Pharmaceutical Research

, 36:164 | Cite as

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

  • Christoph GesenbergEmail author
  • Neil R. Mathias
  • Yan Xu
  • John Crison
  • Ishani Savant
  • Amy Saari
  • David J. Good
  • Jeffrey N. Hemenway
  • Ajit S. Narang
  • Richard R. Schartman
  • Naiyu Zheng
  • Adela Buzescu
  • Jatin Patel
Research Paper



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.


dissolution pH effect precipitation risk assessment supersaturation 



Biopharmaceutics classification system


Ethylenediaminetetraacetic acid




Fasted state simulated intestinal fluid


Fed state simulated intestinal fluid




Hydrochloric acid


Physiologically-based pharmacokinetic




Simulated gastric fluid


Simulated intestinal fluid


Compliance with Ethical Standards

Ethical Approval

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.


  1. 1.
    Budha NR, Frymoyer A, Smelick GS, Jin JY, Yago MR, Dresser MJ, et al. Drug absorption interaction between oral targeted anticancer agents and PPIs: is pH-dependent solubility the Achilles heel of targeted therapy? Clin Pharmacol Ther. 2012;92:203–13.CrossRefGoogle Scholar
  2. 2.
    Mitra A, Kesisoglou F. Impaired drug absorption due to high stomach pH: a review of strategies for mitigation of such effects to enable pharmaceutical product development. Mol Pharm. 2013;10(11):3970–9.CrossRefGoogle Scholar
  3. 3.
    Lahner E, Annibale B, Delle-Fave G. Systematic review: impaired drug absorption related to the co-administration of antisecretory therapy. Aliment Pharmacol Ther. 2009;29:1219–29.CrossRefGoogle Scholar
  4. 4.
    Russell TL, Berardi RR, Barnett JL, O’Sullivan TL, Wagner JG, Dressman JB. pH-related changes in the absorption of dipyridamole in the elderly. Pharm Res. 1994;11(1):136–43.CrossRefGoogle Scholar
  5. 5.
    Krishna G, Moton A, Ma L, Medlock MM, McLeod J. Pharmacokinetics and absorption of posaconazole oral suspension under various gastric conditions in healthy volunteers. Antimicrob Agents Chemother. 2009;53(3):958–66.CrossRefGoogle Scholar
  6. 6.
    McColl KEL, El-Omar E, Gillen D. Interactions between H. pylori infection, gastric acid secretion and anti-secretory therapy. Br Med Bull. 1998;54(1):121–38.CrossRefGoogle Scholar
  7. 7.
    Russell TL, Berardi RR, Barnett JL, Dermentzoglou LC, Jarvenpaa KM, Schmaltz SP, et al. Upper gastrointestinal pH in seventy nine healthy, elderly, north American men and women. Pharm Res. 1993;10(2):187–96.CrossRefGoogle Scholar
  8. 8.
    Morihara M, Aoyagi N, Kaniwa N, Kojima S, Ogata H. Assessment of gastric acidity of Japanese subjects over last 15 years. Biol Pharm Bull. 2001;24(3):313–5.CrossRefGoogle Scholar
  9. 9.
    Gao Y, Carr RA, Spence JK, Wang WW, Turner TM, Lipari JM, et al. A pH-dilution method for estimation of biorelevant drug solubility along the gastrointestinal tract: application to physiologically based pharmacokinetic modeling. Mol Pharm. 2010;7(5):1516–26.CrossRefGoogle Scholar
  10. 10.
    Zhou R, Moench P, Heran C, Lu X, Mathias N, Faria TN, et al. pH-dependent dissolution in vitro and absorption in-vivo of weakly basic drugs: development of a canine model. Pharm Res. 2005;22(2):188–92.CrossRefGoogle Scholar
  11. 11.
    Mathias NR, Xu Y, Patel D, Grass M, Caldwell B, Jager C, et al. Assessing the risk of pH dependent absorption for new molecular entities: a novel in vitro dissolution test, physicochemical analysis, and risk assessment strategy. Mol Pharm. 2013;10:4063–73.CrossRefGoogle Scholar
  12. 12.
    Fancher RM, Zhang H, Sleczka B, Derbin G, Rockar R, Marathe P. Development of a canine model to enable the preclinical assessment of pH-dependent absorption of test compounds. J Pharm Sci. 2011;100(7):2979–88.CrossRefGoogle Scholar
