Population PKPD Modeling of BACE1 Inhibitor-Induced Reduction in Aβ Levels In Vivo and Correlation to In Vitro Potency in Primary Cortical Neurons from Mouse and Guinea Pig

Janson, Juliette; Eketjäll, Susanna; Tunblad, Karin; Jeppsson, Fredrik; Berg, Stefan von; Niva, Camilla; Radesäter, Ann-Cathrin; Fälting, Johanna; Visser, Sandra A.G.

doi:10.1007/s11095-013-1189-y

Cited by 9 publications

(11 citation statements)

References 56 publications

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“…Additionally, computational models, such as in vitro-in vivo extrapolation (IVIVE), physiologically based pharmacokinetic (PBPK), and pharmacodynamics (PD) modeling, are currently applied in the field of toxicology and regulatory testing, but might be suitable to define kinetics and dynamics of compound exposure, predict their long term effects in relation to AD [47, 48, 112], and assess therapeutic potential of novel compounds for AD treatment [113–115]. …”

Section: Limitations Of Alternative Approaches and Strategies To Overmentioning

confidence: 99%

Alzheimer disease research in the 21st century: past and current failures, new perspectives and funding priorities

et al. 2016

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Much of Alzheimer disease (AD) research has been traditionally based on the use of animals, which have been extensively applied in an effort to both improve our understanding of the pathophysiological mechanisms of the disease and to test novel therapeutic approaches. However, decades of such research have not effectively translated into substantial therapeutic success for human patients. Here we critically discuss these issues in order to determine how existing human-based methods can be applied to study AD pathology and develop novel therapeutics. These methods, which include patient-derived cells, computational analysis and models, together with large-scale epidemiological studies represent novel and exciting tools to enhance and forward AD research. In particular, these methods are helping advance AD research by contributing multifactorial and multidimensional perspectives, especially considering the crucial role played by lifestyle risk factors in the determination of AD risk. In addition to research techniques, we also consider related pitfalls and flaws in the current research funding system. Conversely, we identify encouraging new trends in research and government policy. In light of these new research directions, we provide recommendations regarding prioritization of research funding. The goal of this document is to stimulate scientific and public discussion on the need to explore new avenues in AD research, considering outcome and ethics as core principles to reliably judge traditional research efforts and eventually undertake new research strategies.

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Section: Limitations Of Alternative Approaches and Strategies To Overmentioning

confidence: 99%

Alzheimer disease research in the 21st century: past and current failures, new perspectives and funding priorities

et al. 2016

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“…Several studies on the pharmacokinetics (PK) and the pharmacodynamics (PD) of BACE1 and g-secretase inhibitors have been reported (Lu et al, 2012(Lu et al, , 2013Parkinson et al, 2013;Janson et al, 2014). Liu et al (2013) proposed a mechanistic PK-PD model of BACE1 inhibition in monkeys.…”

Section: Introductionmentioning

confidence: 99%

Systems Pharmacology Analysis of the Amyloid Cascade after -Secretase Inhibition Enables the Identification of an A 42 Oligomer Pool

Maanen

Steeg

Michener

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The deposition of amyloid-b (Ab) oligomers in brain parenchyma has been implicated in the pathophysiology of Alzheimer's disease. Here we present a systems pharmacology model describing the changes in the amyloid precursor protein (APP) pathway after administration of three different doses (10, 30, and 125 mg/kg) of the b-secretase 1 (BACE1) inhibitor MBi-5 in cisterna magna ported rhesus monkeys. The time course of the MBi-5 concentration in plasma and cerebrospinal fluid (CSF) was analyzed in conjunction with the effect on the concentrations of the APP metabolites Ab42, Ab40, soluble b-amyloid precursor protein (sAPP) a, and sAPPb in CSF. The systems pharmacology model contained expressions to describe the production, elimination, and brain-to-CSF transport for the APP metabolites.Upon administration of MBi-5, a dose-dependent increase of the metabolite sAPPa and dose-dependent decreases of sAPPb and Ab were observed. Maximal inhibition of BACE1 was close to 100% and the IC 50 value was 0.0256 mM (95% confidence interval, 0.0137-0.0375). A differential effect of BACE1 inhibition on Ab40 and Ab42 was observed, with the Ab40 response being larger than the Ab42 response. This enabled the identification of an Ab42 oligomer pool in the systems pharmacology model. These findings indicate that decreases in monomeric Ab responses resulting from BACE1 inhibition are partially compensated by dissociation of Ab oligomers and suggest that BACE1 inhibition may also reduce the putatively neurotoxic oligomer pool.

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“…Novel computational models that are currently applied in toxicology, such as in vitro-in vivo extrapolation, physiologically based pharmacokinetic and pharmacodynamics modeling, suitable to define kinetics and dynamics of compound exposure and to predict chemical long term effects [119], might be applied to predict the absorption, distribution, metabolism, and excretion of chemicals, such as chlorpyrifos [120] and manganese [121], both implicated in A␤ deposition [47,122], and also to assess the efficacy of compounds for AD treatment, such as ␤-secretase inhibitors [123], the bioactive phytocompound curcumin [124], and APOE 4 inhibitors [125].…”

Section: Computational Models Data Extrapolation and Functional Stumentioning

confidence: 99%

A Human-Based Integrated Framework forAlzheimer’s Disease Research

Pistollato

Cavanaugh

Chandrasekera

2015

JAD

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Abstract. Animal models of Alzheimer's disease (AD) have been extensively utilized for decades in an effort to elucidate the pathophysiological mechanisms of this disease and to test novel therapeutic approaches. However, research success has not effectively translated into therapeutic success for human patients. This translational failure is partially due to the overuse of animal models that cannot accurately recapitulate human AD etiopathogenesis or drug responses and the inadequate use of human-relevant research methods. Here, we propose how to mitigate this translational barrier by employing human-based methods to elucidate disease processes occurring at multiple levels of complexity, accounting for gene and protein expression and the impact of disease at the cellular, tissue/organ, individual, and population levels. In particular, novel human-based cellular and computational models, together with epidemiological and clinical studies, represent the ideal tools to facilitate human-relevant data acquisition, in the effort to better elucidate AD pathogenesis in a human-based setting and design more effective treatments and preventive strategies. Our analysis indicates that a paradigm shift toward human-based, rather than animal-based research is required in the face of the ever-increasing prevalence of AD in the 21st century.

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Population PKPD Modeling of BACE1 Inhibitor-Induced Reduction in Aβ Levels In Vivo and Correlation to In Vitro Potency in Primary Cortical Neurons from Mouse and Guinea Pig

Abstract: The strong in vivo-in vitro correlation increased the confidence in using human cell lines for screening and optimization of BACE1 inhibitors. This can optimize the design and reduce the number of preclinical in vivo effect studies.

Cited by 9 publications

References 56 publications

Alzheimer disease research in the 21st century: past and current failures, new perspectives and funding priorities

Alzheimer disease research in the 21st century: past and current failures, new perspectives and funding priorities

Systems Pharmacology Analysis of the Amyloid Cascade after -Secretase Inhibition Enables the Identification of an A 42 Oligomer Pool

A Human-Based Integrated Framework forAlzheimer’s Disease Research

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