# Pharmacokinetics - Summary

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# 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 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 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

6 Exclusive Property of the Council for the Advancement of Pyrethroid Human Risk Assessment, LLC (CAPHRA)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 7 Exclusive Property of the Council for the Advancement of 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 8 Exclusive Property of the Council for the Advancement of Pyrethroid Human Risk Assessment, LLC (CAPHRA)

# 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. • B ased 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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