Use of PBPK Modeling and Toxicokinetics/Toxicodynamics (TK/TD) for Sensitive Populations and Lifestages

Hugh A. Barton ILSI Annual Meeting January 22, 2007 Outline

• Background • Lifestages • Lactational exposure • PK Polymorphisms • Conclusions

This presentation does not necessarily reflect EPA policy. What is Pharmacokinetics? • What the body does to a chemical • Absorption, Distribution, Metabolism, Excretion (ADME) • Pharmacokinetics = Toxicokinetics • Pharmacodynamics: What the chemical does to the body (PD=TD) Pharmacokinetics & Age/Lifestage • Pregnancy (mother & embryo/fetus) • Lactation (mother & preweaning offspring) • Post-weaning juvenile/child • Puberty • Young Adult/Adult • Aged Corley RA, Mast TJ, Carney EW, Rogers JM, Daston GP. Evaluation of physiologically based models of pregnancy and lactation for their application in children's health risk assessments. Crit Rev Toxicol. 2003;33(2):137-211 Evaluating Risks to Early Ages • Extrapolation from adult to children Changes in exposure Changes in pharmacokinetics/toxicokinetics Changes in pharmacodynamics/toxicodynamics • Extrapolation across-species Toxicity studies: developmental (in utero), 2- generation reproductive/developmental, developmental neurotoxicity PK PD (window of susceptibility, critical period) Predicting Across Sensitive Populations, Lifestages, Species

Neonatal Model Maternal Model

Lung Lung

Poorly Richly Perfused Perf. Richly Perfused Poorly Perf. Liver Mammary Gut Metabolism Liver

Metab Gut

Placenta

Liver

Brain

Body

Embryo/Fetal Model Mapping Cross-species

birth weaning

PK&PD PK&PD

birth weaning

PD PK Lactational Modeling

• Different dosing approaches in reproductive studies • Gavage: constant mg/kg/day to dam • Diet or drinking water: unadjusted constant ppm • Up to 3-fold increased mg/day during lactation • Diet: adjusted ppm during lactation • ~constant mg/day during lactation to dam • Different chemical properties • Half life • Milk: dam’s plasma ratio • Metabolism BBPK Model for Early Post-Natal Exposure

Dam Ked Dose Kad Cd Feeding vs. Gavage Vd

Milk

Cm Weaning on PND21 Vm

Kap

Post-weaning Exposure Pups N*V Kap p Kep Feeding vs. Gavage Cp

N = number of pups/litter Biological Changes during Post-Natal Period

• Factors influencing maternal exposure during lactation Increase in dam body weight Increasing dam food consumption • Factors influencing pup exposure during lactation and early post-weaning Increase in pup body weight Changing pup milk consumption during lactation Increased post-weaning pup food consumption • Factors to be implemented Consumption of dam’s food during late lactation Changes in PK during development (PK different from the dam) Changes in Body Weight and Food Consumption of Rat Dam

70 400 350 60 300 50 250 early 40 200 late 150 30 100 20 Body Weight (g) Body 50 10

0 Feed Consumption (g/day) 0 Prebreed Gestation Lactation Prebreed Gestation Lactation Lactational Summary • Internal concentrations in pups and dams vary across lactational and early post-natal period Dependent upon half life Dependent upon PK similarity/difference to adult Dependent upon exposure regimen • Post-weaning exposure of pups can be higher than the lactational exposure. Gas Exchange

Brain

Rats: GI Tract Arterial Pups: 20 g (10 day) Liver Adult: 200 g (60 day)

Metabolism Venous Aged: 450 g (2 yr) Kidney

Fat

Slowly Perfused

Rapidly Perfused Physiological Parameters in PBPK Models Cardiac Index vs Age

120

100

CI-S&H CI-A&H 60 CI-V&A CI-D

20 Cardiac Index (mL/min/100g)

0 0 100 200 300 400 500 600 700 800 Age (days) PBPK models often scale flows and clearances (including metabolism) by BW0.75 and tissue volumes by BW. This is an ASSUMPTION!! VOCs: Rats, 500 ppm

Ranked by Lipophilicity

Cl Cl Cl H Cl O Cl

C C C C H C Cl Cl C H >> > > > H3C C CH2CH3 > Cl Cl Cl Cl Cl H Perchloroethylene Trichloroethylene Benzene Chloroform Methylethylketone Methylene Chloride

Ranked by Water Solubility

O Cl Cl Cl H Cl Cl

H3C C CH2CH3 >> Cl C H > H C Cl > > C C > C C

H Cl Cl Cl Cl Cl Methylethylketone Methylene Chloride Chloroform Benzene Trichloroethylene Perchloroethylene

Rodriguez et al. (2007) submitted Chloroform: Rats – 6 hr, 500 ppm

CHLOROFORM

30 Adult

25 PND10 Aged 20

15 CV (mg/L)CV

0 0 5 10 15 20 25 time (hrs)

Venous Concentration of VOCs After a 500 ppm Exposure for 6 Hours Methyl Ethyl Ketone: Rats – 6 hr, 500 ppm

METHYLETHYLKETONE

140

120 Adult

100 PND10 Aged

60 CV (mg/L)

0 0 5 10 15 20 25 time (hrs) Trichloroethylene: Rats – 6 hr, 500 ppm

TRICHLOROETHYLENE

30 Adult

25 PND10 Aged

15 CV (mg/L)

0 0 5 10 15 20 25 time (hrs) Modeling Population Variability

Nong A, McCarver DG, Hines RN, Krishnan K. Modeling interchild differences in pharmacokinetics on the basis of subject-specific data on physiology and hepatic CYP2E1 levels: a case study with toluene. Toxicol Appl Pharmacol. Fig. 5. Inhalation PBPK model simulations of venous blood concentrations in 2006 214(1):78-87. children (n = 116; from birth to 17 years old) exposed for 7 h to 17 ppm of toluene. This exposure concentration and duration correspond to those of a previous study in which adult volunteers were exposed to toluene for collection of data on blood concentrations (represented as symbols) (Tardif et al., 1997). PK Polymorphisms

Jonsson F, Johanson G. A Bayesian analysis of the influence of GSTT1 polymorphism on the cancer risk estimate for dichloromethane. Toxicol Appl Pharmacol. 2001 174(2):99-112.

Inclusion of all three GSTT1 genotypes (0/0, +/0, and +/+) Conclusions • PBPK models are valuable tools for analyzing, predicting, hypothesizing changes in dosimetry for sensitive populations and lifestages • PK in animals and humans of different ages • Lactational modeling has implications for developmental toxicity study interpretation • Polymorphisms of PK determinants and role in population risk estimates Conclusions • Possible modeling applications for sensitive populations: PK differences due to changes in physiology and biochemistry (e.g., age, lifestage, health status, nutritional status, genetics) Evaluate differences in pharmacodynamic events included in models (e.g., enzyme inhibition, GSH depletion) or in linked models (e.g., hormonal regulation). Acknowledgements

• Miyoung Yoon, NRC • Chester Rodriguez, US EPA