Establishing the Safe Space via Physiologically Based Biopharmaceutics Modeling. Case Study: Fevipiprant/QAW039.

Area of Science:

• Biopharmaceutics
• Pharmacokinetics
• Drug Product Quality

Background:

• Physiologically based pharmacokinetic (PBPK) and absorption modeling are crucial in biopharmaceutics for establishing safe operating spaces for drug product attributes like dissolution.
• Understanding the impact of in vitro dissolution on in vivo performance is essential for drug development and commercial scale-up.

Purpose of the Study:

• To establish a fevipiprant (QAW039) dissolution safe space using clinical data and in vitro dissolution profiles.
• To assess the impact of dissolution on the in vivo performance of immediate-release fevipiprant tablets.
• To define acceptance criteria for dissolution that ensure bioequivalence.

Main Methods:

• Simulations using GastroPlus™ software with quality control dissolution profiles as inputs.
• Utilizing clinical pharmacokinetic (PK) data from bioequivalent and non-bioequivalent fevipiprant formulations.
• Developing a predictive model to estimate in vivo dissolution and human exposure.

Main Results:

• A fevipiprant dissolution safe space was successfully established.
• The model accurately predicted the performance of various oral dosage forms (150–500 mg).
• A dissolution specification of Q=80% dissolved in ≤60 minutes defined the safe space boundaries.
• The commercial scale batch dissolution profile fell within the anticipated bioequivalence region.

Conclusions:

• The established safe space supports wider dissolution acceptance criteria (e.g., >10% difference for bioequivalent batches) than traditional f2 similarity analyses.
• PBPK modeling provides confidence in drug product quality and bioequivalence predictions.
• This approach enhances the understanding of the relationship between in vitro dissolution and in vivo performance for immediate-release dosage forms.