Alberto Russu (1), Johannes Streffer (2), Luc Tritsmans (3), An Vermeulen (1)
(1) Model Based Drug Development, (2) Experimental Medicine, and (3) Neuroscience Development, Janssen Research & Development, Beerse, Belgium
Objectives: Amyloid reduction via BACE inhibition is a potential therapeutic target in Alzheimer’s Disease [1]. JNJ-54861911 is a potent oral BACE inhibitor tested in Phase I clinical trials [2]. The objectives of this work are: (i) to model the plasma and CSF pharmacokinetics (PK) of JNJ-54861911, (ii) to model the pharmacodynamic (PD) effect of JNJ-54861911 on CSF Abeta1-40 reduction as a marker of target engagement, and (iii) to assess the dose- and exposure-response of JNJ-54861911 on CSF Abeta1-40 after repeated daily dosing.
Methods: Plasma and CSF concentrations of JNJ-54861911, dosed as a suspension or a tablet, were obtained from healthy elderly volunteers in a Phase 1 multiple ascending dose trial, and analyzed via population PK modeling with NONMEM 7.1.0 [3]. Serial CSF samples to assess JNJ-54861911 PK and the time course of amyloid markers were obtained via 36-hour catheterization [2]. Drug effect was modeled by linking JNJ-54861911 CSF concentrations to CSF Abeta1-40 reduction via a semi-mechanistic indirect response PK/PD model (see e.g. [4]).
Results: A two-compartment PK model with sequential zero and first order absorption with linear disposition captured the PK of JNJ-54861911 in plasma. Individual CSF PK profiles were essentially parallel to the respective plasma profiles and were described as a scaled version of the plasma concentration (mean ratio between CSF and free plasma concentration = 62%, plasma free fraction = 6%). JNJ-54861911 resulted in a potent and sustained CSF Abeta1-40 reduction (plasma IC50 = 21ng/mL; apparent CSF Abeta1-40 turnover half-life = 13h). Simulation of steady-state average CSF Abeta1-40 reduction evidenced that (i) a dose of 10mg q.d. results in >50% reduction in the majority of subjects, (ii) a dose of 25mg q.d. attains robust (>80%) reduction in most subjects, and (iii) Abeta reduction approaches 90% at a dose of 50mg q.d. and improves only marginally for higher doses.
Conclusions: The integrated, semi-mechanistic population PK/PD model captured the time course of JNJ-54861911 PK and allowed to link plasma concentrations to CSF concentrations, which are possibly reflective of brain penetration [5]. Modeling and simulation of CSF Abeta1-40 time course helped to quantify the dose- and exposure-response of JNJ-54861911 and allowed to infer a potential range of therapeutic doses for long-term treatment.
References:
[1] Karran E, Mercken M, Strooper BD. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 2011; 10:698-712
[2] Timmers M, Van Broeck B, Slemmon J et al. Profiling the dynamics of CSF and plasma Abeta reduction with JNJ-54861911, an oral BACE inhibitor. 12th International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders (AD/PD) 2015, Nice, France, March 2015
[3] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA
[4] Liu X, Wong H, Scearce-Levie K et al. Mechanistic pharmacokinetic-pharmacodynamic modeling of BACE1 inhibition in monkeys: Development of a predictive model for amyloid precursor protein processing. Drug Metab Dispos 2013; 41:1319-1328
[5] Westerhout J, Ploeger B, Smeets J et al. Physiologically based pharmacokinetic modeling to investigate regional brain distribution kinetics in rats. AAPS J 2012; 14:543-553
Reference: PAGE 24 (2015) Abstr 3479 [www.page-meeting.org/?abstract=3479]
Poster: Drug/Disease modeling - CNS