Application of Physiologically-Based Pharmacokinetic (PBPK) Modeling in IND Submissions
Physiologically-based pharmacokinetic (PBPK) modeling is a computational approach used to simulate the absorption, distribution, metabolism, and excretion (ADME) of compounds in humans and animals using anatomical and physiological parameters. In the context of IND submissions, PBPK models provide a powerful tool for bridging preclinical and clinical data, guiding dose selection, predicting tissue exposure, and informing safety margins.
PBPK models are constructed using compartments that represent real tissues or organs, each defined by parameters such as tissue volume, blood flow, and permeability. These models incorporate in vitro data, such as hepatic microsomal clearance or plasma protein binding, and combine them with in vivo ADME data to simulate systemic exposure under various dosing regimens. In toxicology, PBPK modeling helps compare internal doses between test species and humans, supports extrapolation across exposure routes, and refines human equivalent dose (HED) calculations from animal NOAELs.
For drugs with narrow therapeutic indices or complex distribution kinetics, PBPK models help predict accumulation in sensitive tissues, such as the brain or heart, and enable early identification of potential toxicities. They also provide a framework for evaluating drug–drug interactions, special populations (e.g., pediatrics or renal impairment), and interspecies differences. Regulatory agencies increasingly accept PBPK models as part of IND and NDA submissions when well-validated and supported by experimental data.
The growing use of PBPK modeling represents a shift toward mechanistically driven toxicology and pharmacokinetics. When integrated with toxicology findings, these models help create a more complete safety profile, supporting rational clinical development and regulatory decision-making.