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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
  • 247 Downloads

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.

Keywords

dissolution pH effect precipitation risk assessment supersaturation 

Abbreviations

BCS

Biopharmaceutics classification system

EDTA

Ethylenediaminetetraacetic acid

EtOH

Ethanol

FaSSIF

Fasted state simulated intestinal fluid

FeSSIF

Fed state simulated intestinal fluid

GI

Gastrointestinal

HCl

Hydrochloric acid

PBPK

Physiologically-based pharmacokinetic

PK

Pharmacokinetic

SGF

Simulated gastric fluid

SIF

Simulated intestinal fluid

Notes

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.

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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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