Interspecies scaling, allometry, physiological time, and the ground plan of pharmacokinetics

Boxenbaum, Harold

doi:10.1007/bf01062336

Cited by 648Pharmacogenetics and Drug MetabolismPharmaceutical studies and practicesAnimal testing and alternatives

Interspecies scaling, allometry, physiological time, and the ground plan of pharmacokinetics

Boxenbaum, Harold·1982·Journal of Pharmacokinetics and Biopharmaceutics

DOI 10.1007/bf01062336

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In general, the allometric exponent b is approximately 0.75 for CL and chemical-specific factors associated with metabolism (e.g., Vmax), 1 for volume of organs and blood flows, and 0.25 for physiological times.
“In general, a is drug dependent and b is parameter-type dependent, which are approximately 0.75 for CL and chemical-specific factors associated with metabolism (e.g., Vmax), 1 for volume of organs and blood flows, and 0.25 for physiological times [18,88].”
From Interpretation of Non-Clinical Data for Prediction of Human Pharmacokinetic Parameters: In Vitro-In Vivo Extrapolation and Allometric Scaling (2019) · cites this paper as [18]

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“Boxenbaum (1982, 1984) suggested the incorporation of maximum lifespan potential (MLP) as a correction factor to normalize for the metabolic capacity of different species.”
Background
A global examination of allometric scaling for predicting human drug clearance and the prediction of large vertical allometry**This work was presented at the American Association of Pharmaceutical Scientists Annual meeting, Salt Lake City, USA, Oct. 26, 2003.
Tang, H., & Mayersohn, M. (2006) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20481 · Cited by 89 · see citing works
Deterministic Chaos and Fractal Complexity in the Dynamics of Cardiovascular Behavior: Perspectives on a New Frontier
Sharma, V. K. (2009) · The Open Cardiovascular Medicine Journal · doi:10.2174/1874192400903010110 · Cited by 82 · see citing works
“The concept of physiological time arises from Meyen’s perspective and is defined by Boxenbaum as “a species-dependent unit of chronological time required to complete a speciesindependent physiological event” [34].”
Background
Scaling basic toxicokinetic parameters from rat to man.
Bachmann, K., Pardoe, D., & White, D. (1996) · Environmental Health Perspectives · doi:10.1289/ehp.96104400 · Cited by 90 · see citing works
Concepts and Issues with Interspecies Scaling in Zoological Pharmacology
Hunter, R., & Isaza, R. (2008) · Journal of zoo and wildlife medicine · doi:10.1638/2008-0041.1 · Cited by 84 · see citing works
Allometric relationships between the pharmacokinetics of propofol in rats, children and adults.
Knibbe, C., Zuideveld, K. P., Aarts, L., Kuks, P., & Danhof, M. (2005) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2005.02239.x · Cited by 84 · see citing works
Evaluating the Use of Antibody Variable Region (Fv) Charge as a Risk Assessment Tool for Predicting Typical Cynomolgus Monkey Pharmacokinetics
Bumbaca Yadav, D., Sharma, V. K., Boswell, C. A., Hotzel, I., Tesar, D., Shang, Y., Ying, Y., Fischer, S. K., Grogan, J. L., Chiang, E. Y., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.692434 · Cited by 82 · see citing works
Comprehensive Assessment of Human Pharmacokinetic Prediction Based on In Vivo Animal Pharmacokinetic Data, Part 1: Volume of Distribution at Steady State
Lombardo, F., Waters, N. J., Argikar, U. A., Dennehy, M. K., Zhan, J., Gunduz, M., Harriman, S. P., Berellini, G., Rajlic, I. L., & Obach, R. S. (2012) · The Journal of Clinical Pharmacology · doi:10.1177/0091270012440281 · Cited by 83 · see citing works
“The exponent (b) is expected to be close to 1 in the case of VDss because this is the typical exponent for allometric scaling of tissue and organ volumes across species.(6) If we assume that passive diffusion is largely governing the distribution of solutes (drugs) within the body, although that may not always be the…”
Background
On the anticipation of the human dose in first-in-man trials from preclinical and prior clinical information in early drug development