  13. 13.
    Mitra A, Kesisoglou F, Beauchamp M, Zhu W, Chiti F, Wu Y. Using absorption simulation and gastric pH modulated dog model for formulation development to overcome achlorhydria effect. Mol Pharm. 2011;8:2216–23.CrossRefGoogle Scholar
  14. 14.
    Mathias NR, Crison J. The use of modeling tools to drive efficient oral product design. AAPS J. 2012;14:591–600.CrossRefGoogle Scholar
  15. 15.
    Alam MA, Ali R, Al-Jenoobi FI, Al-Mohizea AM. Solid dispersions: a strategy for poorly aqueous soluble drugs and technology updates. Expert Opin Drug Deliv. 2012;9(11):1419–40.CrossRefGoogle Scholar
  16. 16.
    Tran PH, Tran TT, Lee KH, Kim DJ, Lee BJ. Dissolution-modulating mechanism of pH modifiers in solid dispersion containing weakly acidic or basic drugs with poor water solubility. Expert Opin Drug Deliv. 2010;7(5):647–61.CrossRefGoogle Scholar
  17. 17.
    Badawy SIF, Hussain MA. Microenvironmental pH modulation in solid dosage forms. J Pharm Sci. 2007;96(5):948–59.CrossRefGoogle Scholar
  18. 18.
    Badawy SIF, Gray D, Zhao F, Sun D, Schuster AE, Hussain MA. Formulation of solid dosage forms to overcome gastric pH interaction of the factor Xa inhibitor, BMS-561389. Pharm Res. 2006;23(5):989–96.CrossRefGoogle Scholar
  19. 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
  20. 20.
    Litou C, Vertzoni M, Goumas C, Vasdekis V, Xu W, Kesisoglou F, et al. Characterization of the human upper gastrointestinal contents in the fasted state under hypo- and a-chlorhydric gastric conditions of typical drug - drug interaction studies. Pharm Res. 2016;33:1399–412.CrossRefGoogle Scholar
  21. 21.
    Serajuddin ATM. Salt formation to improve drug solubility. Adv Drug Deliv Rev. 2007;59:603–16.CrossRefGoogle Scholar
  22. 22.
    Stephenson GA, Aburub A, Woods TA. Physical stability of salts of weak bases in the solid-state. J Pharm Sci. 2011;100(5):1607–17.CrossRefGoogle Scholar
  23. 23.
    Ovesen L, Bendtsen F, Tage-Jensen U, Pedersen NT, Gram BR, Rune SJ. Intraluminal pH in the stomach, duodenum, and proximal jejunum in normal subjects and patients with exocrine pancreatic insufficiency. Gastroenterology. 1986;90(4):958–62.CrossRefGoogle Scholar
  24. 24.
    Fallingborg J. Intraluminal pH of the human gastrointestinal tract. Dan Med Bull. 1999;46(3):183–96.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Christoph Gesenberg
    • 1
    • 2
    Email author
  • Neil R. Mathias
    • 1
  • Yan Xu
    • 1
    • 3
  • John Crison
    • 1
  • Ishani Savant
    • 4
    • 5
  • Amy Saari
    • 1
    • 6
  • David J. Good
    • 1
  • Jeffrey N. Hemenway
    • 1
    • 7
  • Ajit S. Narang
    • 1
    • 8
  • Richard R. Schartman
    • 9
    • 10
  • Naiyu Zheng
    • 11
  • Adela Buzescu
    • 11
  • Jatin Patel
    • 1
    • 12
  1. 1.Drug Product Science and TechnologyBristol-Myers Squibb CompanyNew BrunswickUSA
  2. 2.Pharmaceutical Candidate OptimizationBristol-Myers Squibb CompanyPrincetonUSA
  3. 3.Quantitative Clinical Pharmacology, Acerta PharmaLLC, A Member of the AstraZeneca GroupSouth San FranciscoUSA
  4. 4.Clinical PharmacologyBristol-Myers Squibb CompanyPrincetonUSA
  5. 5.Clinical Pharmacology and Translational MedicineEisai Inc.Woodcliff LakeUSA
  6. 6.Drug Safety EvaluationBristol-Myers Squibb CompanyNew BrunswickUSA
  7. 7.Formulation and Process DevelopmentGilead Sciences, Inc.Foster CityUSA
  8. 8.Small Molecule Pharmaceutical SciencesGenentech, Inc.South San FranciscoUSA
  9. 9.Pharmaceutical Candidate OptimizationBristol-Myers Squibb CompanyWallingfordUSA
  10. 10.PreFormulation SolutionsWallingfordUSA
  11. 11.Bioanalytical SciencesBristol-Myers Squibb CompanyPrincetonUSA
  12. 12.Constellation PharmaceuticalsCambridgeUSA

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