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  1. Animal Studies andHuman Health Consequences Sorell L. Schwartz, Ph.D. Department of Pharmacology Georgetown University Medical Center

  2. Pharmacokinetics Action of the body on the chemical System: Absorption, distribution, metabolism, elimination (ADME) Output: Concentration-time relationships Pharmacodynamics Action of the chemical on the body System: Biological ligands or other targets in the biophase. Output: Biological response Pharmacokinetics v. Pharmacodynamics

  3. Pharmacokinetic Dose Extrapolation

  4. Heart weight Lung weight Skeletal weight Muscle weight GI tract weight Lung weight Skin weight Liver weight (?) Kidney weight (?) Tidal volume Vital capacity Blood volume Interspecies Scaling(Essentially) IsometricProportion to body weight is constant across species

  5. b ~ 0.25 Heart rate Circulation time Respiratory rate b ~ 0.75 Basal metabolic rate Blood flow Clearance (flow limited?) Interspecies ScalingAllometricProportion to body weight varies exponentially across speciesY = aWbY = Pharmacokinetic parameter;W = Body weighta = Allometric coefficient; b = scaling exponent

  6. Pharmacokinetic FactorsAffecting Efficacy of Interspecies Extrapolations • Volume of distribution • Clearance • Absorption & Bioavailability

  7. Volume of Distribution • Quantitatively describes the distribution of the chemical throughout the body, and ultimately to the biophase (site of action). The greater the volume of distribution, the greater the biological half life. • Scalable based on interspecies composition relationships and physical chemical factors (QSPR).

  8. Clearance (Cl)Blood flow (Q) · Extraction Ratio (ER) • Volume of blood per unit time (e.g. L/min) from which chemical is completely extracted. The higher the clearance, the smaller the half-life. • Blood flow is allometrically scalable across mammalian species • Extraction can occur by diffusion mechanism (e.g., glomerular filtration in the kidney) or by metabolic mechanism (e.g., liver). • Clearance can be flow-limited (high ER) or capacity limited (low ER). Flow-limited clearance across species is more likely to be scalable than capacity-limited clearance

  9. Absorption & Bioavailability (F) • The greater the ERH , the greater the likelihood that interspecies differences in absorbed dose will be magnified! • Why? • ERH = 0.8 1 – ERH = 0.2 • Consider 12.5% reduction in ER • ERH = 0.7 1 – ERH = -.3, a 50% increase in effective dose • Conversely • ERH = 0.2 1 – ERH = 0.8 • Consider 50% reduction in ER • ERH = 0.1 1 – ERH = 0.9, a 12.5% increase in effective dose

  10. Absorption & BioavailabilityInterspecies Scalability The greater the ERH , the greater the likelihood that interspecies differences in absorbed dose will be magnified! Why? ERH = 0.8 1 – ERH = 0.2 Consider 12.5% reduction in ER ERH = 0.7 1 – ERH = -.3, a 50% increase in effective dose Conversely ERH = 0.2 1 – ERH = 0.8 Consider 50% reduction in ER ERH = 0.1 1 – ERH = 0.9, a 12.5% increase in effective dose

  11. Allometric ReliabilityLikely to be More Reliable • GI absorption • Volume of distribution • Blood flow • Clearance: Where clearance is flow limited across species (ERH is high), variations in ERH will have less influence on interspecies variations. • Bioavailability: Where ERH is low across species, variations in ERH will have less influence on interspecies variations.

  12. Allometric ReliabilityLikely to be Less Reliable • Clearance: Where clearance is capacity limited across species (ERH is low), variations in ERH will have more influence on interspecies variations. • Bioavailability: Where ERH is high across species, variations in ERH will have a greater influence on interspecies variations.

  13. Allometric Approaches toClearance Approach 1 Cl = a · Wb (Neoteny) Approach 2 Cl = a · Wb/MLP Approach 3 Cl = a · Brb · Wc Approach 4 Cl = a · Wb/Br MLP = Maximum lifespan potential; Br = Brain weight (Adapted from T. Lave et al., Clin. Pharmacokin. 36:211, 1999)

  14. Allometric Approaches toClearance (Empirical) Approach 5 Cl = Clan(in vivo) · Clh(hepatocytes)/Clan(hepatocytes) Approach 6 Clh = a · Clan Approach 7 Clh = Clan · Clh(hepatocytes)/Clan(hepatocytes) · (Wh/Wan)0.86

  15. Physiologically Based PK-PD Model

  16. PBPK Modeling of Metabolite

  17. Application of PBPK Modeling to Low Dose/Interspecies Extrapolation Developing a Human PBPK Model • Use the tissue:blood partition coefficients developed from the animal model, or by physical chemical extrapolation. • Use values for organ clearance based on either human experimental data (in vivo or in vitro) OR by allometric extrapolation developed in at least two other species.

  18. Application of PBPK modeling to Low Dose/Interspecies Extrapolation • Use the human PBPK model to identify the daily intake resulting in a target tissue concentration equivalent to the target tissue concentration in the experimental animal that was associated with the observed response. • If there is insufficient information to develop a human PBPK model, extrapolate the estimated animal intake associated with the observed response to a human intake using an appropriate allometric relationship.

  19. Applications of PBPK Modeling in Risk Assessment • Interspecies extrapolation • Prediction of target site (biophase) concentration • Dose extrapolation in cases of non-linear pharmacokinetics • Low dose extrapolation • Route of exposure extrapolation • Relative risk from multiple routes of exposure • Estimation of exposure based on biological markers