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
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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.
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.
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.
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.
Keywordsdissolution pH effect precipitation risk assessment supersaturation
Biopharmaceutics classification system
Fasted state simulated intestinal fluid
Fed state simulated intestinal fluid
Simulated gastric fluid
Simulated intestinal fluid
Compliance with Ethical Standards
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments. Informed consent was obtained from all individual participants included in the study.
Animal studies were performed in accordance with the standards recommended by the Guide for Care and Use for Laboratory Animals (Institute of Animal Laboratory Resources, 1995) and were approved by the institutional animal care use committee with full consideration to experimental refinement, reduction in animal use, and replacement with in vitro methods.
Conflict of Interest
The authors declare that they have no conflict of interest.
- 19.Dickinson PA, Abu Rmaileh R, Ashworth L, Barker AL, Burke WM, Patterson CM, et al. An investigation into the utility of a multi-compartmental, dynamic system of the upper gastrointestinal tract to support formulation development and establish bioequivalence of poorly soluble drugs. AAPS J. 2012;14(2):196–205.CrossRefGoogle Scholar