Evidence map›Paper›PMID 26225254›Full record

ArticleCPT: pharmacometrics & systems pharmacology2015

Integration of Physiologically-Based Pharmacokinetic Modeling into Early Clinical Development: An Investigation of the Pharmacokinetic Nonlinearity.

L Zhou, J Gan, H Yoshitsugu, X Gu, J D Lutz, E Masson, W G Humphreys

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in CPT: pharmacometrics & systems pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
0.4field-weighted citation impact, top 30% 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

1 citing paper in PubMed, 3 citations in OpenAlex.

  1. 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

7 authors at 2 institutions in 3 countries.

L ZhouDepartment of Biotransformation, Bristol-Myers Squibb Princeton, New Jersey, USA.
J GanDepartment of Biotransformation, Bristol-Myers Squibb Princeton, New Jersey, USA.
H YoshitsuguExploratory Clinical and Translational Research, Bristol-Myers Squibb Princeton, New Jersey, USA ; Clinical Pharmacology & PPDM, Japan Development, MSD K.K. Tokyo, Japan.
X GuDepartment of Biotransformation, Bristol-Myers Squibb Princeton, New Jersey, USA.
J D LutzDepartment of Biotransformation, Bristol-Myers Squibb Princeton, New Jersey, USA.
E MassonExploratory Clinical and Translational Research, Bristol-Myers Squibb Princeton, New Jersey, USA ; Quantitative Clinical Pharmacology, AstraZeneca Waltham, Massachusetts, USA.
W G HumphreysDepartment of Biotransformation, Bristol-Myers Squibb Princeton, New Jersey, USA.
Bristol-Myers Squibb (Sweden) · SEMSD K.K. (Japan) · JP

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

BMS-911543, a promising anticancer agent, exhibited time-dependent and dose-dependent nonlinear pharmacokinetics (PKs) in its first-in-human (FIH) study. Initial physiologically based pharmacokinetic (PBPK) modeling efforts using CYP1A2-mediated clearance kinetics were unsuccessful; however, further model analysis revealed that CYP1A2 time-dependent inhibition (TDI) and perhaps other factors could be keys to the nonlinearity. Subsequent experiments in human liver microsomes showed that the compound was a time-dependent inhibitor of CYP1A2 and were used to determine the enzyme inactivation parameter values. In addition, a rat tissue distribution study was conducted and human plasma samples were profiled to support the refinement of the PBPK model. It was concluded that the interplay between four BMS-911543 properties, namely, low solubility, saturation of the metabolizing enzyme CYP1A2, CYP1A2 TDI, and CYP1A2 induction likely resulted in the time-dependent and dose-dependent nonlinear PKs. The methodology of PBPK model-guided unmasking of compound properties can serve as a general practice for mechanistic understanding of a new compound's disposition.

Identifiers

PMID26225254
PMCPMC4452934
OpenAlexW1848602875

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC
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.