Differences in P-glycoprotein activity in human and rodent blood\u2013brain barrier assessed by mechanistic modelling

Laurens F M Verscheijden,Jan B Koenderink,Saskia N De Wildt,Frans G M Russel

doi:10.1007/s00204-021-03115-y

Abstract

Variation in the efficacy and safety of central nervous system drugs between humans and rodents can be explained by physiological differences between species. An important factor could be P-glycoprotein (Pgp) activity in the blood–brain barrier (BBB), as BBB expression of this drug efflux transporter is reportedly lower in humans compared to mouse and rat and subject to an age-dependent increase. This might complicate animal to human extrapolation of brain drug disposition and toxicity, especially in children. In this study, the potential species-specific effect of BBB Pgp activity on brain drug exposure was investigated. An age-dependent brain PBPK model was used to predict cerebrospinal fluid and brain mass concentrations of Pgp substrate drugs. For digoxin, verapamil and quinidine, in vitro kinetic data on their transport by Pgp were derived from literature and used to scale to in vivo parameters. In addition, age-specific digoxin transport was simulated for children with a postnatal age between 25 and 81 days. BBB Pgp activity in the model was optimized using measured CSF data for the Pgp substrates ivermectin, indinavir, vincristine, docetaxel, paclitaxel, olanzapine and citalopram, as no useful in vitro data were available. Inclusion of Pgp activity in the model resulted in optimized predictions of their brain concentration. Total brain-to-plasma AUC values (Kp,brain) in the simulations without Pgp were divided by the Kp,brain values with Pgp. Kp ratios ranged from 1 to 45 for the substrates investigated. Comparison of human with rodent Kp,brain ratios indicated ≥ twofold lower values in human for digoxin, verapamil, indinavir, paclitaxel and citalopram and ≥ twofold higher values for vincristine. In conclusion, BBB Pgp activity appears species-specific. An age-dependent PBPK model-based approach could be useful to extrapolate animal data to human adult and paediatric predictions by taking into account species-specific and developmental BBB Pgp expression.

Highlights

Rodent studies are performed during non-clinical development of drug candidates for the assessment of their effectivity and safety
Human model-based predictions for digoxin, verapamil, indinavir, paclitaxel and citalopram resulted in ≥ twofold lower Kp ratios compared to rodent studies
Transport across the blood–brain barrier was modelled for drugs that enter the brain via passive diffusion only and for typical P-gp drug substrates

Summary

Introduction

Rodent studies are performed during non-clinical development of drug candidates for the assessment of their effectivity and safety. Species differences in Pgp expression and activity could result in an inaccurate estimate of xenobiotic BBB penetration and neurotoxic. Previous studies suggested that Pgp expression is lower in humans compared to rodents (Al Feteisi et al 2018; Uchida et al 2011). Prediction of Pgp activity is complicated by differences in expression between subgroups, as, for instance, Pgp expression in children is lower compared to adults, potentially making this population more susceptible to higher substrate brain exposures (Lam et al 2015; Verscheijden et al 2020b)

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Results

Conclusion