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Animal Studies and Human Health Consequences. Sorell L. Schwartz, Ph.D. Department of Pharmacology Georgetown University Medical Center. Pharmacokinetics Action of the body on the chemical System: Absorption, distribution, metabolism, elimination (ADME)

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Animal Studies and Human Health Consequences

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Animal Studies andHuman Health Consequences

Sorell L. Schwartz, Ph.D.

Department of Pharmacology

Georgetown University Medical

Center


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


Pharmacokinetic Dose Extrapolation


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


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


Pharmacokinetic FactorsAffecting Efficacy of Interspecies Extrapolations

  • Volume of distribution

  • Clearance

  • Absorption & Bioavailability


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).


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


Absorption & Bioavailability (F)

where

fabs = fraction absorbed from GI lumen

fg = fraction metabolized by GI tissue

ERH = hepatic extraction ratio, equivalent to hepatic “first pass” effect

1 - F = “presystemic elimination”


Absorption & BioavailabilityInterspecies Scalability

The greater the ERH , the greater the likelihood that interspecies differences in absorbed dose will be magnified!

Why?

ERH = 0.81 – ERH = 0.2

Consider 12.5% reduction in ER

ERH = 0.71 – ERH = -.3, a 50% increase in effective dose

Conversely

ERH = 0.21 – ERH = 0.8

Consider 50% reduction in ER

ERH = 0.11 – ERH = 0.9, a 12.5% increase in effective dose


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.


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.


Allometric Approaches toClearance

Approach 1 Cl = a · Wb

(Neoteny)

Approach 2Cl = a · Wb/MLP

Approach 3Cl = 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)


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


Physiologically Based PK-PD Model


PBPK Modeling of Metabolite


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.


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.


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


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