ADME Simulations: Insights into Bioavailability and Pharmacokinetics

How Crystal Pharmatech, a leading CRDMO, leverages GastroPlus® to guide small molecule development and manufacturing decisions.

GastroPlus® Background

• GastroPlus® is an advanced software tool used in pharmaceutical development for physiologically-based pharmacokinetic (PBPK) modeling.

• GastroPlus® leverages in-vivo and in-vitro data to simulate and predict the ADME profile of drug candidates in animal and human models.

• It simulates partitioning and absorption for 9 different segments of the GI tract.

Crystal Pharmatech and GastroPlus®

1. First, we gather all available data, including:

• Physicochemical properties

• Dose, dosage form, dose frequency

• IV data

• PO data

2. Then, we build the animal models.

• Animal models are consistently updated as new PK data becomes available

• Species-specific modeling accounts for differences in GIT, metabolism, and more

3. Next, we leverage the data and models built in GastroPlus® to generate human PK predictions including:

• Human-specific bioavailability and PK

• Impact on F% from varying doses and dosing frequency

4. Finally, we analyze the parameter sensitivity to understand what we can do to maximize in vivo performance.

• Human-specific bioavailability and PK

• Impact on F% from varying doses and dosing frequency

Outcomes:

• GastroPlus®, combined with experienced solid-state chemists and formulators, can provide invaluable insights for lead candidate selection and the optimal GLP Tox and FIH formulation approaches.

• The insights gained by integrating GastroPlus® into your research and development strategy save drug innovators time, money, and material.

Crystal Pharmatech background

• To be pulled from previous flyers…

GastroPlus® Case Study

An innovator with a first-in-class drug is heading into GLP Tox. Toxicity is difficult to obtain and the FIH dose is uncertain, so the client set a high target exposure in GLP Tox.

• What dose is needed to reach the high target exposure in GLP Tox and enable flexibility in FIH dose escalation?

• Based on the dose, determined with the help of PBPK modeling, what is the best formulation to proceed with?

Modeling Enterohepatic Recirculation (EHC) in Dogs

• The dog model was preferred over the rat model as rats do not have a gallbladder.

• Model guided by oral data to determine the amount of EHC.

• Predicted dog clearance was used to scale into human model.

• Human model shows high fraction absorbed driven by EHC with strong bioavailability

• Due to uncertainty in the amount of EHC, the lower limit without EHC was also generated to establish a “worst case scenario”.

• Parameter sensitivity showed increased solubility will improve bioavailability, but by a limited amount.

This indicated the bioavailability may not be entirely solubility limited.

• Particle size is predicted to have an impact on bioavailability.

This dictated the particle size range that was adequate to achieve target.

• Increasing dose is predicted to have an impact on bioavailability.

Solubility limited drug and increasing dose increase precipitation potential, decreasing bioavailability.

Outcome:

GastroPlus® provided the client and formulation team with critical insights to guide dosing and formulation development strategy, maximizing bioavailability and enabling the greatest flexibility in FIH dose escalation.

• Dose strength reduced from initial estimates to prevent precipitation

• Solubility enhanced with amorphous formulation

• Particle size controlled to maximize the predicted impact