Cerebrospinal Fluid Amyloid-beta (A beta) as an Effect Biomarker for Brain A beta Lowering Verified by Quantitative Preclinical Analyses

MS#220-4546, Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.86). 05/2012; 342(2):366-75. DOI: 10.1124/jpet.112.192625
Source: PubMed

ABSTRACT Reducing the generation of amyloid-β (Aβ) in the brain via inhibition of β-secretase or inhibition/modulation of γ-secretase has been pursued as a potential disease-modifying treatment for Alzheimer's disease. For the discovery and development of β-secretase inhibitors (BACEi), γ-secretase inhibitors (GSI), and γ-secretase modulators (GSM), Aβ in cerebrospinal fluid (CSF) has been presumed to be an effect biomarker for Aβ lowering in the brain. However, this presumption is challenged by the lack of quantitative understanding of the relationship between brain and CSF Aβ lowering. In this study, we strived to elucidate how the intrinsic pharmacokinetic (PK)/pharmacodynamic (PD) relationship for CSF Aβ lowering is related to that for brain Aβ through quantitative modeling of preclinical data for numerous BACEi, GSI, and GSM across multiple species. Our results indicate that the intrinsic PK/PD relationship in CSF is predictive of that in brain, at least in the postulated pharmacologically relevant range, with excellent consistency across mechanisms and species. As such, the validity of CSF Aβ as an effect biomarker for brain Aβ lowering is confirmed preclinically. Meanwhile, we have been able to reproduce the dose-dependent separation between brain and CSF effect profiles using simulations. We further discuss the implications of our findings to drug discovery and development with regard to preclinical PK/PD characterization and clinical prediction of Aβ lowering in the brain.

Download full-text


Available from: Douglas S Johnson, Aug 23, 2015
  • Source
    • "Several of the PK-PD models for APP processing largely rely on the effects of g-secretase inhibition on Ab levels (Craft et al., 2002; Lu et al., 2011; Tai et al., 2012). Recently, Lu et al. (2012) reported a PK-PD model for Ab lowering in CSF and brain in rodents. Fig. 4. GNE-892 significantly inhibited BACE1 in cynomolgus monkeys. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This study was conducted to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of two novel inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme (BACE1), GNE-629 and GNE-892, and to develop a PK-PD model to predict in vivo effects based solely on in vitro activity and PK. GNE-629 and GNE-892 concentrations and PD biomarkers including amyloid β (Aβ) in the plasma and cerebrospinal fluid (CSF), and secreted APPβ (sAPPβ) and secreted APPα (sAPPα) in the CSF were measured following a single oral administration of GNE-629 (100 mg/kg) or GNE-892 (30 or 100 mg/kg) in cynomolgus monkeys. A mechanistic PK-PD model was developed to simultaneously characterize the plasma Aβ and CSF Aβ, sAPPα and sAPPβ using GNE-629 in vivo data. This model was used to predict the in vivo effects of GNE-892 following adjustments based on differences in in vitro cellular activity and PK. The PK-PD model estimated GNE-629 CSF and free plasma IC50 of 0.0033 μM and 0.065 μM, respectively. These differences in CSF and free plasma IC50 suggest different mechanisms are involved in Aβ formation in these two compartments. The predicted in vivo effects for GNE-892 using the PK-PD model were consistent with the observed data. In conclusion, a PK-PD model was developed to mechanistically describe the effects of BACE1 inhibition on Aβ, sAPPβ, and sAPPα in the CSF, and Aβ in the plasma. This model can be used to prospectively predict in vivo effects of new BACE1 inhibitors using just their in vitro activity and PK data.
    Drug metabolism and disposition: the biological fate of chemicals 04/2013; 41(7). DOI:10.1124/dmd.112.050864 · 3.33 Impact Factor
  • Source
    • "As long as the PK/PD relationship for Aβ lowering in CSF is consistently related to that in brain, CSF Aβ may serve as a biomarker for brain Aβ lowering despite the discrepancy in Aβ profiles in the two compartments. Our modeling analyses of seven compounds, across the three mechanisms (BACEi, GSI, and GSM), in three species (mouse, rat, and guinea pig) demonstrated a consistent overlap of the intrinsic PK/PD relationships for brain and CSF over the range of 0–50% lowering in R gen (Lu et al., 2012c). This analysis supports CSF Aβ as a potential biomarker for brain Aβ lowering from the clinical trial standpoint. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Drug discovery can benefit from a proactive-knowledge-attainment philosophy which strategically integrates experimentation and pharmacokinetic/pharmacodynamic (PK/PD) modeling. Our programs for Alzheimer's disease (AD) illustrate such an approach. Compounds that inhibit the generation of brain beta amyloid (Aβ), especially Aβ42, are being pursued as potential disease-modifying therapeutics. Complexities in the PK/Aβ relationship for these compounds have been observed and the data require an advanced approach for analysis. We established a semimechanistic PK/PD model that can describe the PK/Aβ data by accounting for Aβ generation and clearance. The modeling characterizes the in vivo PD (i.e., Aβ lowering) properties of compounds and generates insights about the salient biological systems. The learning from the modeling enables us to establish a framework for predicting in vivo Aβ lowering from in vitro parameters.
    Frontiers in Pharmacology 10/2012; 3:177. DOI:10.3389/fphar.2012.00177 · 3.80 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sequential proteolytic cleavage of the amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex produces the amyloid-β peptide (Aβ), which is believed to play a critical role in the pathology of Alzheimer's disease (AD). The aspartyl protease BACE1 catalyzes the rate-limiting step in the production of Aβ, and as such it is considered to be an important target for drug development in AD. The development of a BACE1 inhibitor therapeutic has proven to be difficult. The active site of BACE1 is relatively large. Consequently, to achieve sufficient potency, many BACE1 inhibitors have required unfavorable physicochemical properties such as high molecular weight and polar surface area that are detrimental to efficient passage across the blood-brain barrier. Using a rational drug design approach we have designed and developed a new series of hydroxyethylamine-based inhibitors of BACE1 capable of lowering Aβ levels in the brains of rats after oral administration. Herein we describe the in vitro and in vivo characterization of two of these molecules and the overall relationship of compound properties [e.g., in vitro permeability, P-glycoprotein (P-gp) efflux, metabolic stability, and pharmacological potency] to the in vivo pharmacodynamic effect with more than 100 compounds across the chemical series. We demonstrate that high in vitro potency for BACE1 was not sufficient to provide central efficacy. A combination of potency, high permeability, low P-gp-mediated efflux, and low clearance was required for compounds to produce robust central Aβ reduction after oral dosing.
    Journal of Pharmacology and Experimental Therapeutics 08/2012; 343(2):460-7. DOI:10.1124/jpet.112.197954 · 3.86 Impact Factor
Show more