(428f) How Modeling Tools Benefit Early to Late Stage Formulation Development and the Design of Clinical Studies

Pharmacokinetic absorption modeling and simulation is widely used through many drug
development stages as a powerful tool for assessing biopharmaceutical risk to, and in silico
data. PK absorption modeling tools leverage in vitro, and in vivo to greatly impact formulation
development, clinical study design, and regulatory submission. The aim of this presentation is
to demonstrate the applications of modeling tools and how they affect drug development
decisions.

Four case studies of absorption modeling and simulations combined with conventional analysis
tools will be presented. Commercially available software (GastroPlus, v8.5) was used to build
PBPK models for the dog and human physiologies. These models were parameterized based
on the compound's physicochemical properties, in vitro biorelevant dissolution in fasted state
simulated intestinal fluid (FaSSIF), fed state simulated intestinal fluid (FeSSIF) and in vivo data
(clearance, plasma time profile, etc.) for each drug.

Rodent and human physiology models in the GastroPlus program were tested, modified, and
optimized to obtain a best reliable model to enable decision making based on certain stage of
the project. Parameter sensitivity analysis was used to analyze the impact of formulation
factors (dose level, particle size, dissolution rate, etc.) to AUG and Cmax in simulated human
clinical studies. The case studies cover:

1. Comparing the exposures and pharmacokinetic profile of crystalline material and amorphous
   dispersions.
2. The impact of drug dose and administration with food on exposure.
3. The impact of particle size on expsoure
4. The impact of patient variability on single and multiple doses using virtual clinical trial
   simulation

An exploratory clinical study was conducted with larger particle size material, higher dose
levels and a standard to evaluate the food effect, dose linearity and particle size risk, and the
results aligned with the GastroPlus predictions. The PBPK model output was used to provide
guidance on evaluating the biopharmaceutical risk in humans and served as enable decision
on formulation development and influencing the clinical development plan.