Lowe, P. J., Hijazi, Y., Luttringer, O., Yin, H., Sarangapani, R., & Howard, D. (2007) · Xenobiotica · doi:10.1080/00498250701648008 · Cited by 82 · see citing works
“Human clearance is then predicted according to: CL ¼ a BWb, ð6Þ where BW is bodyweight of each species (Mahmood and Balian 1996, 1999; Boxenbaum 1982).”
Background
Covariate selection in pharmacometric analyses: a review of methods
Hutmacher, M., & Kowalski, K. (2015) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12451 · Cited by 78 · see citing works
Prediction of Human Pharmacokinetics of Therapeutic Monoclonal Antibodies from Simple Allometry of Monkey Data
Oitate, M., Masubuchi, N., Ito, T., Yabe, Y., Karibe, T., Aoki, T., Murayama, N., Kurihara, A., Okudaira, N., & Izumi, T. (2011) · Drug Metabolism and Pharmacokinetics · doi:10.2133/dmpk.dmpk-11-rg-011 · Cited by 81 · see citing works
Interpretation of Non-Clinical Data for Prediction of Human Pharmacokinetic Parameters: In Vitro-In Vivo Extrapolation and Allometric Scaling
Choi, G.-W., Lee, Y.-B., & Cho, H.-Y. (2019) · Pharmaceutics · doi:10.3390/pharmaceutics11040168 · Cited by 76 · see citing works
Using in vitro and in vivo models to evaluate the oral bioavailability of nutraceuticals.
Ting, Y., Zhao, Q., Xia, C., & Huang, Q.-R. (2015) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf5047464 · Cited by 75 · see citing works
Prediction of human pharmacokinetics—evaluation of methods for prediction of hepatic metabolic clearance
Fagerholm, U. (2007) · Journal of Pharmacy and Pharmacology · doi:10.1211/jpp.59.6.0007 · Cited by 76 · see citing works
“The relationship between skeletal size and body weight (BW) was discussed by Galileo (Boxenbaum 1982) as early as 1637, and Rubner (1983) explored and found a relationship between basal metabolic rate (heat production and oxygen utilization) and body weight of dogs.”
BackgroundMethod
Prediction of the disposition ofβ-lactam antibiotics in humans from pharmacokinetic parameters in animals
Sawada, Y., Hanano, M., Sugiyama, Y., & Iga, T. (1984) · Journal of pharmacokinetics and biopharmaceutics · doi:10.1007/bf01061720 · Cited by 73 · see citing works
“the following equation (37,38): Vr/fuT=( V~- Vp)/fu (11) Because CLp in man is smaller than OH or OR, V is nearly equal to Vss (39): V~s- V (12) where V is the volume of distribution at the terminal phase.”
Background
Preclinical Prediction of Human Brain Target Site Concentrations: Considerations in Extrapolating to the Clinical Setting
Westerhout, J., Danhof, M., & de Lange, E. C. M. (2011) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.22604 · Cited by 72 · see citing works
Prediction of the disposition of nine weakly acidic and six weakly basic drugs in humans from pharmacokinetic parameters in rats
Sawada, Y., Hanano, M., Sugiyama, Y., & Iga, T. (1985) · Journal of pharmacokinetics and biopharmaceutics · doi:10.1007/bf01059331 · Cited by 71 · see citing works
“(1) DPH, (2) HEB, (3) PEB, (4) PBZ, (5) WA, (6) TB, (7) VA, (8) PB, (9) AMB, (10) QD, (11) CPZ, (12) PL, (13) PTZ, (14) DZP, and (15) AP.”
BackgroundMethodInfluential
Species Differences in Distribution and Prediction of Human Vss from Preclinical Data
Berry, L. M., Li, C., & Zhao, Z. (2011) · Drug Metabolism and Disposition · doi:10.1124/dmd.111.040766 · Cited by 69 · see citing works
“Allometry is the extrapolation of pharmacokinetic parameters to one species by fitting a power function to the relationship between the pharmacokinetic parameter from other species and a measure of the size of the species, such as body weight (Boxenbaum, 1982).”
Background
A new era for migraine: Pharmacokinetic and pharmacodynamic insights into monoclonal antibodies with a focus on galcanezumab, an anti-CGRP antibody
Kielbasa, W., & Helton, D. (2019) · Cephalalgia · doi:10.1177/0333102419840780 · Cited by 74 · see citing works
“Body weight is a commonly identified factor that influences mAb PK, which is not surprising based on the theory of allometry and PK principles (86).”
Background
Pharmacokinetics of oxytetracycline in the white shrimp, Litopenaeus setiferus
Reed, L., Siewicki, T., & Shah, J. (2004) · doi:10.1016/s0044-8486(03)00451-4 · Cited by 68
