Elsevier

Life Sciences

Volume 56, Issue 26, 19 May 1995, Pages 473-478
Life Sciences

Pharmacology letter accelerated communication
A new extrapolation method from animals to man: Application to a metabolized compound, mofarotene

https://doi.org/10.1016/0024-3205(95)00234-WGet rights and content

Abstract

Allometric scaling (a technique which uses data obtained in laboratory animals to predict human pharmacokinetics) works well for drugs that are cleared intact, but is less successful with extensively metabolised compounds. This paper describes a new method to improve the accuracy of such projections, by integrating metabolic data obtained in vitro (e.g. with liver microsomes or hepatocytes) into these calculations.

The approach was used prospectively, to predict the clearance of mofarotene (Ro 40-8757) in humans from in vivo kinetic data obtained in mouse, rat and dog. This compound was selected to illustrate this approach because it is exclusively eliminated through metabolism. Without the metabolic correction or using empirical correcting factors, the values predicted for man were 2.7 and 0.6 ml/min/kg. This fell outside the range subsequently obtained in healthy volunteers dosed orally with 300 mg of mofarotene (7.5 ± 4.0 ml/min/kg, n = 12). However, inclusion of the microsomal or hepatocyte data gave values of 5.1 and 4.2 ml/min/kg, respectively, illustrating that the integration of in vitro metabolic data improves the accuracy of kinetic extrapolations. In contrast to the existing empirical techniques, this approach offers a rational basis to predict clearance of metabolized compounds in human.

References (10)

  • T. Omura et al.

    J. Biol. Chem.

    (1964)
  • P.K. Smith et al.

    Anal. Biochem.

    (1985)
  • G. Fabre et al.

    Biochem. Pharmacol.

    (1988)
  • P.O. Seglen
  • J. Mordenti

    J. Pharm. Sci.

    (1986)
There are more references available in the full text version of this article.

Cited by (32)

  • Physiologically based pharmacokinetic (PBPK) modeling of disposition of epiroprim in humans

    2003, Journal of Pharmaceutical Sciences
    Citation Excerpt :

    Some of these approaches employ time normalizations8,9 or other scaling factors that include: protein binding, brain weight,10 or maximum life span potential.11 The use of bile flow rates, and/or in vitro microsome or hepatocyte data, or UDP–glucuronosyltransferase activity to normalize the in vivo CL have also substantially improved the prediction of the in vivo human clearance for drugs that are eliminated via liver metabolism,12–14 either alone or combined with biliary excretion.15,16 In contrast to allometric scaling, the physiologically based pharmacokinetic (PBPK) models provide an opportunity to integrate the data from a variety of processes, to predict the pharmacokinetic profiles.2

View all citing articles on Scopus
View full text