In Vitro-In Vivo Correlation of Blood–Brain Barrier Permeability of Drugs: A Feasibility Study Towards Development of Prediction Methods for Brain Drug Concentration in Humans

• Published in: Pharmaceutical research Vol. 39; no. 7; pp. 1575 - 1586
• Main Authors: Ito, Ryo, Morio, Hanae, Baba, Tomoyo, Sakaguchi, Yasuyuki, Wakayama, Naomi, Isogai, Ryuto, Yamaura, Yoshiyuki, Komori, Takafumi, Furihata, Tomomi
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.07.2022; Springer; Springer Nature B.V
• Subjects: Analysis; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Blood-brain barrier; Brain; Cell culture; Central nervous system; Drug development; Drugs; Feasibility studies; Medical Law; Membrane permeability; Methods; Permeability; Pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Regression analysis; Research Paper; Rhodamine; Rivastigmine; Drug development; Immortalized cell; Physiologically based pharmacokinetic modeling; Central nervous system; Blood–brain barrier
• ISSN: 0724-8741; 1573-904X; 1573-904X
• DOI: 10.1007/s11095-022-03189-y

Purpose In vitro human blood–brain barrier (BBB) models in combination with central nervous system-physiologically based pharmacokinetic (CNS-PBPK) modeling, hereafter referred to as the “BBB/PBPK” method, are expected to contribute to prediction of brain drug concentration profiles in humans. As part of our ongoing effort to develop a BBB/PBPK method, we tried to clarify the relationship of in vivo BBB permeability data to those in vitro obtained from a human immortalized cell-based tri-culture BBB model (hiBBB), which we have recently created. Methods The hiBBB models were developed and functionally characterized as previously described. The in vitro BBB permeabilities (Pe, × 10 –6  cm/s) of seventeen compounds were determined by permeability assays, and in vivo BBB permeabilities (Q ECF ) for eight drugs were estimated by CNS-PBPK modeling. The correlation of the Pe values with the Q ECF values was analyzed by linear regression analysis. Results The hiBBB models showed intercellular barrier properties and several BBB transporter functions, which were enough to provide a wide dynamic range of Pe values from 5.7 ± 0.7 (rhodamine 123) to 2580.4 ± 781.9 (rivastigmine). Furthermore, the in vitro Pe values of the eight drugs showed a good correlation (R 2  = 0.96) with their in vivo Q ECF values estimated from human clinical data. Conclusion We show that in vitro human BBB models provide clinically relevant BBB permeability that can be used as input for CNS-PBPK modeling. Therefore, our findings will encourage the development of a BBB/PBPK method as a promising approach for predicting brain drug concentration profiles in humans.