A physiologically-based pharmacokinetic (PBPK) brain model and its application in simulating drug disposition in brain
L. Gaohua1, S. Neuhoff 1, M. Jamei1, A. Rostami Hodjegan1,2
1Simcyp Limited, Sheffield, UK & 2University of Manchester, Manchester, UK.
Objectives: The aim of this study is to develop a PBPK brain model to explore the effects of transporters present within the blood-brain/cerebrospinal fluid barriers (BBB/BCSFB) on the drug disposition in brain.
Methods: For this purpose, literature was reviewed to collate brain physiological and anatomical attributes as well as any information on transporter abundance and activities on the BBB/BCSFB. A novel 4-compartmental diffusion-limited brain model was developed and implemented in Matlab Simulink®. This model was combined with a whole-body PBPK model. Physiological, anatomical and drug dependent parameters were incorporated into the model to simulate/predict drug disposition into the brain due to intracranial CSF flows and transporter effects.
Results: Depending on the drug properties, (1) the concentrations in the spinal CSF can be very different from that of the cranial CSF; (2) the latter may or may not reflect the drug concentrations in brain mass; and (3) the drug concentration in the intracranial blood may not represent that of the brain mass.
Conclusions: Consistent with reported clinical studies, the model was able to show disparities in drug concentration-time profiles in the intracranial blood, brain mass, cranial and spinal CSF. Such disparities were related to drug properties, particularly the affinities to transporters.