Evidence map›Paper›PMID 28374319›Full record

ArticleThe AAPS journal2017

Application of a PK-PD Modeling and Simulation-Based Strategy for Clinical Translation of Antibody-Drug Conjugates: a Case Study with Trastuzumab Emtansine (T-DM1).

Aman P Singh, Dhaval K Shah

Abstract readValidation Study
PubMed Full text at PMC Publisher
In one paragraph

Article in The AAPS journal, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.

0numbers the graph read from it
0cells of the map it votes in
30citing 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

30 citing papers in PubMed.

  1. Article
  2. Article
  3. Review
  4. Review
  5. Review
  6. Scission-Enhanced Molecular Imaging (SEMI).Bioconjugate chemistry · 2024
    Article
  7. Article
  8. Article
  9. Article
  10. Article
  11. Article
  12. Article
  13. Review
  14. Review
  15. Article
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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

2 authors.

Aman P SinghDepartment of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York at Buffalo, 455 Kapoor Hall, Buffalo, New York, 14214-8033, USA.
Dhaval K ShahDepartment of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York at Buffalo, 455 Kapoor Hall, Buffalo, New York, 14214-8033, USA. dshah4@buffalo.edu.

Funding

Translational Systems Pharmacokinetic Models of Novel Anticancer BiologicsR01GM114179 · NIGMS · STATE UNIVERSITY OF NEW YORK AT BUFFALO · PI SHAH, DHAVAL K · 2015 to 2019
$1.7M
NIGMS NIH HHS R01 GM114179
6 · The paper itself

Abstract

Successful clinical translation of antibody-drug conjugates (ADCs) can be challenging due to complex pharmacokinetics and differences between preclinical and clinical tumors. To facilitate this translation, we have developed a general pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation (M&S)-based strategy for ADCs. Here we present the validation of this strategy using T-DM1 as a case study. A previously developed preclinical tumor disposition model for T-DM1 (Singh and Shah, AAPSJ. 2015; 18(4):861-875) was used to develop a PK-PD model that can characterize in vivo efficacy of T-DM1 in preclinical tumor models. The preclinical data was used to estimate the efficacy parameters for T-DM1. Human PK of T-DM1 was a priori predicted using allometric scaling of monkey PK parameters. The predicted human PK, preclinically estimated efficacy parameters, and clinically observed volume and growth parameters for breast cancer were combined to develop a translated clinical PK-PD model for T-DM1. Clinical trial simulations were performed using the translated PK-PD model to predict progression-free survival (PFS) and objective response rates (ORRs) for T-DM1. The model simulated PFS rates for HER2 1+ and 3+ populations were comparable to the rates observed in three different clinical trials. The model predicted only a modest improvement in ORR with an increase in clinically approved dose of T-DM1. However, the model suggested that a fractionated dosing regimen (e.g., front loading) may provide an improvement in the efficacy. In general, the PK-PD M&S-based strategy presented here is capable of a priori predicting the clinical efficacy of ADCs, and this strategy has been now retrospectively validated for all clinically approved ADCs.

Indexed as

Ado-Trastuzumab EmtansineHumansImmunoconjugatesMaytansineModels, BiologicalTrastuzumabAdo-Trastuzumab EmtansineImmunoconjugatesMaytansineTrastuzumabantibody-drug conjugatesmodeling and simulationobjective response ratesPK-PDpreclinical-to-clinical translationprogression-free survivalT-DM1

Identifiers

PMID28374319
PMCPMC5849468

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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.