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

2. Pharmacokinetics v. Pharmacodynamics 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

3. Pharmacokinetic Dose Extrapolation

4. Interspecies Scaling (Essentially) Isometric Proportion to body weight is constant across species 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

5. Interspecies Scaling Allometric Proportion to body weight varies exponentially across species Y = aW b Y = Pharmacokinetic parameter; W = Body weight a = Allometric coefficient; b = scaling exponent b ~ 0.25 Heart rate Circulation time Respiratory rate b ~ 0.75 Basal metabolic rate Blood flow Clearance (flow limited?)

6. Pharmacokinetic Factors Affecting Efficacy of Interspecies Extrapolations Volume of distribution Clearance Absorption & Bioavailability

7. 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). Volume of Distribution

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) where f abs = fraction absorbed from GI lumen f g = fraction metabolized by GI tissue ER H = hepatic extraction ratio, equivalent to hepatic “first pass” effect 1 - F = “presystemic elimination”

10. Absorption & Bioavailability Interspecies Scalability The greater the ER H, the greater the likelihood that interspecies differences in absorbed dose will be magnified! Why? ER H = 0.81 – ER H = 0.2 Consider 12.5% reduction in ER ER H = 0.71 – ER H = -.3, a 50% increase in effective dose Conversely ER H = 0.21 – ER H = 0.8 Consider 50% reduction in ER ER H = 0.11 – ER H = 0.9, a 12.5% increase in effective dose

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

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

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

14. Allometric Approaches to Clearance ( Empirical ) Approach 5 Cl = Cl an(in vivo) · Cl h(hepatocytes) /Cl an(hepatocytes) Approach 6 Cl h = a · Cl an Approach 7 Cl h = Cl an · Cl h(hepatocytes) /Cl an(hepatocytes) · (W h /W an ) 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