Risk Assessment for Biopharmaceutics Classification System Class IV Molecule Containing Immediate Release Products:...

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Pharmaceutical Regulatory Science

Background:

• Nitrosamines drug substance related impurities (NDSRI) are potent mutagenic carcinogens requiring strict regulatory control.
• Deviations in drug products leading to NDSRI detection post-bioequivalence studies necessitate additional costly studies.
• Current USFDA guidance offers in vitro alternatives for BCS I-III drugs but recommends PBPK for BCS IV immediate-release (IR) formulations.

Purpose of the Study:

• To discuss the application of physiologically based pharmacokinetic (PBPK) modeling as an alternative bioequivalence (BE) methodology for BCS IV IR products.
• To evaluate an in-house in silico tool for early NDSRI risk prediction based on molecular structure.
• To assess the impact of altered permeability and transporter kinetics on clinical exposure in the presence of antioxidants.

Main Methods:

• Utilized an in-house in silico tool for structural analysis and carcinogenic potential prediction of 37 BCS IV molecules.
• Conducted clinical exposure risk assessments using PBPK modeling for five high-risk BCS IV molecules (edoxaban, selumetinib, bosutinib, furosemide, hydrochlorothiazide).
• Evaluated the impact of permeability changes (±10-20%) and transporter kinetics on drug exposure to define a 'permeability safe space'.

Main Results:

• Successfully predicted carcinogenic potential for 37 BCS IV molecules, identifying five for further detailed risk assessment.
• PBPK models demonstrated the influence of altered permeability and transporter function on drug exposure, particularly with antioxidants.
• Determined the 'permeability safe space' by evaluating the effect of minor permeability variations on clinical exposure.

Conclusions:

• PBPK modeling provides a viable alternative bioequivalence strategy for BCS IV IR products, mitigating risks associated with NDSRIs.
• In silico tools and PBPK modeling can proactively identify and manage NDSRI risks, potentially avoiding costly post-approval studies.
• Defining the 'permeability safe space' through PBPK modeling ensures bioequivalence despite formulation changes affecting absorption.