Clinical Relevance of High Plasma Trough Levels of the Kinase Inhibitors Crizotinib, Alectinib, Osimertinib, Dabrafenib, and Trametinib in NSCLC Patients

Abstract

Background: the study aims to evaluate whether high plasma trough levels of the kinase inhibitors (K.I.s) crizotinib, alectinib, osimertinib, dabrafenib, and trametinib were associated with a higher risk of toxicity in non-small-cell lung cancer patients. Methods:In this retrospective cohort study, patients with non-smallcell lung cancer treated with the selected K.I.s were included if at least one plasma trough level at steady state (C min,ss ) was available. Data were extracted from electronic medical records and laboratory databases. The high group for each K.I. was defined as 10% of patients with the highest first C min,ss . The remaining patients were placed in the non-high group. The frequency of dose-limiting toxicities (DLTs), defined as adverse events leading to dose reduction, dose interruption, or permanent discontinuation, was compared between the 2 groups.Results: A total of 542 patients were included in the different K.I. groups. A high C min,ss of crizotinib (n = 96), alectinib (n = 105), osimertinib (n = 227), dabrafenib (n = 52), and trametinib (n = 62

Granulomatous hepatitis: Is it bugs, drugs, or other untoward culprits?

“…In support of our hypothesis, trametinib and dabrafenib are both CYP3A4 and CYP2B6 substrates. In addition, patients with high trough levels of dabrafenib were significantly more likely to experience hepatotoxicity compared to those with lower levels 12 . In clinical trials and from postmarketing surveillance, the majority of patients treated with dabrafenib/trametinib who experience hepatotoxicity do so early in their treatment course and rarely after 4 years of continuous dosing 13,14 .…”