6, Page(s) 1007–1017

Abstract: One of the objectives within the medicinal chemistry discipline is to design tissue targeting molecules. The objective of tissue specificity can be either to gain drug access to the compartment of interest ( ...

Abstract	One of the objectives within the medicinal chemistry discipline is to design tissue targeting molecules. The objective of tissue specificity can be either to gain drug access to the compartment of interest (
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; Animals ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Dogs ; Humans ; Madin Darby Canine Kidney Cells ; Neoplasm Proteins/metabolism
Chemical Substances	ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Neoplasm Proteins
Language	English
Publishing date	2021-03-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.0c00807
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Article ; Online: Insights From an Integrated Physiologically Based Pharmacokinetic Model for Brain Penetration.

Trapa, Patrick E / Belova, Elena / Liras, Jenny L / Scott, Dennis O / Steyn, Stefan J

Journal of pharmaceutical sciences

2016 Volume 105, Issue 2, Page(s) 965–971

Abstract: Central-nervous-system, physiologically based pharmacokinetic (PBPK) models predict exposure profiles in the brain, that is, the rate and extent of distribution. The current work develops one such model and presents improved methods for determining key ... ...

Abstract	Central-nervous-system, physiologically based pharmacokinetic (PBPK) models predict exposure profiles in the brain, that is, the rate and extent of distribution. The current work develops one such model and presents improved methods for determining key input parameters. A simple linear regression statistical model estimates the passive permeability at the blood-brain barrier from brain uptake index data and descriptors, and a novel analysis extracts the relative active transport parameter from in vitro assays taking into consideration both paracellular transport and unstirred water layers. The integrated PBPK model captures the concentration profiles of both rate-restricted and effluxed compounds with high passive permeability. In many cases, compounds distribute rapidly into the brain and are, therefore, not rate limited. The PBPK model is then simplified to a straightforward equation to describe brain-to-plasma ratios at steady state. The equation can estimate brain penetration either from in vitro efflux data or from in vivo results from another species and, therefore, is a valuable tool in the discovery setting.
MeSH term(s)	Animals ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Brain/drug effects ; Brain/metabolism ; Cell Membrane Permeability/drug effects ; Cell Membrane Permeability/physiology ; Humans ; Mice ; Models, Biological ; Pharmaceutical Preparations/chemistry ; Pharmaceutical Preparations/metabolism ; Pharmacokinetics ; Quantitative Structure-Activity Relationship
Chemical Substances	Pharmaceutical Preparations
Language	English
Publishing date	2016-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	3151-3
ISSN	1520-6017 ; 0022-3549
ISSN (online)	1520-6017
ISSN	0022-3549
DOI	10.1016/j.xphs.2015.12.005
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Article ; Online: In Vitro-In Vivo Extrapolation of Intestinal Availability for Carboxylesterase Substrates Using Portal Vein-Cannulated Monkey.

Trapa, Patrick E / Beaumont, Kevin / Atkinson, Karen / Eng, Heather / King-Ahmad, Amanda / Scott, Dennis O / Maurer, Tristan S / Di, Li

Journal of pharmaceutical sciences

2017 Volume 106, Issue 3, Page(s) 898–905

Abstract: Prediction of intestinal availability ( ... ...

Abstract	Prediction of intestinal availability (F
Language	English
Publishing date	2017-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	3151-3
ISSN	1520-6017 ; 0022-3549
ISSN (online)	1520-6017
ISSN	0022-3549
DOI	10.1016/j.xphs.2016.12.001
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Article ; Online: Impact of recovery on fraction unbound using equilibrium dialysis.

Di, Li / Umland, John P / Trapa, Patrick E / Maurer, Tristan S

Journal of pharmaceutical sciences

2012 Volume 101, Issue 3, Page(s) 1327–1335

Abstract: Historically, recovery had been used to evaluate the data quality of plasma protein binding or tissue binding obtained from equilibrium dialysis assays. Low recovery was often indicative of high nonspecific binding, instability, or low solubility. This ... ...

Abstract	Historically, recovery had been used to evaluate the data quality of plasma protein binding or tissue binding obtained from equilibrium dialysis assays. Low recovery was often indicative of high nonspecific binding, instability, or low solubility. This study showed that, when equilibrium was fully established in the dialysis assay, low recovery due to nonspecific binding had no impact on the determination of fraction unbound. The conclusion was supported by the principles of the equilibrium dialysis assay, experimental data, and mathematic simulations. The results suggested that the use of recovery as an acceptance criterion for the equilibrium dialysis assay in drug discovery was too restrictive, and introduced the additional burden of repeating studies unnecessarily.
MeSH term(s)	Animals ; Blood Proteins/metabolism ; Brain/metabolism ; Computer Simulation ; Dialysis/methods ; Drug Discovery ; Humans ; Models, Biological ; Pharmaceutical Preparations/metabolism ; Protein Binding ; Rats ; Rats, Wistar
Chemical Substances	Blood Proteins ; Pharmaceutical Preparations
Language	English
Publishing date	2012-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	3151-3
ISSN	1520-6017 ; 0022-3549
ISSN (online)	1520-6017
ISSN	0022-3549
DOI	10.1002/jps.23013
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Article ; Online: In Vitro-In Vivo Extrapolation of Intestinal Availability for Carboxylesterase Substrates Using Portal Vein-Cannulated Monkey

