Animal Studies andHuman Health Consequences
Sorell L. Schwartz, Ph.D.Department of Pharmacology
Georgetown University Medical Center
Pharmacokinetics v. Pharmacodynamics
PharmacokineticsAction of the body on
the chemicalSystem: Absorption,
distribution, metabolism, elimination (ADME)
Output: Concentration-time relationships
PharmacodynamicsAction of the chemical
on the bodySystem: Biological
ligands or other targets in the biophase.
Output: Biological response
Pharmacokinetic Dose Extrapolation
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 volumeVital capacityBlood volume
Interspecies ScalingAllometric
Proportion to body weight varies exponentially across species
Y = aWb
Y = Pharmacokinetic parameter; W = Body weight
a = Allometric coefficient; b = scaling exponentb ~ 0.25
• Heart rate• Circulation time• Respiratory rate
b ~ 0.75• Basal metabolic rate• Blood flow• Clearance (flow
limited?)
Pharmacokinetic FactorsAffecting Efficacy of Interspecies
Extrapolations
• Volume of distribution
• Clearance
• Absorption & Bioavailability
• 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).
Total mass in bodyV
Concentration in blood
Volume of Distribution
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)
abs g HF = f (1 - f ) (1-ER )
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 = 0.8 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 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
• 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.
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
Allometric Approaches to Clearance
(Adapted from T. Lave et al., Clin. Pharmacokin. 36:211, 1999)
Allometric Approaches to Clearance (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
nmax biophase
0 n50 biophase
E CE E
ED C
n
max biophase0 n
50 biophase
E CE E
ED C
PBPK Modeling of Metabolite
Application of PBPK Modeling to Low Dose/Interspecies
ExtrapolationDeveloping 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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