title: Development of a permeability-limited model of the human brain and cerebrospinal fluid (CSF) to integrate known physiological and biological knowledge: Estimating time varying CSF drug concentrations and their variability using in vitro data.
abstract: A 4-compartment permeability-limited brain (4Brain) model consisting of brain blood, brain mass, cranial and spinal cerebrospinal fluid (CSF) compartments has been developed and incorporated into a whole body physiologically-based pharmacokinetic (PBPK) model within the Simcyp Simulator. The model assumptions, structure, governing equations and system parameters are described. The model in particular considers the anatomy and physiology of the brain and CSF, including CSF secretion, circulation and absorption, as well as the function of various efflux and uptake transporters existing on the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB), together with the known parameter variability. The model performance was verified using in vitro data and clinical observations for paracetamol and phenytoin. The simulated paracetamol spinal CSF concentration is comparable with clinical lumbar CSF data for both intravenous and oral doses. Phenytoin CSF concentration-time profiles in epileptic patients were simulated after accounting for disease-induced over-expression of efflux transporters within the BBB. Various 'what-if' scenarios, involving variation of specific drug and system parameters of the model, demonstrated that the 4Brain model is able to simulate the possible impact of transporter-mediated drug-drug interactions, the lumbar puncture process and the age-dependent change in the CSF turnover rate on the local PK within the brain.
authors.affiliation: Simcyp Limited (a Certara Company), Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK. Electronic address: gaohua.lu@certara.com.
authors.forename: Lu
authors.initials: L
authors.lastname: Gaohua
authors.affiliation: Simcyp Limited (a Certara Company), Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Neuhoff
authors.affiliation: Simcyp Limited (a Certara Company), Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK.
authors.forename: Trevor N
authors.initials: TN
authors.lastname: Johnson
authors.affiliation: Simcyp Limited (a Certara Company), Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK; Manchester Pharmacy School, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Amin
authors.initials: A
authors.lastname: Rostami-Hodjegan
authors.affiliation: Simcyp Limited (a Certara Company), Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK.
authors.forename: Masoud
authors.initials: M
authors.lastname: Jamei
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics; D061605:Administration, Intravenous; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008959:Models, Neurological; D010672:Phenytoin / Q000134:cerebrospinal fluid*; D055815:Young Adult
chemical_list: D000082:Acetaminophen; D010672:Phenytoin
keywords: Blood-cerebrospinal fluid barrier (BCSFB); Blood–brain barrier (BBB); Brain; Inter-individual variability; In vitro-in vivo extrapolation (IVIVE); Lumbar puncture; Modelling and simulation; Physiologically-based pharmacokinetic (PBPK) model; Transporter