loading page

Confounding mitigation for the exposure-response relationship of bevacizumab in colorectal cancer patients
  • +9
  • Sarah Lobet,
  • Morgane Caulet,
  • Gilles Paintaud,
  • Nicolas Azzopardi,
  • Desvignes Céline,
  • Romain Chautard,
  • Christophe Borg,
  • Olivier Capitain,
  • Aurelie Ferru,
  • Olivier Bouché,
  • Thierry Lecomte,
  • David Ternant
Sarah Lobet
1Inserm UMR 1069, Nutrition Croissance et Cancer (N2C), Tours University, Tours, France
Author Profile
Morgane Caulet
Author Profile
Gilles Paintaud
Universite Francois Rabelais de tours
Author Profile
Nicolas Azzopardi
Author Profile
Desvignes Céline
CNRS UMR 7292, Tours, France
Author Profile
Romain Chautard
Author Profile
Christophe Borg
University Hospital of Besançon
Author Profile
Olivier Capitain
Author Profile
Aurelie Ferru
CHU de Poitiers
Author Profile
Olivier Bouché
Centre Hospitalier Universitaire de Reims
Author Profile
Thierry Lecomte
Tours university hospital
Author Profile
David Ternant

Corresponding Author:[email protected]

Author Profile


Aims. The exposure-response relationship of bevacizumab may be confounded by various factors, i.e. baseline characteristics, time-dependent target engagement and recursive relationships between exposure and response. This work aimed at investigating the exposure-response relationships of bevacizumab in mCRC patients while mitigating potential sources of bias. Methods. Bevacizumab pharmacokinetics was described using target-mediated drug disposition (TMDD) modeling. The relationships between target kinetics, and progression-free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both potential biases due to prognostic-driven and response-driven of the concentration-effect relationship were mitigated. These models were used to evaluate the effect of increased antigen target levels and clearance, as well as intensified dosing regimen, on survival. Results. Estimated target-mediated pharmacokinetic parameters in 130 assessed patients were: baseline target levels (R0=8.4 nM), steady-state dissociation constant (KSS=10 nM) and antibody-target complexes elimination constant (kint=0.52 day-1). Distribution of R0 was significantly associated with an increased baseline CEA and circulating VEGF levels, and the presence of extra-hepatic metastases. Unbound target levels (R) significantly influenced both progression and death hazard functions. Increased R0 or CL values led to decreased bevacizumab unbound concentrations, increased R levels, and shortened PFS and OS, whereas increasing bevacizumab dose led to decreased R and longer survival. Conclusion. This study is the first to show the relationship between bevacizumab concentrations, target involvement and clinical efficacy by mitigating potential sources of bias. Most of target amount may be tumoral in mCRC. A more in-depth description of this relationship should be made in future studies.
25 Sep 2023Submitted to British Journal of Clinical Pharmacology
25 Sep 2023Submission Checks Completed
25 Sep 2023Assigned to Editor
25 Sep 2023Review(s) Completed, Editorial Evaluation Pending
04 Oct 2023Reviewer(s) Assigned
01 Nov 2023Editorial Decision: Revise Minor
20 Nov 20231st Revision Received
20 Nov 2023Submission Checks Completed
20 Nov 2023Assigned to Editor
20 Nov 2023Review(s) Completed, Editorial Evaluation Pending