Evidence map›Paper›PMID 31637544›Full record

ArticlePharmaceutical research2019

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 Gesenberg, Neil R Mathias, Yan Xu, John Crison, Ishani Savant, Amy Saari, David J Good, Jeffrey N Hemenway, Ajit S Narang, Richard R Schartman and 3 more

Abstract read
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In one paragraph

Article in Pharmaceutical research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed.

  1. Review
  2. Review
  3. Article
  4. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors.

Christoph GesenbergDrug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey, USA. christoph.gesenberg@bms.com.ORCID http://orcid.org/0000-0003-2374-0610
Neil R MathiasDrug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey, USA.
Yan XuDrug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey, USA.
John CrisonDrug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey, USA.
Ishani SavantClinical Pharmacology, Bristol-Myers Squibb Company, Princeton, New Jersey, USA.
Amy SaariDrug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey, USA.
David J GoodDrug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey, USA.
Jeffrey N HemenwayDrug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey, USA.
Ajit S NarangDrug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey, USA.
Richard R SchartmanPharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Wallingford, Connecticut, USA.
Naiyu ZhengBioanalytical Sciences, Bristol-Myers Squibb Company, Princeton, New Jersey, USA.
Adela BuzescuBioanalytical Sciences, Bristol-Myers Squibb Company, Princeton, New Jersey, USA.
Jatin PatelDrug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey, USA.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

purposeTo 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.

methodsClinical 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.

resultsClinical 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.

conclusionsThe 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.

Indexed as

Computer SimulationIntestinal AbsorptionModels, BiologicalAdministration, OralAnimalsAnti-Ulcer AgentsBiological AvailabilityDogsDrug CompoundingFamotidineFemaleHumansHydrogen-Ion ConcentrationMaleAnti-Ulcer AgentsFamotidinedissolutionpH effectprecipitationrisk assessmentsupersaturation

Identifiers

PMID31637544

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.