Christoph Gesenberg1,2, Neil R Mathias3, Yan Xu3,4, John Crison3, Ishani Savant5,6, Amy Saari3,7, David J Good3, Jeffrey N Hemenway3,8, Ajit S Narang3,9, Richard R Schartman10,11, Naiyu Zheng12, Adela Buzescu12, Jatin Patel3,13. 1. Drug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey, USA. christoph.gesenberg@bms.com. 2. Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey, USA. christoph.gesenberg@bms.com. 3. Drug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey, USA. 4. Quantitative Clinical Pharmacology, Acerta Pharma, LLC, A Member of the AstraZeneca Group, South San Francisco, California, USA. 5. Clinical Pharmacology, Bristol-Myers Squibb Company, Princeton, New Jersey, USA. 6. Clinical Pharmacology and Translational Medicine, Eisai Inc., Woodcliff Lake, New Jersey, USA. 7. Drug Safety Evaluation, Bristol-Myers Squibb Company, New Brunswick, New Jersey, USA. 8. Formulation and Process Development, Gilead Sciences, Inc., Foster City, California, USA. 9. Small Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, California, USA. 10. Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Wallingford, Connecticut, USA. 11. PreFormulation Solutions, Wallingford, Connecticut, USA. 12. Bioanalytical Sciences, Bristol-Myers Squibb Company, Princeton, New Jersey, USA. 13. Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
Abstract
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.
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.
Authors: Yi Gao; Robert A Carr; Julie K Spence; Weili W Wang; Teresa M Turner; John M Lipari; Jonathan M Miller Journal: Mol Pharm Date: 2010-08-17 Impact factor: 4.939
Authors: Neil R Mathias; Yan Xu; Dhaval Patel; Michael Grass; Brett Caldwell; Casey Jager; Jim Mullin; Luke Hansen; John Crison; Amy Saari; Christoph Gesenberg; John Morrison; Balvinder Vig; Krishnaswamy Raghavan Journal: Mol Pharm Date: 2013-09-26 Impact factor: 4.939
Authors: Rong Zhou; Paul Moench; Christopher Heran; Xujin Lu; Neil Mathias; Teresa N Faria; Doris A Wall; Munir A Hussain; Ronald L Smith; Duxin Sun Journal: Pharm Res Date: 2005-02 Impact factor: 4.200