Practical Anticipation of Human Efficacious Doses and Pharmacokinetics Using In Vitro and Preclinical In Vivo Data
Journal Title: The AAPS Journal - Year 2009, Vol 11, Issue 3
Abstract
Accurate predictions of human pharmacokinetic and pharmacodynamic (PK/PD) profiles are critical in early drug development, as safe, efficacious, and “developable” dosing regimens of promising compounds have to be identified. While advantages of successful integration of preclinical PK/PD data in the “anticipation” of human doses (AHD) have been recognized, pharmaceutical scientists have faced difficulties with practical implementation, especially for PK/PD profile projections of compounds with challenging absorption, distribution, metabolism, excretion and formulation properties. In this article, practical projection approaches for formulation-dependent human PK/PD parameters and profiles of Biopharmaceutics Classification System classes I-IV drugs based on preclinical data are described. Case examples for “AHD” demonstrate the utility of preclinical and clinical PK/PD modeling for formulation risk identification, lead candidate differentiation, and prediction of clinical outcome. The application of allometric scaling methods and physiologically based pharmacokinetic approaches for clearance or volume of distribution projections is described using GastroPlus™. Methods to enhance prediction confidence such as in vitro–in vivo extrapolations in clearance predictions using in vitro microsomal data are discussed. Examples for integration of clinical PK/PD and formulation data from frontrunner compounds via “reverse pharmacology strategies” that minimize uncertainty with PK/PD predictions are included. The use of integrated softwares such as GastroPlus™ in combination with established PK projection methods allow the projection of formulation-dependent preclinical and human PK/PD profiles required for compound differentiation and development risk assessments.
Authors and Affiliations
Tycho Heimbach, Suresh B. Lakshminarayana, Wenyu Hu, Handan He
Keywords
Related Articles
- EP ID EP681491
- DOI 10.1208/s12248-009-9136-x
- Views 64
- Downloads 0
New Frontiers—Accelerator Mass Spectrometry (AMS): Recommendation for Best Practices and Harmonization from Global Bioanalysis Consortium Harmonization Team
The technique of accelerator mass spectrometry (AMS) is applicable to the analysis of a wide range of trace elemental isotopes. However, in the context of the pharmaceutical industry, it is invariably used to measure rad...
Resistance to the Translation Initiation Inhibitor Silvestrol is Mediated by ABCB1/P-Glycoprotein Overexpression in Acute Lymphoblastic Leukemia Cells
Protein synthesis is a powerful therapeutic target in leukemias and other cancers, but few pharmacologically viable agents are available that affect this process directly. The plant-derived agent silvestrol specifically...
Effect of nonionic surfactant on transport of surface-active and non-surface-active model drugs and emulsion stability in triphasic systems
Role of bioactivation in drug-induced hypersensitivity reactions
Drug-induced hypersensitivity reactions are a major problem in both clinical treatment and drug development. This review covers recent developments in our understanding of the pathogenic mechanisms involved, with special...
Activation of G-proteins in brain by endogenous and exogenous cannabinoids
The biological response to cannabinoid agonist begins when the agonist-bound receptor activates G-protein Gα subunits, thus initiating a cascade of signal transduction pathways. For this reason, information about...