A Translational Systems Pharmacology Model for Aβ Kinetics in Mouse, Monkey, and Human

CPT Pharmacometrics Syst Pharmacol. 2017 Oct;6(10):666-675. doi: 10.1002/psp4.12211. Epub 2017 Aug 10.

Abstract

A mechanistic model of amyloid beta production, degradation, and distribution was constructed for mouse, monkey, and human, calibrated and externally verified across multiple datasets. Simulations of single-dose avagacestat treatment demonstrate that the Aβ42 brain inhibition may exceed that in cerebrospinal fluid (CSF). The dose that achieves 50% CSF Aβ40 inhibition for humans (both healthy and with Alzheimer's disease (AD)) is about 1 mpk, one order of magnitude lower than for mouse (10 mpk), mainly because of differences in pharmacokinetics. The predicted maximal percent of brain Aβ42 inhibition after single-dose avagacestat is higher for AD subjects (about 60%) than for healthy individuals (about 45%). The probability of achieving a normal physiological level for Aβ42 in brain (1 nM) during multiple avagacestat dosing can be increased by using a dosing regimen that achieves higher exposure. The proposed model allows prediction of brain pharmacodynamics for different species given differing dosing regimens.

MeSH terms

  • Algorithms
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / chemistry*
  • Animals
  • Brain / metabolism*
  • Dose-Response Relationship, Drug
  • Female
  • Haplorhini
  • Humans
  • Kinetics
  • Mice
  • Models, Statistical*
  • Oxadiazoles / pharmacology*
  • Sulfonamides / pharmacology*
  • Translational Medical Research

Substances

  • Amyloid beta-Peptides
  • BMS 708163
  • Oxadiazoles
  • Sulfonamides