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Solubility of Hydrophobic Compounds in Aqueous Solution Using Combinations of Self-assembling Peptide and Amino Acid
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Utilizing physiologically based pharmacokinetic modeling to inform formulation and clinical development for a
John Chung1, Fernando Alvarez-Nunez, Vincent Chow
1Pharmaceutics Research and Development, Amgen, Inc., Thousand Oaks, California.
Journal of Pharmaceutical Sciences
|February 3, 2015
Summary
ARRY-403, a diabetes drug, showed less than dose-proportional exposure due to pH-dependent solubility. Physiologically based pharmacokinetic (PBPK) modeling confirmed dose-limited absorption, guiding clinical study design.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Pharmaceutical Sciences
- Computational Biology
Background:
- ARRY-403 is a novel glucokinase activator investigated for diabetes treatment.
- Initial clinical studies revealed less than dose-proportional drug exposure following single ascending doses.
Purpose of the Study:
- To elucidate the causes of non-linear pharmacokinetics for ARRY-403.
- To develop and refine a physiologically based pharmacokinetic (PBPK) model for ARRY-403.
- To predict the impact of coadministered acid-reducing agents (ARAs) on ARRY-403 exposure.
Main Methods:
- Integrated in vitro physicochemical data with in vivo precipitation time estimations.
- Developed a PBPK model incorporating dose, particle size, and fed/fasted state.
- Performed sensitivity analyses and simulated ARA coadministration using the refined PBPK model.
Main Results:
- PBPK modeling identified dose-limited absorption due to pH-dependent solubility as the primary cause of non-proportional exposure.
- Simulations predicted significant effects of ARAs on ARRY-403 exposure.
- Clinical study with famotidine confirmed the predicted marked effect on ARRY-403 exposure.
Conclusions:
- The study successfully applied a "predict, learn, and confirm" approach using PBPK modeling.
- Physicochemical properties and PBPK modeling are crucial for understanding drug behavior and guiding clinical development.
- PBPK modeling effectively informed formulation development and clinical study design for ARRY-403.
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