Evidence map›Paper›PMID 28850715›Full record

Trial reportBritish journal of clinical pharmacology2018

Clinical significance of CYP2C19 polymorphisms on the metabolism and pharmacokinetics of 11β-hydroxysteroid dehydrogenase type-1 inhibitor BMS-823778.

Yaofeng Cheng, Lifei Wang, Lisa Iacono, Donglu Zhang, Weiqi Chen, Jiachang Gong, William Griffith Humphreys, Jinping Gan

Open access · bronzeAbstract readClinical Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in British journal of clinical pharmacology, 2018. 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
0.9field-weighted citation impact, top 24% of its field
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, 10 citations in OpenAlex.

  1. Trial
  2. Review
  3. Review
  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

8 authors at 1 institution in 3 countries.

Yaofeng ChengPharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, NJ, USA.ORCID http://orcid.org/0000-0002-3875-3070
Lifei WangPharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, NJ, USA.
Lisa IaconoRegulatory Documentation Strategy, Bristol-Myers Squibb, Princeton, NJ, USA.
Donglu ZhangGenentech, South San Francisco, CA, USA.
Weiqi ChenPharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, NJ, USA.
Jiachang GongPharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, NJ, USA.ORCID http://orcid.org/0000-0003-0910-1759
William Griffith HumphreysPharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, NJ, USA.
Jinping GanPharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, NJ, USA.
Bristol-Myers Squibb (Germany) · DE

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

aimsBMS-823778 is an inhibitor of 11β-hydroxysteroid dehydrogenase type-1, and thus a potential candidate for Type 2 diabetes treatment. Here, we investigated the metabolism and pharmacokinetics of BMS-823778 to understand its pharmacokinetic variations in early clinical trials.

methodsThe metabolism of BMS-823778 was characterized in multiple in vitro assays. Pharmacokinetics were evaluated in healthy volunteers, prescreened as CYP2C19 extensive metabolizers (EM) or poor metabolizers (PM), with a single oral dose of [

resultsThree metabolites (<5%) were identified in human hepatocytes and liver microsomes (HLM) incubations, including two hydroxylated metabolites (M1 and M2) and one glucuronide conjugate (M3). As the most abundant metabolite, M1 was formed mainly through CYP2C19. M1 formation was also correlated with CYP2C19 activities in genotyped HLM. In humans, urinary excretion of dosed radioactivity was significantly higher in EM (68.8%; 95% confidence interval 61.3%, 76.3%) than in PM (47.0%; 43.5%, 50.6%); only small portions (<2%) were present in faeces or bile from both genotypes. In plasma, BMS-823778 exposure in PM was significantly (5.3-fold, P = 0.0097) higher than in EM. Furthermore, total radioactivity exposure was significantly higher (P < 0.01) than BMS-823778 exposure in all groups, indicating the presence of metabolites. M1 was the only metabolite observed in plasma, and much lower in PM. In urine, the amount of M1 and its oxidative metabolite in EM was 7-fold of that in PM, while more glucuronide conjugates of BMS-823778 and M1 were excreted in PM.

conclusionsCYP2C19 polymorphisms significantly impacted systemic exposure and metabolism pathways of BMS-823778 in humans.

Indexed as

Polymorphism, Genetic11-beta-Hydroxysteroid Dehydrogenase Type 1AdultCytochrome P-450 CYP2C19Drug Administration ScheduleGenotypeGlucuronidesHealthy VolunteersHepatocytesHumansHydroxylationMaleMicrosomes, LiverOxidation-ReductionPyridinesRenal Elimination11-beta-Hydroxysteroid Dehydrogenase Type 1BMS-823778CYP2C19 protein, humanCytochrome P-450 CYP2C19GlucuronidesHSD11B1 protein, humanPyridinesTriazolesclinical pharmacokineticsCYP2C19drug metabolismgenetic polymorphisms

Identifiers

PMID28850715
PMCPMC5736839
OpenAlexW2753157296

What OpenQuestion holds

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Registered trials

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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.