Pharmacokinetic & Physiologically Based Pharmacokinetic (PBPK) Analysis

Physiologically Based Pharmacokinetic (PBPK) modeling is a mathematical modeling technique for predicting the absorption, distribution, metabolism, and excretion of synthetic or natural chemical substances in humans and other animal species. Exponent offers regulatory, litigation and product-development support to clients that can benefit from PBPK-based analysis, assessment, critical evaluation, or scientific peer-review. Regulatory proceedings and litigation increasingly involve PBPK modeling methods to improve chemical exposure and risk assessments concerning occupational and environmental health, pharmaceuticals, food safety, and medical devices. Exponent scientists are experienced in developing and applying these methods to reconstruct exposure and dose, as well as to improve dose-response characterizations that play a critical role in risk assessment.

PBPK models apply a realistic mathematical description of physiology, anatomy, and biochemistry to simulate exposures by multiple routes to environmental toxicants, trace elements, food additives, or pharmaceuticals. These types of models allow for simulation of the resulting time course of absorption systemic distribution, metabolism (to active or inactive metabolites), and excretion (ADME). An extension of PBPK modeling includes addition of a pharmacodynamic (PD) component, which allows for simulation of not only the pharmacokinetics resulting from an exposure, but also for simulation of the biochemical (toxicological or therapeutic) response resulting from an external exposure or administered dose.

These models improve dose-response characterization by allowing an understanding of the relationship between experimental or environmental levels of exposure (or external or administered dose) and internal dose (target tissue or blood concentrations), as the target tissue concentration is highly correlated with a compound’s toxicity (or in the case of drugs, efficacy). In the case of a PBPK/PD model, such modeling allows for a better understanding of dose-response, as an external dose can then be linked to a particular internal dose that induces the biochemical response (e.g., acetylcholinesterase inhibition by certain insecticides or CYP inhibition by certain drugs). PBPK/PD models allow for simulation of various exposure scenarios, such as dietary, occupational, or clinical dosing regimens, as well as simulation from multiple exposure routes (e.g., dermal, oral, inhalation).

After appropriate validation, PBPK models developed for animals or humans can be applied in various ways. A “forward” approach starts with a set of exposure data, and uses PBPK modeling to estimate corresponding chemical concentrations in the target tissue or blood. A “reverse” approach (known as reverse dosimetry) starts with internal chemical-exposure measures (usually biomonitoring samples of blood, urine, or tissue), and uses PBPK modeling to estimate corresponding levels of external exposure. Statistical and Monte Carlo methods are used to estimate PBPK model parameters and to characterize uncertainty in PBPK model predictions. PBPK models account for both inter- and and intraspecies differences and they can be used to improve the health risk assessment of environmental chemicals. Monte Carlo analysis can be used in combination with the PBPK model in order to characterization population variability with regard to risk through the use of data-derived extrapolation factors. These factors are more specific to the conditions under study and may be considered more scientifically sound than default uncertainty factors that are often applied when deriving risk values. PBPK modeling can also be used to guide drug development, as internal concentrations within the therapeutic index or those resulting from a particular dosing regimen can be estimated both in animals and humans.

Our PBPK modeling team applies PBPK techniques to complement and enhance exposure and risk assessments for specific chemicals/agents, such as petroleum hydrocarbons, metals, pesticides, phthalates, organic solvents, and volatile/halogenated compounds . This expertise is also available to support pre-clinical pharmaceutical and medical-device evaluations (e.g., concerning expected rates of absorption, stability in tissues, hepatic clearance, and temporal plasma and tissue concentration profiles, of test agents or materials, their metabolites, or any related contaminants).

Exponent PBPK-related Publications

Bogen, KT, Heilman J. Reassessment of MTBE cancer potency considering modes of action for MTBE and its metabolites. Crit Rev Toxicol 2015 doi.10.3109/10408444.2015.1052367 (in press).

Bogen KT. An adjustment factor for mode of action uncertainty with dual-mode carcinogens: The case of naphthalene-induced nasal tumors in rats. Risk Anal 2008; 28(4):1033–1051.

Bogen KT, Swirsky Gold L. Trichloroethylene cancer risk: simplified calculation of PBPK-based MCLs for cytotoxic endpoints. Regul Toxicol Pharmacol 1997; 25:2642.

Loccisano, AE, Campbell, J, Andersen, ME, Clewell, HJ. Evaluation and prediction of pharmacokinetics of PFOA and PFOS in the monkey and human using a PBPK model. Regul Toxicol Pharmacol 2011; 59: 157-175. 

Loccisano, AE, Campbell, J, Butenhoff, JL, Andersen, ME, Clewell, HJ. Comparison and evaluation of pharmacokinetics of PFOA and PFOS in the adult rat using a physiologically based pharmacokinetic model. Reprod Toxicol 2012; 33: 452-467. 

Loccisano, AE, Campbell, J, Butenhoff, JL, Andersen, ME, Clewell, HJ. Evaluation of placental and lactational pharmacokinetics of PFOA and PFOS in the pregnant, lactating, fetal, and neonatal rat using a physiologically based pharmacokinetic model. Reprod Toxicol 2012; 33: 468-490. 

Loccisano, AE, Longnecker, MP, Campbell, J, Andersen, ME, Clewell, HJ. Development of PBPK models for PFOA and PFOS for human pregnancy and lactation life stages. J Toxicol Environ Health A 2013; 76: 25-57. 

Verner, MA, Loccisano, AE, Morken, NH, Yoon, M, Wu, H, McDougall, R, Maisonet, M, Marcus, M, Kishi, R, Miyashita, C, Chen, MH, Hsieh, WS, Andersen, ME, Clewell, HJ, Longnecker, MP. Association of Perfluoroalkyl Substances (PFAS) with Lower Birth Weight: An Evaluation of Potential Confounding by Glomerular Filtration Rate Using a Physiologically Based Pharmacokinetic Model (PBPK. Environ Health Persp. 2015; 123: 1317-1324. 

Campbell, JL, Van Landingham, C, Crowell, S, Gentry, R, Kaden, D, Fiebelkorn, S, Loccisano, A, Clewell, HJ. A preliminary regional PBPK model of lung metabolism for improving species dependent descriptions of 1,3-butadiene and its metabolites. Chem Biol Interact 2015; 238: 102-110.

PBPK figure 1 

Figure 1.Exponent PBPK modeling expertise was used to adapt biokinetic models for (a) soluble cobalt injected over a 20-day period into circulating human blood at age 20, and (b-d) for blood lead concentration (BPb) after human oral intake of lead. TWA = time-weighted average.

PBPK figure 2

Figure 2. Applications of Exponent’s Mathematica-implemented CalEPA OEHHA  “Legget+” biokinetic model for lead (Pb): (a) kinetics of blood lead (BPb) after oral vs. inhalation exposure to Pb, (b) predicted increase over 1.5-µg/dL background BPb level due to episodic exposures to ~0.15 µg/m3 of Pb in air associated with coal fly-ash dust.



News & Events