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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

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Abstract

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 (QECF) for eight drugs were estimated by CNS-PBPK modeling. The correlation of the Pe values with the QECF 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 (R2 = 0.96) with their in vivo QECF 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.

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Abbreviations

BBB:

Blood-brain barrier

CNS:

Central nervous system

HBMEC:

Human brain microvascular endothelial cells

HASTR:

Human astrocytes

HBPC:

Human brain pericytes

prHBMEC:

Primary human BMEC

hprBBB:

Primary HBMEC-based BBB models

hiBBB:

Human immortalized cell-based BBB models

tsSV40T:

Temperature sensitive simian virus 40 large tumor-antigen

SLC:

Solute carrier

ABC:

ATP Binding Cassette

P-gp:

P-glycoprotein

BCRP:

Breast cancer resistance protein

LAT1:

L-type amino acid transporter 1

H+/OC antiporter:

Proton/organic cation antiporter

VE-cadherin:

Vascular endothelial-cadherin

ZO-1:

Zonula occludens 1

JAM-A:

Junctional adhesion molecule A

GLUT1:

Glucose transporter 1

TfR:

Transferrin receptor

FcRn:

Neonatal Fc receptor

INSR:

Insulin receptor

MFSD2A:

The major facilitator superfamily domain containing 2A

qPCR:

Quantitative real-time PCR

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

TEER:

Trans-endothelial electrical resistance

LY:

Lucifer yellow

R123:

Rhodamine123

CysA:

Cyclosporin A

ER:

Efflux ratio

Pe:

Permeability coefficient

IVIVC:

In vitro-in vivo Correlation

fu, p :

Drug unbound fraction in the plasma

NONMEM:

Non-linear mixed effect model

ECF:

Extracellular fluid

LV:

Lateral ventricle

TFV:

Third and fourth ventricle

CM:

Cisterna magna

SAS:

Subarachnoid space

CSF:

Cerebrospinal fluid

PK:

Pharmacokinetics

PPK:

Population PK

PBPK:

Physiologically based pharmacokinetics

LC–MS/MS:

Liquid chromatography with tandem mass spectrometry

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Acknowledgements

This work was supported by research funds from Eisai (Tokyo, Japan) and Ono Pharmaceuticals (Osaka, Japan), and partly by grants from JSPS KAKENHI (19K07214), and AMED under Grant Number JP17be0304322h0001. Otherwise, we have no financial relationship to disclose for this manuscript.

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Authors and Affiliations

  1. Research Center of Neurology, Ono Pharmaceutical Co., Ltd., Osaka, Japan

    Ryo Ito

  2. Laboratory of Clinical Pharmacy & Experimental Therapeutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan

    Hanae Morio, Tomoyo Baba, Yasuyuki Sakaguchi, Ryuto Isogai & Tomomi Furihata

  3. Global Drug Metabolism and Pharmacokinetics Tsukuba, Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan

    Naomi Wakayama & Takafumi Komori

  4. Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka, Japan

    Yoshiyuki Yamaura

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  1. Ryo Ito
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Correspondence to Tomomi Furihata.

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Conflict of interest

Conflict of interest statements related to research funds are provided in the acknowledgement section, and the model development method herein has been applied for a patent (No. 2020–065670). There is another related patent application (No. 2020–007041). The authors declare that they do not have any other conflicts of interest.

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Ito, R., Morio, H., Baba, T. et al. 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. Pharm Res 39, 1575–1586 (2022). https://doi.org/10.1007/s11095-022-03189-y

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