Application of in vitro data in physiologically-based kinetic models for quantitative in vitro-in vivo extrapolation: A case-study for baclofen

• Published in: Toxicology in vitro Vol. 76; p. 105223
• Main Authors: Kasteel, Emma E.J., Lautz, Leonie S., Culot, Maxime, Kramer, Nynke I., Zwartsen, Anne
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2021; Elsevier
• Subjects: Adult; Animals; Baclofen; Baclofen - administration & dosage; Baclofen - cerebrospinal fluid; Baclofen - pharmacokinetics; Biological Assay; Blood-Brain Barrier - metabolism; Cattle; Child; Children; Coculture Techniques; Computer Simulation; Electrodes; Endothelial Cells - metabolism; Female; GABA-B Receptor Agonists - administration & dosage; GABA-B Receptor Agonists - cerebrospinal fluid; GABA-B Receptor Agonists - pharmacokinetics; Humans; Kinetics; Life Sciences; Male; Microelectrode array (MEA); Models, Biological; Muscle Relaxants, Central - administration & dosage; Muscle Relaxants, Central - cerebrospinal fluid; Muscle Relaxants, Central - pharmacokinetics; Pericytes - metabolism; Pharmaceutical sciences; Pharmacology; Physiologically-based pharmacokinetic modelling; Quantitative in vitro to in vivo extrapolation (QIVIVE); Toxicology; Microelectrode array (MEA); Quantitative in vitro to in vivo extrapolation (QIVIVE); Children; Physiologically-based pharmacokinetic modelling; Baclofen; Microelectrode array; Physiologically-based pharmacokinetic modelling PBPK
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2021.105223

Physiologically-based kinetic (PBK) models can simulate concentrations of chemicals in tissues over time without animal experiments. Nevertheless, in vivo data are often used to parameterise PBK models. This study aims to illustrate that a combination of kinetic and dynamic readouts from in vitro assays can be used to parameterise PBK models simulating neurologically-active concentrations of xenobiotics. Baclofen, an intrathecally administered drug to treat spasticity, was used as a proof-of-principle xenobiotic. An in vitro blood-brain barrier (BBB) model was used to determine the BBB permeability of baclofen needed to simulate plasma and cerebrospinal concentrations. Simulated baclofen concentrations in individuals and populations of adults and children generally fall within 2-fold of measured clinical study concentrations. Further, in vitro micro-electrode array recordings were used to determine the effect of baclofen on neuronal activity (cell signalling). Using quantitative in vitro-in vivo extrapolations (QIVIVE) corresponding doses of baclofen were estimated. QIVIVE showed that up to 4600 times lower intrathecal doses than oral and intravenous doses induce comparable neurological effects. Most simulated doses were in the range of administered doses. This show that PBK models predict concentrations in the central nervous system for various routes of administration accurately without the need for additional in vivo data. •A next-generation PBK model using solely in silico and in vitro data as input.•A specialised CNS-PBPK model is needed to simulate CSF concentrations.•Using QIVIVE, equivalent doses were related to in vitro effect concentrations.•Intrathecal doses induce same effects as ~4600× higher oral and intravenous doses.