Using PBPK to Simulate Target Biopredictive Dissolution Profiles for Long-Acting Injectables - Where to Begin With...

Area of Science:

• Pharmaceutical Sciences
• Pharmacokinetics
• Drug Delivery

Background:

• Long-acting injectables (LAIs) offer improved medication adherence and sustained drug exposure.
• Biopredictive in vitro dissolution testing is crucial for LAI formulation development and quality control.
• Understanding in vivo dissolution mechanisms is essential for developing accurate in vitro tests.

Purpose of the Study:

• To quantify the impact of in vivo parameters (critical bioavailability attributes) on LAI dissolution.
• To utilize physiologically based pharmacokinetic (PBPK) models for simulating LAI dissolution profiles.
• To establish a design space for biopredictive in vitro dissolution testing methods for LAIs.

Main Methods:

• Developed PBPK models for methylprednisolone acetate LAI.
• Simulated in vivo dissolution profiles by varying critical bioavailability attributes (particle size, solubility, diffusion layer thickness, diffusion coefficient, depot volume).
• Compared simulated in vivo dissolution with existing in vitro data.

Main Results:

• Simulated in vivo dissolution profiles showed significantly slower drug release (80-100% dissolved over 1200 hours) compared to standard in vitro tests (approx. 90% dissolved in 90 minutes).
• Model performance varied based on the source of attribute values (literature vs. prediction).
• The study identified key parameters influencing dissolution rate and profile.

Conclusions:

• In vitro dissolution conditions mimicking low fluid velocities (larger effective particle size, diffusion layer thickness) are needed for biopredictive testing.
• PBPK modeling with plausible attribute value ranges can simulate target dissolution profiles.
• This approach aids in developing robust in vitro dissolution test methods for LAI formulations.