Trapa, Patrick E. / Beaumont, Kevin / Atkinson, Karen / Eng, Heather / King-Ahmad, Amanda / Scott, Dennis O. / Maurer, Tristan S. / Di, Li

American Pharmacists Association® Journal of Pharmaceutical Sciences. 2017,

2017

Abstract: Prediction of intestinal availability (FaFg) of carboxylesterase (CES) substrates is of critical importance in designing oral prodrugs with optimal properties, projecting human pharmacokinetics and dose, and estimating drug-drug interaction potentials. A ...

Abstract	Prediction of intestinal availability (FaFg) of carboxylesterase (CES) substrates is of critical importance in designing oral prodrugs with optimal properties, projecting human pharmacokinetics and dose, and estimating drug-drug interaction potentials. A set of ester prodrugs were evaluated using in vitro permeability (parallel artificial membrane permeability assay and Madin-Darby canine kidney cell line-low efflux) and intestinal stability (intestine S9) assays, as well as in vivo portal vein-cannulated cynomolgus monkey. In vitro-in vivo extrapolation (IVIVE) of FaFg was developed with a number of modeling approaches, including a full physiologically based pharmacokinetic (PBPK) model as well as a simplified competitive-rate analytical solution. Both methods converged as in the PBPK simulations enterocyte blood flow behaved as a sink, a key assumption in the competitive-rate analysis. For this specific compound set, the straightforward analytical solution therefore can be used to generate in vivo predictions. Strong IVIVE of FaFg was observed for cynomolgus monkey with R2 of 0.71-0.93. The results suggested in vitro assays can be used to predict in vivo FaFg for CES substrates with high confidence.
Keywords	In vitro-in vivo extrapolation ; gut first-pass extraction ; fraction absorbed ; portal vein-cannulated monkey ; intestine S9 ; carboxylesterase ; CAT ; CES ; CLint ; Fa ; FaFg ; Fg ; GI ; IV ; IVIVE ; Km ; LC-MS/MS ; MDCK-LE ; MRT ; PAMPA ; PK ; PBPK ; PSA ; PVC ; Rb ; UGT ; UV ; Vmax
Language	English
Publishing place	Elsevier Inc.
Document type	Article ; Online
Note	Pre-press version
ZDB-ID	3151-3
ISSN	1520-6017 ; 0022-3549
ISSN (online)	1520-6017
ISSN	0022-3549
DOI	10.1016/j.xphs.2016.12.001
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Article ; Online: Enhancing ketamine translational pharmacology via receptor occupancy normalization.

Shaffer, Christopher L / Osgood, Sarah M / Smith, Deborah L / Liu, JianHua / Trapa, Patrick E

Neuropharmacology

2014 Volume 86, Page(s) 174–180

Abstract: Ketamine is used preclinically and clinically to study schizophrenia and depression. Accordingly, it is imperative to understand the temporal relationship between the central concentrations and N-methyl-d-aspartate receptor (NMDAR) interactions of both ... ...

Abstract	Ketamine is used preclinically and clinically to study schizophrenia and depression. Accordingly, it is imperative to understand the temporal relationship between the central concentrations and N-methyl-d-aspartate receptor (NMDAR) interactions of both ketamine and norketamine, its primary active metabolite, across species to assess the translatability of animal models to humans and the back-translation of clinical observations to the preclinical realm. However, such an interspecies normalization of ketamine and norketamine exposures at different clinical and preclinical doses (and their different routes and regimens) is lacking. This work defines the NMDAR occupancy (RO) time course following single doses of ketamine in rats, nonhuman primates (nhp) and humans to allow direct interspecies comparisons of specific ketamine-mediated pharmacodynamics via RO normalization. Total plasma concentration (Cp)-time profiles of ketamine and norketamine were generated from rats and nhp following a single, memory-impairing dose of ketamine; neuropharmacokinetics were determined in rats. [(3)H]MK-801-displacement studies in rats determined estimated mean (95% confidence interval) unbound plasma concentrations (Cp,u) for ketamine and norketamine producing 50% RO (IC50) of 1420 (990, 2140) nM and 9110 (5870, 13700) nM, respectively. Together, these datasets transformed Cp,u-time data to predicted RO (ROpred)-time profiles for rats, nhp and humans at behaviorally relevant ketamine doses. Subsequently, this approach helped determine an infusion paradigm in rats producing a ROpred-time profile mirroring that for a clinically antidepressant infusion. The described indication-independent methodology allows normalization to RO at any time following any ketamine dose (regardless of route or regimen) in any species by simply quantifying the Cp of ketamine and norketamine. Matching temporal RO relationships in animals and humans should allow direct comparisons of specific ketamine-dependent NMDAR-based pharmacodynamics.
MeSH term(s)	Animals ; Depression/drug therapy ; Depression/physiopathology ; Dizocilpine Maleate/pharmacokinetics ; Excitatory Amino Acid Antagonists/pharmacokinetics ; Excitatory Amino Acid Antagonists/pharmacology ; Ketamine/analogs & derivatives ; Ketamine/pharmacokinetics ; Ketamine/pharmacology ; Macaca fascicularis ; Male ; Memory/drug effects ; Memory/physiology ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/metabolism ; Species Specificity ; Tritium
Chemical Substances	Excitatory Amino Acid Antagonists ; Receptors, N-Methyl-D-Aspartate ; Tritium (10028-17-8) ; Ketamine (690G0D6V8H) ; Dizocilpine Maleate (6LR8C1B66Q) ; norketamine (XQY6JVF94X)
Language	English
Publishing date	2014-11
Publishing country	England
Document type	Journal Article
ZDB-ID	218272-5
ISSN	1873-7064 ; 0028-3908
ISSN (online)	1873-7064
ISSN	0028-3908
DOI	10.1016/j.neuropharm.2014.07.008
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Article ; Online: In Vitro-In Vivo Extrapolation of Key Transporter Activity at the Blood-Brain Barrier.

