Translational CNS Steady-State Drug Disposition Model in Rats, Monkeys, and Humans for Quantitative Prediction of Brain-to-Plasma and Cerebrospinal Fluid-to-Plasma Unbound Concentration Ratios

Abstract

Capturing unbound drug exposure in the brain is crucial to evaluate pharmacological effects for drugs acting on the central nervous system. However, to date, there are no reports of validated prediction models to determine the brain-to-plasma unbound concentration ratio (Kp,uu,brain) as well as the cerebrospinal fluid (CSF)-to-plasma unbound concentration ratio (Kp,uu,CSF) between humans and other species. Here, we developed a translational CNS steady-state drug disposition model to predict Kp,uu,brain and Kp,uu,CSF across rats, monkeys, and humans by estimating the relative activity factors (RAF) for MDR1 and BCRP in addition to scaling factors (γ and σ) using the molecular weight, logD, CSF bulk flow, and in vitro transport activities of these transporters. In this study, 68, 26, and 28 compounds were tested in the rat, monkey, and human models, respectively. Both the predicted Kp,uu,brain and Kp,uu,CSF values were within the 3-fold range of the observed values (71, 73, and 79%; 79, 88, and 78% of the compounds, respectively), indicating successful prediction of Kp,uu,brain and Kp,uu,CSF in the three species. The overall predictivity of the RAF approach is consistent with that of the relative expression factor (REF) approach. As the established model can predict Kp,uu,brain and Kp,uu,CSF using only in vitro and physicochemical data, this model would help avoid ethical issues related to animal use and improve CNS drug discovery workflow.

Evaluation of the reliability and applicability of human unbound brain-to-plasma concentration ratios

“…K p,uu,brain in rats, monkeys and humans, measured and in silico predicted MDR-1 and BCRP substrate specificities and in silico predicted passive P e were used for the analysis. Sato et al 2021 was the main source of rat, monkey and human K p,uu,brain -values and MDR-1 and BCRP substrate specificities. Additional rat and human K p,uu,brain -values were taken from Summerfield et al 2008.…”

“…Blood-brain barrier permeability (BBB P e ) and unbound brain-to-plasma concentration ratio (K p,uu, brain ) are relevant parameters describing the brain uptake potential of compounds (Summerfield et al 2008; Syvänen et al 2009; Chen et al 2011; Sato et al 2021; Loryan et al 2022). BBB efflux by transporter proteins, mainly MDR-1 and BCRP, is an essential factor determining K p,uu, brain (Chen et al 2011; Sato et al 2021; Loryan et al 2022).…”

“…K p,uu,brain -values are commonly estimated in vivo in rats and monkeys and predicted using in silico methodology (Summerfield et al 2008; Syvänen et al 2009; Chen et al 2011; Sato et al 2021; Loryan et al 2022). Provided that there are sufficiently strong correlations between preclinical estimates/models and human clinical values, human K p,uu,brain -values and brain uptake potential can be predicted using such estimates.…”

In Vitro to In Vivo Extrapolation Linked to Physiologically Based Pharmacokinetic Models for Assessing the Brain Drug Disposition

“…Numerous QSAR models have been developed for predicting the log BB (the logarithm value of brain to blood concentration ratio) ( 30 – 32 ) and the log PS (the logarithm value of permeability surface area product) ( 33 – 35 ). As data in humans are sparse these QSAR models are generally established based upon non-human, generally rat data.…”

Unbound Brain-to-Plasma Partition Coefficient, Kp,uu,brain—a Game Changing Parameter for CNS Drug Discovery and Development

“…Furthermore and in parallel, the striving to minimize animal usage and increase throughput led to the development of various in vitro cell culture BBB models (95)(96)(97)(98)(99)(100)(101)(102). For instance, values of apparent permeability (P app ) in cell monolayers have been used to estimate the time required to reach distribution equilibrium between brain and plasma, and bidirectional transporter assays of P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) can provide useful insights on efflux transport at the BBB (59,96,98,(103)(104)(105)(106)(107)(108)(109)(110)(111).…”