Pharmacokinetically-guided dosing to improve the efficacy of brigatinib
in non-small cell lung cancer patients
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.