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

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

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

T Karelina et al. CPT Pharmacometrics Syst Pharmacol. .
Free PMC article

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.

Figures

Figure 1
Figure 1
Schematic representation of processes considered in the model. (a) Processes related to endogenous Aβ40. Dashed arrows stand for transport with bulk flow. Solid arrows designate reactions, biosynthesis, degradations and transport mediated by proteins (uptake, efflux, and transcytosis). List of abbreviations:  CBC99, CBIF99, COT99 are C99 in brain cells (BC), brain interstitial fluid (BIF) and other tissues (OT), respectively,  ABC40, ABIF40,  ACSF40,  APL40, AOT40 are Aβ40 in BC, BIF, CSF, PL, and OT, respectively. Processes designation: synthesis of amyloid β precursor protein C99 in BC, BIF, OT  VrelBC, VrelBIF, VrelOT, respectively; transformation of C99 to Aβ (Aβ hereafter refers to both Aβ40 and Aβ42 unless specified) catalyzed by γ‐secretase in BC, BIF, and OT (processes VgsBC40, VgsBIF40, VgsOT40); Bulk phase (nonreceptor‐mediated) degradation of Aβ in BC, BIF, and OT (processes VdegBC40, VdegBIF40, VdegOT40); transport of Aβ between BC and BIF (processes VtrBIF_BC40); transport of Aβ with bulk flow from BIF to cerebrospinal fluid (CSF), from BIF to plasma (PL) and from CSF to PL (processes VflowBIF_CSF40, VflowBIF_PL40, VflowCSF_PL40); protein‐mediated transport of Aβ via BBB (between PL and BIF), via BCSFB (between PL and CSF) and between PL and OT (processes VtrPL_BIF40,  VtrPL_CSF40, VtrPL_OT40); degradation of Aβ during passage through BBB (between PL and BIF), BCSFB (between PL and CSF) and between PL and OT (processes VdegPL_BIF40,  VdegPL_CSF40, VdegPL_OT40). (b) Complete scheme of the model for all species: left part, endogenous Aβ species; right, labeled Aβ. Processes are analogous to (a), but names are not given for simplification. Red asterisk indicates 13C‐label or 125I‐label. List of abbreviations:  CBC99, CBIF99, COT99 and CBC99, CBIF99, COT99 are endogenous and 13C‐labeled C99 in BC, BIF, and OT, respectively;  ABC40, ABIF40,  ACSF40,  APL40, AOT40 and ABC40, ABIF40,  ACSF40,  APL40, AOT40 are endogenous and 13C‐labeled (125I‐labeled) Aβ40 in BC, BIF, CSF, PL, and OT, respectively;  ABC42, ABIF42,  ACSF42,  APL42, AOT42 and ABC42, ABIF42,  ACSF42,  APL42, AOT42 are endogenous and 13C‐labeled (125I‐labeled) Aβ42 in BC, BIF, CSF, PL, and OT, respectively.
Figure 2
Figure 2
Verification of the model on the mouse data. (a) Steady state concentrations of Aβ40 and Aβ42 in mouse brain, CSF, and PL . Experimental data were taken from Ref. 45. Bars for experiments represent mean from across different animals (from 6 to 60 animals for different data items), bars for model represent average population model prediction. (b) Aβ40 (expressed in % of steady state baseline level) in brain, CSF, and plasma, and Aβ42 in brain in the mouse treated with a single dose of 30 or 150 mg/kg of avagacestat. Symbols represent data10 and curves model simulations. Plasma Aβ40 and brain Aβ42 were not used during the fitting.
Figure 3
Figure 3
Verification of the model on the human and monkey data. (a) Steady‐state concentrations of Aβ40 and Aβ42 in brain, CSF, and PL for healthy (green) and AD (red) humans (used for fitting) and monkey (yellow, not used for fitting) predicted by the model (95% CI). Prediction for monkey was obtained by allometric scaling from human model. Experimental data (points with SE) were taken from Refs. 27, 28, 29, 30, 31,45–59. (b) Verification of the model against avagacestat data. Time dependence of Aβ40, Aβ42 in CSF and Aβ40 in plasma resulted from single administration of 50, 200 and 400 mg of avagacestat to healthy subjects. Aβ40 is expressed as % of steady state base level (placebo adjusted). Dots correspond to measured data taken from Refs. 8,11,17,50; lines denote confidence bands and median calculated by the model and Hessian for human‐fitted parameters.
Figure 4
Figure 4
Comparison of avagacestat dose‐effect (a) and exposure‐response (b) relationships for mouse and humans (healthy and AD individuals). (a) Dose dependence of amplitude of Aβ40 and Aβ42 decrease resulting from single dose administration of avagacestat (expressed as % of steady state base level) in mouse (green line) healthy human (blue line), and AD human in brain (red line) and CSF; (b) dependence of Aβ40 and Aβ40 AUEC (area under effect curve) from avagacestat AUC (area under curve for concentration). Symbols correspond to measured data: circles correspond to data used for fitting,10 crosses correspond to data used for validation of human CSF predictions,8, 11, 17, 50 and mouse brain Aβ42. 10
Figure 5
Figure 5
Simulations of Aβ42 (given in nM) maximal inhibition during multiple dosing (3 days) in AD subjects. (a) Comparison of predicted confidence bands (obtained by 4,200 replicates from log‐normal distribution of parameters using Hessian matrix) for BC and BIF Aβ42 minimal concentrations during 3 days of GSI administration once daily with levels supposed to be safe (or normal). Solid and dashed lines, confidence bands calculated by the model; colored regions, regions of physiologically safe values. Calculations were made for doses from 5 mg to 10,000 mg. (b) Simulation of Aβ42 inhibition dynamics for 3 days of different dosing regimens of avagacestat: comparison of Aβ42 in BC (upper panel) and BIF (lower panel) with normal values; q.d., once a day; b.i.d., twice a day; t.i.d., three times a day; q.i.d., four times a day. (c) AUC for different avagacestat dosing regimens.

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