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 |

- Author Guidelines
- Bentham Author Support Services (BASS)
- 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
-
QSAR and Complex Network Recognition of miRNAs in Stem Cells
Current Bioinformatics A Comprehensive Review on Pharmacognostical Investigation and Pharmacology of Typhonium trilobatum
The Natural Products Journal Statin Treatment Non-adherence and Discontinuation: Clinical Implications and Potential Solutions
Current Pharmaceutical Design Therapeutic Manipulation of the Immune System: Enhancement of Innate and Adaptive Mucosal Immunity
Current Pharmaceutical Design Once-a-Day (QD) vs Twice-Daily (BID) Nevirapine as Simplification in PITreated Patients After 2 mos. of BID Induction
Current HIV Research HPMC- A Marvel Polymer for Pharmaceutical Industry-Patent Review
Recent Advances in Drug Delivery and Formulation Semi-dynamic Control of FCM Initialization for Automatic Extraction of Inflamed Appendix from Ultrasonography
Current Medical Imaging A Phosphoproteomics Approach to Identify Candidate Kinase Inhibitor Pathway Targets in Lymphoma-Like Primary Cell Lines
Current Drug Discovery Technologies Bridging the Gap Between Structural Bioinformatics and Receptor Research: The Membrane-embedded, Ligand-gated, P2X Glycoprotein Receptor
Current Topics in Medicinal Chemistry Leukotriene A4 Hydrolase as a Target for Cancer Prevention and Therapy
Current Cancer Drug Targets Cytoprotection and Immunomodulation in Cancer Therapy
Current Medicinal Chemistry - Anti-Cancer Agents Determination of Residual Solvents in Eprosartan Mesylate by Static Headspace Gas Chromatographic Method Optimized by Response Surface Methodology
Current Pharmaceutical Analysis Doripenem: A New Addition to the Carbapenem Class of Antimicrobials
Recent Patents on Anti-Infective Drug Discovery An Evidence-Based Systematic Review of Stevia by the Natural Standard Research Collaboration
Cardiovascular & Hematological Agents in Medicinal Chemistry Should the Incorporation of Structural Alerts be Restricted in Drug Design? An Analysis of Structure-Toxicity Trends with Aniline-Based Drugs
Current Medicinal Chemistry From Natural Products to Designer Drugs: Development and Molecular Mechanisms Action of Novel Anti-Microtubule Breast Cancer Therapeutics
Current Topics in Medicinal Chemistry Genomic and Epigenetic Complexity of the FOXF1 Locus in 16q24.1: Implications for Development and Disease
Current Genomics Drug Repositioning for Treatment of Movement Disorders: From Serendipity to Rational Discovery Strategies
Current Topics in Medicinal Chemistry The Interaction Between Gender and Diabetes Mellitus in the Coronary Heart Disease Risk
Current Pharmaceutical Design Complex Obesity
Current Pediatric Reviews