Clinical manifestations and pharmacokinetic properties of brigatinib/brigatinib

Brigatinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor designed to overcome the resistance mechanism of crizotinib and is approved for the treatment of ALK-positive advanced or metastatic non-small cell lung cancer. Following a single oral dose of brigatinib 30-240 mg, the median time to reach maximum plasma concentration is 1 to 4 hours. In patients with advanced malignancies, brigatinib was dose linear over the dose range of 60 to 240 mg once daily. A high-fat meal has no clinically meaningful effect on the systemic exposure of brigatinib (area under the plasma concentration-time curve); therefore, brigatinib may be taken with or without food.

In a population pharmacokinetic analysis, a three-compartment pharmacokinetic model with transport-absorption compartments was found to be sufficient to describe the pharmacokinetics of brigatinib. In addition, population pharmacokinetic analysis showed that no dose adjustment was necessary based on body weight, age, race, sex, total bilirubin (<1.5 times the upper limit of normal), and mild to moderate renal impairment. Data from dedicated phase I trials indicate that no dose adjustment is required in patients with mild or moderate hepatic impairment, whereas a dose reduction of approximately 40% (e.g., from 180 to 120 mg) is recommended in patients with severe hepatic impairment and by approximately 50% (e.g., from 180 to 90 mg) in patients with severe renal impairment.

Brigatinib is mainly metabolized by cytochrome P450 (CYP) 3A. The results of clinical drug interaction studies and physiologically based pharmacokinetic analysis indicate that the combination of strong or moderate CYP3A inhibitors or inducers with brigatinib should be avoided. If coadministration with strong or moderate CYP3A inhibitors cannot be avoided, the brigatinib dose should be reduced by approximately 50% (strong CYP3A inhibitors) or approximately 40% (moderate CYP3A inhibitors), respectively.