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Pharmacokinetically-guided dosing to improve the efficacy of brigatinib in non-small cell lung cancer patients
  • +3
  • Simon Koele,
  • Stijn van Beek,
  • Anthonie van der Wekken,
  • Berber Piet,
  • Michel van den Heuvel,
  • Rob ter Heine
Simon Koele
Radboud University Medical Center, Radboud Institute for Health sciences
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Stijn van Beek
Radboud University Medical Cente, Radboud Institute for Health Sciences
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Anthonie van der Wekken
University of Groningen, University Medical Centre Groningen
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Berber Piet
Radboud University Medical Center
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Michel van den Heuvel
Radboud University Medical Center
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Rob ter Heine
Radboud University Medical Center, Radboud Institute for Health sciences
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Abstract

Brigatinib was recently approved for the treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer and is dosed according to a one-dose-fits-all paradigm. We aimed to identify a pharmacokinetically-guided precision dosing strategy to improve treatment response with brigatinib through simulations using a previously published pharmacokinetic-pharmacodynamic model. Dosing strategies explored were the approved 180mg QD, the highest tolerable dose tested in clinical trials: 240mg QD, and two precision dosing strategies targeting the median trough concentrations following 180mg QD, and 240mg QD. We investigated the impact of alternative dosing regimens on progression-free survival (PFS), overall survival (OS), and the probability of developing a grade ≥2 rash or grade ≥2 amylase increase. Median PFS and OS increased by 1.6 and 7.8 months, respectively between the currently approved dosing strategy and precision dosing to the median trough concentration of the 240mg dosing strategy, with only a minor increase in the probability of developing toxicity.

Peer review status:ACCEPTED

06 Jul 2021Submitted to British Journal of Clinical Pharmacology
07 Jul 2021Submission Checks Completed
07 Jul 2021Assigned to Editor
07 Jul 2021Reviewer(s) Assigned
26 Jul 2021Review(s) Completed, Editorial Evaluation Pending
27 Jul 2021Editorial Decision: Revise Major
19 Aug 20211st Revision Received
21 Aug 2021Assigned to Editor
21 Aug 2021Submission Checks Completed
21 Aug 2021Review(s) Completed, Editorial Evaluation Pending
23 Aug 2021Reviewer(s) Assigned
06 Sep 2021Editorial Decision: Revise Minor
08 Sep 20212nd Revision Received
09 Sep 2021Assigned to Editor
09 Sep 2021Submission Checks Completed
09 Sep 2021Review(s) Completed, Editorial Evaluation Pending
12 Sep 2021Editorial Decision: Accept