Mechanism-based PK–PD model for the prolactin biological system response following an acute dopamine inhibition challenge: quantitative extrapolation to humans
Stevens, J., Ploeger, B., Hammarlund-Udenaes, M., Osswald, G., van der Graaf, P. H., Danhof, M., & de Lange, E. (2012) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-012-9262-4 · Cited by 62
“human situation allometric scaling principles were applied to scale the first order rate constants for human prolactin release and elimination (ki,hum) [14].”
Method
Prediction of Clearance, Volume of Distribution and Half-Life by Allometric Scaling and by Use of Plasma Concentrations Predicted from Pharmacokinetic Constants: A Comparative Study
Mahmood, I. (1999) · Journal of Pharmacy and Pharmacology · doi:10.1211/0022357991773320 · Cited by 59 · see citing works
Correlation of Plasma Clearance of 54 Extensively Metabolized Drugs Between Humans and Rats: Mean Allometric Coefficient of 0.66
Chiou, W. L., Robbie, G. J., Chung, S. M., Wu, T., & Ma, C. (1998) · Pharmaceutical Research · doi:10.1023/a:1011974226596 · Cited by 61 · see citing works
Prospective Predictions of Human Pharmacokinetics for Eighteen Compounds
Zhang, T., Heimbach, T., Lin, W., Zhang, J., & He, H. (2015) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.24373 · Cited by 56 · see citing works
Plasma and Brain Concentrations of Doxycycline after Single and Repeated Doses in Wild-Type and APP23 Mice
Lucchetti, J., Fracasso, C., Balducci, C., Passoni, A., Forloni, G., Salmona, M., & Gobbi, M. (2018) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.118.252064 · Cited by 67 · see citing works
“When planning treatment schedules in animals, one must also take into account that the drug’sPKprofile varies as a function of body weight (Boxenbaum, 1982).”
Background
Translational aspects of blood–brain barrier transport and central nervous system effects of drugs: From discovery to patients
de Lange, E. D., & Hammarlund-Udenaes, M. (2015) · Clinical pharmacology and therapy · doi:10.1002/cpt.76 · Cited by 56 · see citing works
“However, living mammals in essence share the same biological processes, and, therefore, knowledge of the condition-dependent rate and extent of an individual process provides a foundation for interspecies extrapolation.(56)”
Background
Methods for Identifying a Default Cross-Species Scaling Factor
Rhomberg, L. R., & Lewandowski, T. A. (2006) · Human and Ecological Risk Assessment An International Journal · doi:10.1080/10807030600977269 · Cited by 43 · see citing works
“…(ADME) of toxicants and their associated health effects can be drawn together into a single scheme by referring to the concept of physiological time (Dedrick et al. 1970; Dedrick 1973; Boxenbaum 1982, 1983, 1984, 1986; Lindstedt and Calder 1976, 1981; Mordenti 1986; Lindstedt 1987; Travis 1990).”
Background
Allometric Scaling of Pharmacodynamic Responses: Application to 5-Ht1A Receptor Mediated Responses from Rat to Man
Zuideveld, K. P., van der Graaf, P. H., Peletier, L., & Danhof, M. (2007) · Pharmaceutical Research · doi:10.1007/s11095-007-9336-y · Cited by 55
“In particular, drug metabolism is an area where methods based on allometric scaling principles have become a basis for the scaling preclinical of pharmacokinetic (PK) models to predict the time course of drug concentrations in man (4,5).”
Method
Interspecies Scaling: Predicting Volumes, Mean Residence Time and Elimination Half-life.* Some Suggestions
Mahmood, I. (1998) · Journal of Pharmacy and Pharmacology · doi:10.1111/j.2042-7158.1998.tb06190.x · Cited by 53 · see citing works
Physiologically based approaches towards the prediction of pharmacokinetics:in vitro–in vivoextrapolation
Buck, S. S. D., & Mackie, C. E. (2007) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.3.6.865 · Cited by 58 · see citing works
“For example, allometric scaling, which considers that a number of anatomical, physiological and biochemical variables and can be scaled across species as a power function of the bodyweight, has been the dominant method for interspecies scaling of human PK parameters [105-107] .”
Method
