Abstract
This review focuses on a discussion of the controversies in allometric scaling (AS) for predicting human clearance from a mathematical and statistical perspective. First, a history of allometric scaling in comparative biology and its use in pharmacokinetics are reviewed. It is shown that the application of AS in predicting human clearance values based on a limited number of animal species (typically, 3 or 4) contains fundamental statistical errors from when AS was first introduced from comparative biology. Second, the mathematical nature of various allometrically-based methods is revealed and the soundness of these methods is assessed. It is demonstrated that any of these methods, which incorporate a correction factor in a traditional allometric approach (varying-exponent allometry), not only reduces the statistical power of the allometric analysis, but are also incorrect with regard to aspects of biology. Finally, it is concluded that allometry remains a valuable tool for predicting human clearance, and should be applied in the context of a fixed exponent. However, fixed-exponent allometry does not provide satisfactory accuracy in predicting human clearance, since it is not able to capture the biological differences among species. Therefore, it is recommended that the overall effort in predicting human pharmacokinetics should be directed to the collection and generation of reliable data (both in vitro and in vivo) along with a better understanding of the DMPK properties of the chemical entity.
Keywords: Clearance, fixed-exponent allometry, varying-exponent allometry, in vitro-in vivo extrapolation
Current Topics in Medicinal Chemistry
Title: Controversies in Allometric Scaling for Predicting Human Drug Clearance: An Historical Problem and Reflections on What Works and What Does Not
Volume: 11 Issue: 4
Author(s): Huadong Tang and Michael Mayersohn
Affiliation:
Keywords: Clearance, fixed-exponent allometry, varying-exponent allometry, in vitro-in vivo extrapolation
Abstract: This review focuses on a discussion of the controversies in allometric scaling (AS) for predicting human clearance from a mathematical and statistical perspective. First, a history of allometric scaling in comparative biology and its use in pharmacokinetics are reviewed. It is shown that the application of AS in predicting human clearance values based on a limited number of animal species (typically, 3 or 4) contains fundamental statistical errors from when AS was first introduced from comparative biology. Second, the mathematical nature of various allometrically-based methods is revealed and the soundness of these methods is assessed. It is demonstrated that any of these methods, which incorporate a correction factor in a traditional allometric approach (varying-exponent allometry), not only reduces the statistical power of the allometric analysis, but are also incorrect with regard to aspects of biology. Finally, it is concluded that allometry remains a valuable tool for predicting human clearance, and should be applied in the context of a fixed exponent. However, fixed-exponent allometry does not provide satisfactory accuracy in predicting human clearance, since it is not able to capture the biological differences among species. Therefore, it is recommended that the overall effort in predicting human pharmacokinetics should be directed to the collection and generation of reliable data (both in vitro and in vivo) along with a better understanding of the DMPK properties of the chemical entity.
Export Options
About this article
Cite this article as:
Tang Huadong and Mayersohn Michael, Controversies in Allometric Scaling for Predicting Human Drug Clearance: An Historical Problem and Reflections on What Works and What Does Not, Current Topics in Medicinal Chemistry 2011; 11 (4) . https://dx.doi.org/10.2174/156802611794480945
DOI https://dx.doi.org/10.2174/156802611794480945 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Lipid-Lowering Therapy in HIV-Infected Patients: Relationship with Antiretroviral Agents and Impact of Substance-Related Disorders
Current Vascular Pharmacology Quantitative Analysis of Microbial Metabolism in the Human Large Intestine
Current Nutrition & Food Science From Natural Products to Designer Drugs: Development and Molecular Mechanisms Action of Novel Anti-Microtubule Breast Cancer Therapeutics
Current Topics in Medicinal Chemistry The Use of Nitric Oxide Synthase Inhibitors in Inflammatory Diseases: A Novel Class of Anti-Inflammatory Agents
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Perfusion Computed Tomography and its Application in Oncologic Practice
Current Molecular Imaging (Discontinued) Cellular and Physiological Effects of Probiotics and Prebiotics
Mini-Reviews in Medicinal Chemistry Immunotherapy for Conformational Diseases
Current Pharmaceutical Design Colchicine, Biologic Agents and More for the Treatment of Familial Mediterranean Fever. The Old, the New, and the Rare
Current Medicinal Chemistry A Phosphoproteomics Approach to Identify Candidate Kinase Inhibitor Pathway Targets in Lymphoma-Like Primary Cell Lines
Current Drug Discovery Technologies Hypoxia-Inducible Factor-1 in Arterial Disease: A Putative Therapeutic Target
Current Vascular Pharmacology Development of Global Consensus of Dengue Virus Envelope Glycoprotein for Epitopes Based Vaccine Design
Current Computer-Aided Drug Design Personalizing Medicine from Birth: Are Countries Prepared for the Ethical, Legal, and Social Challenges?
Current Pharmacogenomics and Personalized Medicine Statin Treatment Non-adherence and Discontinuation: Clinical Implications and Potential Solutions
Current Pharmaceutical Design Changing Pain Management Strategy from Opioid-centric Towards Improve Postoperative Cognitive Dysfunction with Dexmedetomidine
Current Drug Metabolism Current and Emerging Therapies in Neuroendocrine Tumors: Impact of Genetic Targets on Clinical Outcomes
Clinical Cancer Drugs Determination of Residual Solvents in Eprosartan Mesylate by Static Headspace Gas Chromatographic Method Optimized by Response Surface Methodology
Current Pharmaceutical Analysis Knowledge, Attitude, and Behavior in Avoiding Environmental Tobacco Smoke Exposure at Home among Pregnant Women
Current Women`s Health Reviews Hyaluronic Acid: The Reason for Its Variety of Physiological and Biochemical Functional Properties
Applied Clinical Research, Clinical Trials and Regulatory Affairs Adverse Drug Reactions Related to Drug Administration in Hospitalized Patients
Current Drug Safety Protocatechuic Acid Alkyl Esters: Hydrophobicity As a Determinant Factor for Inhibition of NADPH Oxidase
Current Medicinal Chemistry