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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
Animal Studies andHuman Health Consequences

Sorell L. Schwartz, Ph.D.

Department of Pharmacology

Georgetown University Medical

Center

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

Pharmacokinetics v. Pharmacodynamics
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

Interspecies Scaling(Essentially) IsometricProportion to body weight is constant across species
slide5
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 factors affecting efficacy of interspecies extrapolations
Pharmacokinetic FactorsAffecting Efficacy of Interspecies Extrapolations
  • Volume of distribution
  • Clearance
  • Absorption & Bioavailability
volume of distribution
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
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
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 bioavailability interspecies scalability
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

allometric reliability likely to be more reliable
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 reliability likely to be less reliable
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 to clearance
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)

allometric approaches to clearance empirical
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

application of pbpk modeling to low dose interspecies extrapolation
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 extrapolation18
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
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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