Evidence map›Paper›PMID 38700808›Full record

ArticleDrugs in R&D2024

Retrospective Assessment of Translational Pharmacokinetic-Pharmacodynamic Modeling Performance: A Case Study with Apitolisib, a Dual PI3K/mTOR Inhibitor.

Anita Moein, Jin Y Jin, Matthew R Wright, Bruno Alicke, Harvey Wong

2 registry-linked trialsAbstract readClinical Trial, Phase IMulticenter Study
PubMed Full text at PMC Publisher
In one paragraph

Article in Drugs in R&D, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 2 registered trials, which are not on this map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing 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.

NCT00854126 phase1completednot on this map

An Open-label, Phase I, Dose-escalation Study Evaluating GDC-0980 Administered Once Weekly in Patients With Refractory Solid Tumors and Non-hodgkin's Lymphoma

TypeinterventionalSponsorGenentech, Inc.Ran2009 to 2012Enrolled38ConditionsNon-Hodgkin's Lymphoma, Solid CancersArmsGDC-0980
NCT00854152 phase1completednot on this map

An Open-label, Phase I, Dose-Escalation Study Evaluating the Safety, Tolerability, and Maximally Tolerated Dose of GDC-0980 Administered Once Daily in Patients With Refractory Solid Tumors and Non-Hodgkin's Lymphoma

TypeinterventionalSponsorGenentech, Inc.Ran2009 to 2014Enrolled121ConditionsNon-Hodgkin's Lymphoma, Solid CancersArmsGDC-0980
3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Review
  2. Thieno[3,2-International journal of molecular sciences · 2026
    Review
  3. 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

5 authors.

Anita MoeinFaculty of Pharmaceutical Sciences, University of British Columbia, Office 5505, Pharmaceutical Sciences Building, Vancouver, BC, Canada.
Jin Y JinGenentech, Inc., South San Francisco, CA, USA.
Matthew R WrightGenentech, Inc., South San Francisco, CA, USA.
Bruno AlickeGenentech, Inc., South San Francisco, CA, USA.
Harvey WongFaculty of Pharmaceutical Sciences, University of British Columbia, Office 5505, Pharmaceutical Sciences Building, Vancouver, BC, Canada. harvey.wong@ubc.ca.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

BACKGROUND AND

objectivesDespite significant progress in biomedical research, the rate of success in oncology drug development remains inferior to that of other therapeutic fields. Mechanistic models provide comprehensive understanding of the therapeutic effects of drugs, which is crucial for designing effective clinical trials. This study was performed to acquire a better understanding of PI3K-AKT-TOR pathway modulation and preclinical to clinical translational bridging for a specific compound, apitolisib (PI3K/mTOR inhibitor), by developing integrated mechanistic models.

methodsIntegrated pharmacokinetic (PK)-pharmacodynamic (PD)-efficacy models were developed for xenografts bearing human renal cell adenocarcinoma and for patients with solid tumors (phase 1 studies) to characterize relationships between exposure of apitolisib, modulation of the phosphorylated Akt (pAkt) biomarker triggered by inhibition of the PI3K-AKT-mTOR pathway, and tumor response.

resultsBoth clinical and preclinical integrated models show a steep sigmoid curve linking pAkt inhibition to tumor growth inhibition and quantified that a minimum of 35-45% pAkt modulation is required for tumor shrinkage in patients, based on platelet-rich plasma surrogate matrix and in xenografts based on tumor tissue matrix. Based on this relationship between targeted pAkt modulation and tumor shrinkage rate, it appeared that a constant pAkt inhibition of 61% and 65%, respectively, would be necessary to achieve tumor stasis in xenografts and patients.

conclusionsThese results help when it comes to evaluating the translatability of the preclinical analysis to the clinical target, and provide information that will enhance the value of future preclinical translational dose-finding and dose-optimization studies to accelerate clinical drug development. TRIAL REGISTRY: ClinicalTrials.gov NCT00854152 and NCT00854126.

Indexed as

Carcinoma, Renal CellKidney NeoplasmsMTOR InhibitorsPhosphoinositide-3 Kinase InhibitorsAnimalsAntineoplastic AgentsCell Line, TumorFemaleHumansMiceNeoplasmsProto-Oncogene Proteins c-aktRetrospective StudiesTOR Serine-Threonine KinasesXenograft Model Antitumor AssaysAntineoplastic AgentsMTOR InhibitorsMTOR protein, humanPhosphoinositide-3 Kinase InhibitorsProto-Oncogene Proteins c-aktTOR Serine-Threonine Kinases

Identifiers

PMID38700808
PMCPMC11315854

What Socratic holds

Textmetadata
LicenceCC BY-NC
Read underepoch 390

Registered trials

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 Socratic graph.