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.
Keywords: Aβ, experimentation, quantitative modeling, efficiency, drug discovery
Citation: Lu Y (2012) Integrating experimentation and quantitative modeling to enhance discovery of beta amyloid lowering therapeutics for Alzheimer’s disease. Front. Pharmacol. 3:177. doi: 10.3389/fphar.2012.00177
Received: 24 June 2012; Accepted: 14 September 2012;
Published online: 04 October 2012.
Edited by:David Riddell, Pfizer, USA
Reviewed by:Marcus Rattray, University of Reading, UK
Copyright: © 2012 Lu. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: Yasong Lu, Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Mail Stop #220-4546, Eastern Point Road, Groton, CT 06340, USA. e-mail: firstname.lastname@example.org