Pharmacokinetics - Summary

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Pyrethroid Human Risk Assessment, LLC (CAPHRA) 1
Pharmacokinetics - Summary

• Multiple in vivo rat studies, including new CAPRHA-sponsored studies demonstrate 

significantly elevated brain levels in juveniles versus adults at the same dose;

• Existing and CAPHRA-sponsored data have led to refinements in the developing rat 

PBPK model proving the viability of In Vitro to In Vivo Extrapolation;

• Rat PBPK predictions are consistent with in vivo determinations that at high doses, 

due to limited metabolic capacity, juvenile rats have higher plasma and brain levels 

than adults. This is accompanied by in vivo observations of neurotoxicity in 

juvenile rats at comparable administered doses to adults that are exhibiting 

minimal or no toxicity.

• Model predictions also confirm that as doses are lowered, the age-related 

differential disappears. At lower doses, the young rat has adequate capacity to 

metabolize the administered dose.

• Because of the species differences in Cyp/CES and earlier ontogeny of pyrethroidmetabolizing enzymes in humans versus the rat, and age –related changes in 

physiologic factors, the developing human PBPK model predicts that juvenile 

humans will have lower plasma and brain concentrations than adults.

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Hypothesis #3:

Data can support read-across from a limited 

number of pyrethroids to the entire class

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Data to Support Read-Across

• The Seven Core Pyrethroids

– Type I 

• Bifenthrin, Permethrin, Pyrethrum, 

Prallethrin

– Type II 

• Cypermethrin, Deltamethrin

– Mixed 

• Esfenvalerate

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Status

D Studies Complete

U Studies Underway

X Studies Planned

M Model- Predicted Values

N Not Needed

? Uncertain if Needed

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CAPHRA Research Program - Data Development Plans 

Phase I Phase II Phase III

Program Element Deltamethrin Permethrin (cis, trans) Remaining 5 core actives Remaining 

Pyrethroids

PHARMACODYNAMICS

In Vivo - Acoustic Startle Response (ASR) Done Done N N

In Vivo - Detailed Clinical Observations (DCO) Done Done N N

In Vitro - Rat Neurolemma Done Done X N

In Vitro - Human Ion Channels Done Done Done N

PBPK MODEL PARAMETERIZATION

Partition Coefficients Done Done M? M?

Kinetics (Clint) - Human Adult - in vitro

Microsomes/cytosol U X N N

Estimated via expressed enzymes U X X X

Kinetics (Clint) - Human Juvenile - in vitro

Microsomes/cytosol X N N N

Estimated via expressed enzymes U X X X

Kinetics (Km, Vmax) - Rat Adult - in vitro 

Microsomes/cytosol/plasma D X X N

Kinetics (Km, Vmax)- Rat Juvenile - in vitro 

Microsomes/cytosol/plasma D X X N

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Pyrethroid Human Risk Assessment, LLC (CAPHRA)
Phase I Phase II Phase III

Program Element Deltamethrin Permethrin (cis, trans) Remaining 5 core actives Remaining 

Pyrethroids

Pharmacokinetics - Rat - in vivo D D

X - limited (e.g., brain & 

plasma, 2 doses @ 3 times) N

Plasma Protein Binding

Human Adult D D X ?

Human Juvenile D D X ?

Rat Adult D D X N

Rat Juvenile D D X N

Transport Systems - Blood Brain Barrier (BBB)

In vitro D X ?

In situ U X X

Transport Systems - Gastrointestinal (GI) Tract

CACO-2 D X X N

Ex vivo U X ? N

PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING

Human - Adult D X X ?

Human - Juvenile D X X ?

Rat - Adult D X N N

Rat - Juvenile D X N N

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Conclusions

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Age-Related Sensitivity – Pharmacokinetics

Criteria for Assessment

• Is the target tissue concentration following a given 

environmentally relevant dose of deltamethrin 

similar to or less in a 1-2 year old child compared to 

an adult human? 

– Less than. Because of the species differences in CYP/CES 

and earlier ontogeny of pyrethroid-metabolizing enzymes 

in humans versus the rat, and age–related changes in 

physiologic factors, the developing human PBPK model 

predicts that juvenile humans will have lower plasma and 

brain concentrations of deltamethrin than adults following 

an identical administered dose.

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Age-Related Sensitivity – Pharmacodynamics

Criteria for Assessment

• Rat In Vivo Studies

– Are target tissue concentrations associated with NOAELs 

for neurotoxicity in PND15 rats comparable or higher than 

in adult rats?

• Higher. Predicted brain Cmax levels in PND15 and adult 

rats at the common NOAEL for neurotoxicity (1 

mg/kg/day) indicate that the brain Cmax would be ~4x 

higher in PND15 than in adults. This suggests that, if 

anything, the PND15 animals are less sensitive to 

pyrethroids than adults. 

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Age-Related Sensitivity – Pharmacodynamics

Criteria for Assessment

• Human Ion Channels

Are the channel most associated with early post-natal life more 

sensitive to effects from pyrethroids than a channel that becomes 

predominate later in life?

• The channel most prevalent in juveniles aged 1-2 years (and 

most likely, adults) is less sensitive than the isoform more 

prevalent at birth. Therefore, at the level of the isolated 

human ion channel, the evidence argues against any PD 

difference likely to favor increased sensitivity of the young 

(older than ~6 months).

• Moreover, the studies confirmed other reports that human 

channels are less sensitive to pyrethroids than rats.

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Age-Related Sensitivity – Pharmacodynamics

Criteria for Assessment

• Neurolemma from Rat Brains

– Do the responses to deltamethrin differ between rat 

neurolemma preparations derived from PND15 and Adult 

rats?

• Rat neurolemma studies conducted with a wide range 

of deltamethrin and permethrin concentrations show 

no age-related differences in sensitivity (relative 

potency).

• Both pyrethroids appeared to be more efficacious on 

the adult versus the juvenile neurolemma-injected 

oocytes.

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Conclusions

• Based on our work with deltamethrin age-related 

pharmacodynamic differences are unlikely to play a role in juvenile 

sensitivity. 

• Key species-specific pharmacokinetic differences between rats and 

humans making human significantly more adept at pyrethroid 

detoxification. 

• Based on existing and new data on deltamethrin and the 

application of IVIVE, the developing human model predicts that 

age-related pharmacokinetic differences lead to lower (not higher, 

as with the developing rat model) plasma and brain concentrations.

• All things considered, juveniles are not likely to be more sensitive to 

deltamethrin neurotoxicity than adults. 

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Thank You

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