Interspecies extrapolation of physiological pharmacokinetic parameter distributions

Karen Watanabe-Sailor, Frédéric Y. Bois

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Three methods (multiplicative, additive, and allometric) were developed to extrapolate physiological model parameter distributions across species, specifically from rats to humans. In the multiplicative approach, the rat model parameters are multiplied by the ratio of the mean values between humans and rats. Additive scaling of the distributions is defined by adding the difference between the average human value and the average rat value to each rat value. Finally, allometric scaling relies on established extrapolation relationships using power functions of body weight. A physiologically-based pharmacokinetic model was fitted independently to rat and human benzene disposition data. Human model parameters obtained by extrapolation and by fitting were used to predict the total bone marrow exposure to benzene and the quantity of metabolites produced in bone marrow. We found that extrapolations poorly predict the human data relative to the human model. In addition, the prediction performance depends largely on the quantity of interest. The extrapolated models underpredict bone marrow exposure to benzene relative to the human model. Yet, predictions of the quantity of metabolite produced in bone marrow are closer to the human model predictions. These results indicate that the multiplicative and allometric techniques were able to extrapolate the model parameter distributions, but also that rats do not provide a good kinetic model of benzene disposition in humans.

Original languageEnglish (US)
Pages (from-to)741-754
Number of pages14
JournalRisk Analysis
Volume16
Issue number6
DOIs
StatePublished - Dec 1996
Externally publishedYes

Fingerprint

Pharmacokinetics
Extrapolation
Rats
Benzene
Bone
Bone Marrow
Metabolites
scaling
disposition
Physiological models
Values
body weight
Body Weight
Kinetics

Keywords

  • Benzene
  • interspecies extrapolation
  • Monte Carlo parameterization
  • physiologically-based pharmacokinetics

ASJC Scopus subject areas

  • Social Sciences (miscellaneous)
  • Safety, Risk, Reliability and Quality

Cite this

Interspecies extrapolation of physiological pharmacokinetic parameter distributions. / Watanabe-Sailor, Karen; Bois, Frédéric Y.

In: Risk Analysis, Vol. 16, No. 6, 12.1996, p. 741-754.

Research output: Contribution to journalArticle

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