title: A Generic Multi-Compartmental CNS Distribution Model Structure for 9 Drugs Allows Prediction of Human Brain Target Site Concentrations.
abstract: Predicting target site drug concentration in the brain is of key importance for the successful development of drugs acting on the central nervous system. We propose a generic mathematical model to describe the pharmacokinetics in brain compartments, and apply this model to predict human brain disposition.
  
  
  
  A mathematical model consisting of several physiological brain compartments in the rat was developed using rich concentration-time profiles from nine structurally diverse drugs in plasma, brain extracellular fluid, and two cerebrospinal fluid compartments. The effect of active drug transporters was also accounted for. Subsequently, the model was translated to predict human concentration-time profiles for acetaminophen and morphine, by scaling or replacing system- and drug-specific parameters in the model.
  
  
  
  A common model structure was identified that adequately described the rat pharmacokinetic profiles for each of the nine drugs across brain compartments, with good precision of structural model parameters (relative standard error <37.5%). The model predicted the human concentration-time profiles in different brain compartments well (symmetric mean absolute percentage error <90%).
  
  
  
  A multi-compartmental brain pharmacokinetic model was developed and its structure could adequately describe data across nine different drugs. The model could be successfully translated to predict human brain concentrations.
authors.affiliation: Division of Pharmacology, Cluster Systems Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Division of Pharmacology, Cluster Systems Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Pyry A
authors.initials: PA
authors.lastname: Välitalo
authors.affiliation: Division of Pharmacology, Cluster Systems Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Dirk-Jan
authors.initials: DJ
authors.lastname: van den Berg
authors.affiliation: Division of Pharmacology, Cluster Systems Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Robin
authors.initials: R
authors.lastname: Hartman
authors.affiliation: Division of Pharmacology, Cluster Systems Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Willem
authors.initials: W
authors.lastname: van den Brink
authors.affiliation: Division of Pharmacology, Cluster Systems Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Yin Cheong
authors.initials: YC
authors.lastname: Wong
authors.affiliation: Quantitative Sciences, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Dymphy R
authors.initials: DR
authors.lastname: Huntjens
authors.affiliation: Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands.
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Proost
authors.affiliation: Quantitative Sciences, Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Vermeulen
authors.affiliation: Department of Clinical Pharmacology & Exploratory Development, Astellas Pharma BV, Leiden, The Netherlands.
authors.forename: Walter
authors.initials: W
authors.lastname: Krauwinkel
authors.affiliation: Division of Pharmacology, Cluster Systems Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Suruchi
authors.initials: S
authors.lastname: Bakshi
authors.affiliation: Department of Medicine and Pharmacy, University of Poitiers, Poitiers, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Aranzana-Climent
authors.affiliation: Department of Medicine and Pharmacy, University of Poitiers, Poitiers, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchand
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, University Hospital Center of Poitiers, Poitiers, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Dahyot-Fizelier
authors.affiliation: Department of Medicine and Pharmacy, University of Poitiers, Poitiers, France.
authors.forename: William
authors.initials: W
authors.lastname: Couet
authors.affiliation: Division of Pharmacology, Cluster Systems Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.affiliation: Division of Pharmacology, Cluster Systems Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Johan G C
authors.initials: JG
authors.lastname: van Hasselt
authors.affiliation: Division of Pharmacology, Cluster Systems Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. ecmdelange@lacdr.leidenuniv.nl.|Leiden University Gorlaeus Laboratories, Einsteinweg 55, 2333CC, Leiden, The Netherlands. ecmdelange@lacdr.leidenuniv.nl.
authors.forename: Elizabeth C M
authors.initials: EC
authors.lastname: de Lange
mesh_terms: D000082:Acetaminophen / Q000493:pharmacokinetics*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D006801:Humans; D008297:Male; D008954:Models, Biological; D008962:Models, Theoretical; D009020:Morphine / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution / Q000502:physiology
chemical_list: D000082:Acetaminophen; D009020:Morphine
keywords: blood-brain barrier; central nervous system (CNS); human prediction; pharmacokinetics; translational model