Development of a non-human primate model to support CNS translational research: Demonstration with D-amphetamine exposure and dopamine response

Joost H. Folgering, Minha Choi, Christina Schlumbohm, Marcel M. van Gaalen, Robert Stratford Jr.

Research output: Contribution to journalArticle

Abstract

Background: Challenges specific to the discovery and development of candidate CNS drugs have led to implementation of various in silico, in vitro and in vivo approaches to improve the odds for commercialization of novel treatments. New method: Advances in analytical methodology and microdialysis probe design have enabled development of a non-human primate model capable of measuring concentrations of drugs or endogenous chemicals in brain extracellular fluid (ECF) and cerebrospinal fluid (CSF). Linking these to population modeling reduces animal numbers to support predictive translational sciences in primates. Application to measure D-amphetamine exposure and dopamine response in ECF and CSF demonstrate the approach. Results: Following a 0.1 mg/kg intravenous bolus dose of D-amphetamine, a population approach was used to build a plasma compartmental-based and brain physiologic-based pharmacokinetic (PK) model linking drug concentrations in plasma to brain ECF and CSF concentrations. Dopamine was also measured in brain ECF. The PK model was used to simulate the relationship between D-amphetamine exposure and dopamine response in ECF over a wide dose range. Comparisons with existing methods: Ability to co-sample and measure drug and endogenous substances in blood, brain ECF and/or CSF, coupled with population modeling, provides an in vivo approach to evaluate CNS drug penetration and effect in non-human primates. Conclusions: A method to measure drug and endogenous neurochemicals in non-human primate brain fluids is demonstrated. Its basis in non-human primates merits improved confidence regarding predictions of drug exposure and target engagement in human CNS.

Original languageEnglish (US)
Pages (from-to)71-81
Number of pages11
JournalJournal of Neuroscience Methods
Volume317
DOIs
StatePublished - Apr 1 2019
Externally publishedYes

Fingerprint

Translational Medical Research
Amphetamine
Extracellular Fluid
Primates
Dopamine
Cerebrospinal Fluid
Pharmaceutical Preparations
Brain
Pharmacokinetics
Population
Microdialysis
Computer Simulation

Keywords

  • Amphetamine
  • Dopamine
  • Microdialysis
  • Non-human primate
  • Population modeling
  • Translational sciences

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Development of a non-human primate model to support CNS translational research : Demonstration with D-amphetamine exposure and dopamine response. / Folgering, Joost H.; Choi, Minha; Schlumbohm, Christina; van Gaalen, Marcel M.; Stratford Jr., Robert.

In: Journal of Neuroscience Methods, Vol. 317, 01.04.2019, p. 71-81.

Research output: Contribution to journalArticle

@article{8451fcc45976402caa9ad09a83d4ba8b,
title = "Development of a non-human primate model to support CNS translational research: Demonstration with D-amphetamine exposure and dopamine response",
abstract = "Background: Challenges specific to the discovery and development of candidate CNS drugs have led to implementation of various in silico, in vitro and in vivo approaches to improve the odds for commercialization of novel treatments. New method: Advances in analytical methodology and microdialysis probe design have enabled development of a non-human primate model capable of measuring concentrations of drugs or endogenous chemicals in brain extracellular fluid (ECF) and cerebrospinal fluid (CSF). Linking these to population modeling reduces animal numbers to support predictive translational sciences in primates. Application to measure D-amphetamine exposure and dopamine response in ECF and CSF demonstrate the approach. Results: Following a 0.1 mg/kg intravenous bolus dose of D-amphetamine, a population approach was used to build a plasma compartmental-based and brain physiologic-based pharmacokinetic (PK) model linking drug concentrations in plasma to brain ECF and CSF concentrations. Dopamine was also measured in brain ECF. The PK model was used to simulate the relationship between D-amphetamine exposure and dopamine response in ECF over a wide dose range. Comparisons with existing methods: Ability to co-sample and measure drug and endogenous substances in blood, brain ECF and/or CSF, coupled with population modeling, provides an in vivo approach to evaluate CNS drug penetration and effect in non-human primates. Conclusions: A method to measure drug and endogenous neurochemicals in non-human primate brain fluids is demonstrated. Its basis in non-human primates merits improved confidence regarding predictions of drug exposure and target engagement in human CNS.",
keywords = "Amphetamine, Dopamine, Microdialysis, Non-human primate, Population modeling, Translational sciences",
author = "Folgering, {Joost H.} and Minha Choi and Christina Schlumbohm and {van Gaalen}, {Marcel M.} and {Stratford Jr.}, Robert",
year = "2019",
month = "4",
day = "1",
doi = "10.1016/j.jneumeth.2019.02.005",
language = "English (US)",
volume = "317",
pages = "71--81",
journal = "Journal of Neuroscience Methods",
issn = "0165-0270",
publisher = "Elsevier",

