Utilization of In Vitro, In Vivo and In Silico Tools to Evaluate the pH-Dependent Absorption of a BCS Class II Compound and Identify a pH-Effect Mitigating Strategy
- Resource Type
- Original Paper
- Authors
- Gesenberg, Christoph; Mathias, Neil R.; Xu, Yan; Crison, John; Savant, Ishani; Saari, Amy; Good, David J.; Hemenway, Jeffrey N.; Narang, Ajit S.; Schartman, Richard R.; Zheng, Naiyu; Buzescu, Adela; Patel, Jatin
- Source
- Pharmaceutical Research: An Official Journal of the American Association of Pharmaceutical Scientists. 36(12)
- Subject
- dissolution
pH effect
precipitation
risk assessment
supersaturation
- Language
- English
- ISSN
- 0724-8741
1573-904X
Purpose: To describe a stepwise approach to evaluate the pH effect for a weakly basic drug by in vitro, in vivo and in silico techniques and identify a viable mitigation strategy that addresses the risk.Methods: Clinical studies included assessment of the pH effect with famotidine. In vitro dissolution was evaluated in various biorelevant media and in a pH-shift test. PK studies in dogs were conducted under pentagastrin or famotidine pre-treatment and GastroPlus was employed to model human and dog PK data and simulate the performance in human.Results: Clinical data indicated considerable pH dependent absorption of the drug when dosed in the presence of H2-antagonists. In vitro dissolution and in vivo dog data confirmed that the observed pH effect was due to reduced dissolution rate and lower solubility at increased gastric and intestinal pH. A salt form was identified to overcome the effect by providing fast dissolution and prolonged supersaturation. GastroPlus simulations predicted a mitigation of the pH effect by the salt.Conclusions: The drug exhibited a strong pH-effect in humans. The in vitro, in vivo and modeling approach provides a systematic workflow to evaluate the risk of a new drug and identify a strategy able to mitigate the risk.