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Extemporaneous preparation strategy for early phase clinical studies
Rampurna P Gullapalli1, Carolyn L Mazzitelli1, Christina M Charriez1
1Dart NeuroScience LLC, 12278 Scripps Summit Dr., San Diego, CA 92131, United States.
International Journal of Pharmaceutics
|July 29, 2018
Summary
Extemporaneous preparations (EPs) enabled stable oral formulations of the investigational drug DNS-7801. This approach allowed for flexible dosing and achieved dose-proportional exposure in early phase clinical studies.
Area of Science:
- Pharmaceutical Sciences
- Clinical Pharmacology
- Drug Development
Background:
- Extemporaneous preparations (EPs) are increasingly utilized in early phase clinical studies to expedite new medicine development.
- Effective EP strategies demand 'fit-for-purpose' formulation, preparation, and administration with safety, flexibility, cost-effectiveness, and site adaptability.
- DNS-7801, a weakly basic compound, shows pH-dependent solubility, posing risks of variable in vivo exposure.
Purpose of the Study:
- To develop a stable and adaptable extemporaneous preparation (EP) formulation for the investigational compound DNS-7801 for oral administration in early phase clinical studies.
- To assess the pharmacokinetic profile of DNS-7801 following oral administration of the developed EP in non-elderly and elderly subjects.
- To evaluate the compatibility of the EP formulation with a common beverage for taste masking.
Main Methods:
- Formulation of DNS-7801 solutions using a citrate buffer at pH 3.0 and hydroxypropylbetadex to ensure solubility and stability.
- Assessment of formulation stability under various conditions relevant to oral administration.
- Evaluation of compatibility with apple juice for taste masking purposes.
- Pharmacokinetic analysis of DNS-7801 (Cmax, AUC0-24, AUC0-∞) after oral administration in non-elderly and elderly subjects.
Main Results:
- A stable DNS-7801 solution was successfully formulated using citrate buffer (pH 3.0) and hydroxypropylbetadex.
- The formulation demonstrated stability upon manipulation for oral administration and was compatible with apple juice.
- Oral administration of the EP resulted in dose-proportional Cmax, AUC0-24, and AUC0-∞ in both non-elderly and elderly participants.
- The EP approach provided significant flexibility in adjusting DNS-7801 concentration and/or volume for dose selection.
Conclusions:
- Extemporaneous preparation using a citrate buffer and hydroxypropylbetadex is a viable strategy for formulating DNS-7801 solutions for oral administration.
- The developed EP formulation ensures stable drug product and enables dose-proportional pharmacokinetics, supporting its use in early phase clinical trials.
- The flexibility in dose adjustment offered by the EP approach is a key advantage for adaptive trial designs and personalized medicine development.
Keywords:
CompatibilityEarly phase developmentExtemporaneous preparationFirst-in-humanHydroxypropylbetadexOral solutionPharmacokineticsStabilityTaste maskingMore Related Videos
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