Pharmacokinetics in Animals and Humans of a First-in-Class Peptide Deformylase Inhibitor
Ramanathan-Girish, S., McColm, J., Clements, J., Taupin, P., Barrowcliffe, S., Hevizi, J., Safrin, S., Moore, C., Patou, G., Moser, H., et al. (2004) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.48.12.4835-4842.2004 · Cited by 53
“standard allometric equation (2) was used: Y aW (1)”
Method
Prediction of human pharmacokinetics – evaluation of methods for prediction of volume of distribution
Fagerholm, U. (2007) · Journal of Pharmacy and Pharmacology · doi:10.1211/jpp.59.9.0001 · Cited by 47 · see citing works
“Similar comparisons and findings were made for dog and human fu,pl data for 15 substances (data taken from Boxenbaum (1982), Sawada et al (1984) and Lin (1995)).”
Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics
de Lange, E. C. M., van den Brink, W., Yamamoto, Y., de Witte, W. E. A., & Wong, Y. C. (2017) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2017.1380623 · Cited by 52 · see citing works
“The focus should therefore be on the design of quantitative in vivo animal studies such that translational pharmacology approaches can be applied [25,36,37,61,89], which will be discussed below.”
Background
Population Pharmacokinetics of Intermittent Vancomycin in Children with Cystic Fibrosis
Stockmann, C. R., Sherwin, C. M. T., Zobell, J. T., Lubsch, L. M., Young, D. C., Olson, J. A., Noyes, B. E., Ampofo, K., & Spigarelli, M. G. (2013) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/phar.1320 · Cited by 58 · see citing works
Allometric analysis of ciprofloxacin and enrofloxacin pharmacokinetics across species.
Cox, S., Cottrell, M., Smith, L., Papich, M., Frazier, D., & Bartges, J. (2004) · Journal of Veterinary Pharmacology and Therapeutics · doi:10.1111/j.1365-2885.2004.00560.x · Cited by 50
“where y is the value of the pharmacokinetic parameter and x the body weight (Boxenbaum, 1982; Riond & Riviere, 1990; Pashov et al., 1997; Riviere et al., 1997).”
Background
Practical approaches to dose selection for first-in-human clinical trials with novel biopharmaceuticals.
Tibbitts, J., Cavagnaro, J., Haller, C., Marafino, B. J., Andrews, P., & Sullivan, J. T. (2010) · Regulatory toxicology and pharmacology : RTP · doi:10.1016/j.yrtph.2010.06.007 · Cited by 48 · see citing works
“The use of preclinical species PK to estimate human PK is often referred to as interspecies scaling (Boxenbaum, 1982).”
Background
ACCURACY OF ALLOMETRICALLY PREDICTED PHARMACOKINETIC PARAMETERS IN HUMANS: ROLE OF SPECIES SELECTION
Tang, H., & Mayersohn, M. (2005) · Drug Metabolism and Disposition · doi:10.1124/dmd.105.004127 · Cited by 42 · see citing works
“The observed power function is empirical, although there is some possible underlying physiological rationale (Boxenbaum, 1982; Mordenti, 1986).”
Background
Mixed-effects modelling of the interspecies pharmacokinetic scaling of pegylated human erythropoietin
Jolling, K., Ruixo, J. J. P., Hemeryck, A., Vermeulen, A., & Greway, T. (2005) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2005.01.002 · Cited by 46 · see citing works

Authors: Boxenbaum, H.
Affiliations: University of Connecticut (US)
Corresponding author: Boxenbaum, Harold
Venue: Journal of Pharmacokinetics and Biopharmaceutics
Publisher: Springer Science and Business Media LLC
Published: 1982-04
Volume: 10
Issue: 2
Pages: 201-227
ISSN: 0090-466X (ISSN-L)
DOI: 10.1007/bf01062336
OpenAlex: W2042099048
Cited by: 648
References: 56
Citations by year: 2026: 16 · 2025: 12 · 2024: 12 · 2023: 13 · 2022: 11 · 2021: 15 · 2020: 18 · 2019: 24 · 2018: 25 · 2017: 10 · 2016: 17 · 2015: 27 · 2014: 14 · 2013: 21 · 2012: 25
FWCI: 9.61
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Journal of Pharmacokinetics and Biopharmaceutics (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
Keywords: interspecies scaling, allometry, body size, physiological time, creatinine clearance, interspecies variation, drug metabolism, longevity
MeSH terms: Animals, Body Weight, Creatinine, Pharmaceutical Preparations, Humans, Kinetics, Liver, Research Design, Species Specificity, Statistics as Topic, Time Factors

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