}

TY - JOUR

T1 - Development of a non-human primate model to support CNS translational research

T2 - Demonstration with D-amphetamine exposure and dopamine response

AU - Folgering, Joost H.

AU - Choi, Minha

AU - Schlumbohm, Christina

AU - van Gaalen, Marcel M.

AU - Stratford Jr., Robert

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Background: Challenges specific to the discovery and development of candidate CNS drugs have led to implementation of various in silico, in vitro and in vivo approaches to improve the odds for commercialization of novel treatments. New method: Advances in analytical methodology and microdialysis probe design have enabled development of a non-human primate model capable of measuring concentrations of drugs or endogenous chemicals in brain extracellular fluid (ECF) and cerebrospinal fluid (CSF). Linking these to population modeling reduces animal numbers to support predictive translational sciences in primates. Application to measure D-amphetamine exposure and dopamine response in ECF and CSF demonstrate the approach. Results: Following a 0.1 mg/kg intravenous bolus dose of D-amphetamine, a population approach was used to build a plasma compartmental-based and brain physiologic-based pharmacokinetic (PK) model linking drug concentrations in plasma to brain ECF and CSF concentrations. Dopamine was also measured in brain ECF. The PK model was used to simulate the relationship between D-amphetamine exposure and dopamine response in ECF over a wide dose range. Comparisons with existing methods: Ability to co-sample and measure drug and endogenous substances in blood, brain ECF and/or CSF, coupled with population modeling, provides an in vivo approach to evaluate CNS drug penetration and effect in non-human primates. Conclusions: A method to measure drug and endogenous neurochemicals in non-human primate brain fluids is demonstrated. Its basis in non-human primates merits improved confidence regarding predictions of drug exposure and target engagement in human CNS.

AB - Background: Challenges specific to the discovery and development of candidate CNS drugs have led to implementation of various in silico, in vitro and in vivo approaches to improve the odds for commercialization of novel treatments. New method: Advances in analytical methodology and microdialysis probe design have enabled development of a non-human primate model capable of measuring concentrations of drugs or endogenous chemicals in brain extracellular fluid (ECF) and cerebrospinal fluid (CSF). Linking these to population modeling reduces animal numbers to support predictive translational sciences in primates. Application to measure D-amphetamine exposure and dopamine response in ECF and CSF demonstrate the approach. Results: Following a 0.1 mg/kg intravenous bolus dose of D-amphetamine, a population approach was used to build a plasma compartmental-based and brain physiologic-based pharmacokinetic (PK) model linking drug concentrations in plasma to brain ECF and CSF concentrations. Dopamine was also measured in brain ECF. The PK model was used to simulate the relationship between D-amphetamine exposure and dopamine response in ECF over a wide dose range. Comparisons with existing methods: Ability to co-sample and measure drug and endogenous substances in blood, brain ECF and/or CSF, coupled with population modeling, provides an in vivo approach to evaluate CNS drug penetration and effect in non-human primates. Conclusions: A method to measure drug and endogenous neurochemicals in non-human primate brain fluids is demonstrated. Its basis in non-human primates merits improved confidence regarding predictions of drug exposure and target engagement in human CNS.

KW - Amphetamine

KW - Dopamine

KW - Microdialysis

KW - Non-human primate

KW - Population modeling

KW - Translational sciences

UR - http://www.scopus.com/inward/record.url?scp=85061750739&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061750739&partnerID=8YFLogxK

U2 - 10.1016/j.jneumeth.2019.02.005

DO - 10.1016/j.jneumeth.2019.02.005

M3 - Article

C2 - 30768951

AN - SCOPUS:85061750739

VL - 317

SP - 71

EP - 81

JO - Journal of Neuroscience Methods

JF - Journal of Neuroscience Methods

SN - 0165-0270

ER -