The allometric approach for interspecies scaling of pharmacokinetics and toxicity of anti-cancer drugs. 1995

J W Paxton
Department of Pharmacology and Clinical Pharmacology, University of Auckland School of Medicine, New Zealand.

1. The rationale for extrapolation or 'scaling' across animal species is based on their underlying anatomical, physiological and biochemical similarities. 2. Research carried out in the 19th and early 20th century resulted in Benedict's famous 'mouse-to-elephant' graph which showed that the log of the basal metabolic rate plotted against the log of bodyweight (W) produced a straight line with a slope of 0.76. Since then it has become apparent that a number of other physiological variables (Y) exhibit a similar relationship which can be represented by the general allometric equation, Y = alpha W beta; where beta is the slope of the log-log plot and alpha is the intercept on the y axis. 3. The major pharmacokinetic parameters such as clearance and volume of distribution of many drugs are also related to W in a similar manner. 4. This empirical approach does not require a strong mathematical background and offers a relatively simple method of predicting the kinetics of anti-cancer drugs in patients from pre-clinical animal data. 5. The occurrence of major qualitative and quantitative differences in the metabolism of drugs between species is probably the single greatest complicating factor in the use of animals as predictors of drug toxicity and kinetics in patients. 6. Despite this, the allometric approach is useful for allowing the estimation of a more appropriate starting dose for some drugs in a Phase I trial, which might result in potential savings in escalation steps and maximize the chance that the dose which an individual receives has the potential for therapeutic value.

UI MeSH Term Description Entries
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D013045 Species Specificity The restriction of a characteristic behavior, anatomical structure or physical system, such as immune response; metabolic response, or gene or gene variant to the members of one species. It refers to that property which differentiates one species from another but it is also used for phylogenetic levels higher or lower than the species. Species Specificities,Specificities, Species,Specificity, Species
D017321 Clinical Trials, Phase I as Topic Works about studies performed to evaluate the safety of diagnostic, therapeutic, or prophylactic drugs, devices, or techniques in healthy subjects and to determine the safe dosage range (if appropriate). These tests also are used to determine pharmacologic and pharmacokinetic properties (toxicity, metabolism, absorption, elimination, and preferred route of administration). They involve a small number of persons and usually last about 1 year. This concept includes phase I studies conducted both in the U.S. and in other countries. Clinical Trials, Phase I,Drug Evaluation, FDA Phase I,Evaluation Studies, FDA Phase I,Human Microdosing Trial,Phase 1 Clinical Trial,Phase I Clinical Trial,Phase I Clinical Trials,Clinical Trials, Phase 1,Drug Evaluation, FDA Phase 1,Drug Evaluation, FDA Phase I as Topic,Evaluation Studies, FDA Phase 1,Human Microdosing Trials,Microdosing Trials, Human,Phase 1 Clinical Trials,Microdosing Trial, Human,Trial, Human Microdosing,Trials, Human Microdosing

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