Use of in vitro data in developing a physiologically based pharmacokinetic model: Carbaryl as a case study

Area of Science:

• Toxicology and Risk Assessment
• Pharmacokinetics and Pharmacodynamics
• Computational Biology

Background:

• In vitro data are increasingly vital for chemical risk assessment.
• Physiologically based pharmacokinetic (PBPK) modeling integrates experimental data to link in vitro concentrations to human exposures.
• A key challenge for PBPK models is the need for extensive chemical-specific parameters.

Purpose of the Study:

• To demonstrate an in vitro data-based parameterization approach for developing a PBPK/PD model.
• To use carbaryl as a case study for this in vitro to in vivo extrapolation (IVIVE) approach.
• To explore the potential of this method for other anticholinesterase compounds and environmental chemicals.

Main Methods:

• Performed in vitro experiments to obtain carbaryl-specific pharmacokinetic (PK) and pharmacodynamic (PD) parameters.
• Measured metabolic clearance and cholinesterase (ChE) interaction parameters in rat and human tissues.
• Extrapolated in vitro PK/PD data to a whole-body PBPK model using biologically appropriate scaling.

Main Results:

• Developed a PBPK/PD model for carbaryl parameterized with in vitro data.
• Successfully predicted carbaryl's in vivo kinetics and ChE inhibition dynamics.
• Demonstrated a reasonably successful IVIVE approach for PBPK model development using carbaryl.

Conclusions:

• The in vitro data-based PBPK/PD modeling approach is effective for chemical risk assessment.
• This IVIVE methodology can be applied to other carbamates and environmental chemicals.
• The approach minimizes the need for in vivo human data in PBPK model development and risk assessment.