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
-
Discovery of Small Molecule c-Met Inhibitors: Evolution and Profiles of Clinical Candidates
Anti-Cancer Agents in Medicinal Chemistry The Interaction Between Gender and Diabetes Mellitus in the Coronary Heart Disease Risk
Current Pharmaceutical Design Current Biological Therapies for Inflammatory Bowel Disease
Current Pharmaceutical Design Butyrate and Colorectal Cancer: The Role of Butyrate Transport
Current Drug Metabolism The Role of Disproportionality Analysis of Pharmacovigilance Databases in Safety Regulatory Actions: a Systematic Review
Current Drug Safety 21.1 Tesla Magnetic Resonance Imaging Apparatus and Image Interpretation: First Report of a Scientific Advancement
Recent Patents on Medical Imaging Determinants of Smoking Cessation Attempts Among HIV-Infected Patients: Results from a Hospital-Based Prospective Cohort
Current HIV Research Current Status of Primary Cytoreductive Surgery for the Treatment of Advanced Epithelial Ovarian Cancer
Current Cancer Therapy Reviews Prevention of Non-communicable Diseases by Balanced Nutrition: Population- specific Effective Public Health Approaches in Developing Countries
Current Diabetes Reviews Cellular and Physiological Effects of Probiotics and Prebiotics
Mini-Reviews in Medicinal Chemistry Semi-dynamic Control of FCM Initialization for Automatic Extraction of Inflamed Appendix from Ultrasonography
Current Medical Imaging Library of Synthetic Compounds Based on Pyrazole Unit: Design and Screening Against Breast and Colorectal Cancer
Letters in Drug Design & Discovery Avocado (Persea americana) Seed as a Source of Bioactive Phytochemicals
Current Pharmaceutical Design An Update of the Classical and Novel Methods Used for Measuring Fast Neurotransmitters During Normal and Brain Altered Function
Current Neuropharmacology Isolation of Antibodies From Non-Human Primates for Clinical Use
Current Drug Discovery Technologies Radiopharmaceutical Chemistry with Iodine-124: A Non-Standard Radiohalogen for Positron Emission Tomography
Medicinal Chemistry The Frequency of Thrombotic Events Among Adults Given Antifibrinolytic Drugs for Spontaneous Bleeding: Systematic Review and Meta-Analysis of Observational Studies and Randomized Trials
Current Drug Safety Piceatannol Modulates Lung Epithelial Cellular Responses to Pseudomonas aeruginosa
Inflammation & Allergy - Drug Targets (Discontinued) Plant Sterols and Stanols as Cholesterol-Lowering Ingredients in Functional Foods
Recent Patents on Food, Nutrition & Agriculture Studies on Target Genes of General Anesthetics
Current Drug Targets