Prediction of Human Brain Penetration of P-glycoprotein and Breast Cancer Resistance Protein Substrates Using In Vitro Transporter Studies and Animal Models

Four P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrates with human cerebrospinal fluid (CSF) concentrations and preclinical neuropharmacokinetics were used to assess in vitro-in vivo extrapolation of brain penetration in preclinical species and the ability to predict human brain penetration. Unbound brain (C-b,C-u), unbound plasma (C-p,C-u), and CSF compound concentrations (C-CSF) were measured in rats and nonhuman primates (NHPs), and the unbound partition coefficients (C-b,C-u/C-p,C-u and C-CSF/C-p,C-u) were used to assess brain penetration. The results indicated that for P-gp and BCRP dual substrates, brain penetration was severally impaired in all species. In comparison, for P-gp substrates that are weak or non-BCRP substrates, improved brain penetration was observed in NHPs and humans than in rats. Overall, NHP appears to be more predictive of human brain penetration for P-gp substrates with weak or no interaction with BCRP than rat. Although C-CSF does not quantitatively correspond to C-b,C-u for efflux transporter substrates, it is mostly within 3-fold higher of C-b,C-u in rat and NHP, suggesting that C-CSF can be used as a surrogate for C-b,C-u. Taken together, a holistic approach including both in vitro transporter and in vivo neuropharmacokinetics data enables a better estimation of human brain penetration of P-gp/BCRP substrates. (C) 2018 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.