Trapa, Patrick E / Troutman, Matthew D / Lau, Thomas Y / Wager, Travis T / Maurer, Tristan S / Patel, Nandini C / West, Mark A / Umland, John P / Carlo, Anthony A / Feng, Bo / Liras, Jennifer L

Drug metabolism and disposition: the biological fate of chemicals

2019 Volume 47, Issue 4, Page(s) 405–411

Abstract: Understanding the quantitative implications of P-glycoprotein and breast cancer resistance protein efflux is a key hurdle in the design of effective, centrally acting or centrally restricted therapeutics. Previously, a comprehensive physiologically based ...

Abstract	Understanding the quantitative implications of P-glycoprotein and breast cancer resistance protein efflux is a key hurdle in the design of effective, centrally acting or centrally restricted therapeutics. Previously, a comprehensive physiologically based pharmacokinetic model was developed to describe the in vivo unbound brain-to-plasma concentration ratio as a function of efflux activity measured in vitro. In the present work, the predictive utility of this framework was examined through application to in vitro and in vivo data generated on 133 unique compounds across three preclinical species. Two approaches were examined for the scaling of efflux activity to in vivo, namely relative expression as determined by independent proteomics measurements and relative activity as determined via fitting the in vivo neuropharmacokinetic data. The results with both approaches indicate that in vitro efflux data can be used to accurately predict the degree of brain penetration across species within the context of the proposed physiologically based pharmacokinetic framework.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Animals ; Biological Transport/physiology ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Cell Line ; Dogs ; Madin Darby Canine Kidney Cells ; Rats ; Rats, Sprague-Dawley
Chemical Substances	ATP Binding Cassette Transporter, Subfamily B, Member 1
Language	English
Publishing date	2019-01-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
DOI	10.1124/dmd.118.083279
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Article ; Online: Permeability comparison between hepatocyte and low efflux MDCKII cell monolayer.

Li, Rui / Bi, Yi-An / Lai, Yurong / Sugano, Kiyohiko / Steyn, Stefanus J / Trapa, Patrick E / Di, Li

The AAPS journal

2014 Volume 16, Issue 4, Page(s) 802–809

Abstract: Determination of passive permeability is not only important for predicting oral absorption and brain penetration, but also for accurately predicting hepatic clearance. High throughput (HT) measurement of passive permeability across hepatocyte cell ... ...

Abstract	Determination of passive permeability is not only important for predicting oral absorption and brain penetration, but also for accurately predicting hepatic clearance. High throughput (HT) measurement of passive permeability across hepatocyte cell membrane is technically more challenging than using monolayer cell-based permeability assays. In this study, we evaluated if the HT Madin-Darby canine kidney II-low efflux (MDCKII-LE) cell monolayer permeability assay can be used as a surrogate to predict the passive permeability of hepatocytes. Apparent passive permeability of MDCKII-LE is well correlated to passive diffusion clearance of human and rat hepatocytes, suggesting that the HT MDCKII-LE assay can be used as a surrogate to estimate the passive permeability of hepatocytes. In addition, lipophilicity (Log D determined at pH 7.4) was also found to be well correlated with both MDCKII-LE and hepatocyte permeability for most compounds, hence it may serve as another permeability surrogate.
MeSH term(s)	Algorithms ; Animals ; Biological Transport, Active ; Cell Line ; Cell Membrane Permeability/physiology ; Dogs ; Hepatocytes/metabolism ; Humans ; Madin Darby Canine Kidney Cells/metabolism ; Rats ; Species Specificity
Language	English
Publishing date	2014-05-23
Publishing country	United States
Document type	Comparative Study ; Journal Article
ISSN	1550-7416
ISSN (online)	1550-7416
DOI	10.1208/s12248-014-9616-5
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