AAPS J 2021 Jun 3;23(4):81. Epub 2021 Jun 3.
Global DMPK, Preclinical and Translational Sciences, Research, Takeda Pharmaceutical Company Limited, Shonan Health Innovation Park (iPark), 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan.
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 (K) as well as the cerebrospinal fluid (CSF)-to-plasma unbound concentration ratio (K) between humans and other species. Here, we developed a translational CNS steady-state drug disposition model to predict K and K 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. Read More