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Review
. 2009;24(1):16-24.
doi: 10.2133/dmpk.24.16.

Scaling pharmacodynamics from in vitro and preclinical animal studies to humans

Donald E Mager  1 , Sukyung Woo, William J Jusko
Affiliations
Review

Scaling pharmacodynamics from in vitro and preclinical animal studies to humans

Donald E Mager et al. Drug Metab Pharmacokinet. 2009.

Abstract

An important feature of mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) models is the identification of drug- and system-specific factors that determine the intensity and time-course of pharmacological effects. This provides an opportunity to integrate information obtained from in vitro bioassays and preclinical pharmacological studies in animals to anticipate the clinical and adverse responses to drugs in humans. The fact that contemporary PK/PD modeling continues to evolve and seeks to emulate systems level properties should provide enhanced capabilities to scale-up pharmacodynamic data. Critical steps in drug discovery and development, such as lead compound and first in human dose selection, may become more efficient with the implementation and further refinement of translational PK/PD modeling. In this review, we highlight fundamental principles in pharmacodynamics and the basic expectations for in vitro bioassays and traditional allometric scaling in PK/PD modeling. Discussion of PK/PD modeling efforts for recombinant human erythropoietin is also included as a case study showing the potential for advanced systems analysis to facilitate extrapolations and improve understanding of inter-species differences in drug responses.

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Figures

Fig. 1
Fig. 1
Major components of mechanism-based PK/PD models.
Fig. 2
Fig. 2
Sources of information that may be integrated into mechanism-based PK/PD models for scaling to human pharmacodynamics. Predictive techniques (top of arrows) can be augmented by selective measurements (bottom of arrows).
Fig. 3
Fig. 3
PK/PD model diagram for the absorption and disposition of rHuEpo and drug effects on reticulocytes (RET), red blood cells (RBC), and hemoglobin concentrations (Hb) Model is described by Equations 11–17 and symbols are defined in the text.
Fig. 4
Fig. 4
Simulated profiles for reticulocyte, red blood cell (RBC), and hemoglobin concentrations (Hb) in response to rHuEpo given as 150 IU/kg SC three times weekly to healthy male volunteers The symbols represent original data from Ramakrishnan et al. Solid lines are median predicted profiles using a PK/PD model developed in rats (Fig. 3) and allometrically scaled parameters (Table 1). Shaded regions represent the 90% prediction intervals.
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References

    1. Nestorov I. Whole-body physiologically based pharmacokinetic models. Expert Opin. Drug. Metab. Toxicol. 2007;3:235–249. - PubMed
    1. Mager DE. Quantitative structure-pharmacokinetic/pharmacodynamic relationships. Adv. Drug Deliv. Rev. 2006;58:1326–1356. - PubMed
    1. Beliveau M, Lipscomb J, Tardif R, Krishnan K. Quantitative structure-property relationships for interspecies extrapolation of the inhalation pharmacokinetics of organic chemicals. Chem. Res. Toxicol. 2005;18:475–485. - PubMed
    1. Parrott N, Paquereau N, Coassolo P, Lave T. An evaluation of the utility of physiologically based models of pharmacokinetics in early drug discovery. J. Pharm. Sci. 2005;94:2327–2343. - PubMed
    1. Danhof M, de Jongh J, De Lange ECM, Della Pasqua O, Ploeger BA, Voskuyl RA. Mechanism-based pharmacokinetic-pharmacodynamic modeling: Biophase distribution, receptor theory, and dynamical systems analysis. Annu. Rev. Pharmacol. Toxicol. 2007;47:21.21–21.44. - PubMed

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