Development of Mechanistic In Vitro-In Vivo Extrapolation to Support Bioequivalence Assessment of Long-Acting...

Area of Science:

• Pharmacokinetics and Drug Delivery
• Biopharmaceutical Sciences
• Computational Modeling

Background:

• Long-acting injectable (LAI) formulations enhance drug efficacy, safety, and patient compliance through sustained release.
• Challenges in LAI development and regulatory assessment stem from a poor understanding of tissue responses, such as inflammation, at the injection site.
• In silico methods offer a promising avenue for elucidating LAI-physiology interactions.

Purpose of the Study:

• To employ a mechanistic modeling approach to characterize the in vivo performance of DepoSubQ Provera® and its variants in preclinical models.
• To predict human drug exposure by extrapolating findings from animal models.
• To identify key physiological events and product attributes influencing LAI in vivo performance.

Main Methods:

• Utilized a physiologically based pharmacokinetic (PBPK) modeling approach.
• Evaluated critical factors in LAI administration, including particle size and local tissue response.
• Integrated in vitro data with in vivo observations in preclinical species.

Main Results:

• The effective in vivo particle size may exceed the measured in vitro size due to particle aggregation at the injection site.
• Local inflammation was identified as a significant factor, causing a temporary increase in depot volume.
• The PBPK model successfully delineated in vivo performance and informed predictions of human exposure.

Conclusions:

• Mechanistic modeling provides valuable insights into the in vivo performance of LAIs.
• Particle aggregation and local inflammation are critical determinants of LAI drug release and depot behavior.
• This approach can guide the development and regulatory evaluation of LAI drug products by identifying key performance-influencing factors.