Effects of Acid-Reducing Agents on the Pharmacokinetics of Lazertinib in Patients with EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer

Abstract

Introduction: Lazertinib is an irreversible, mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Co-administration of TKIs with acid-reducing agents (ARAs) can lead to potential drug-drug interactions, which decreases solubility and absorption of TKIs and is ultimately associated with reduced efficacy of TKIs. This retrospective analysis evaluated the effect of ARAs on the pharmacokinetics of lazertinib using data obtained from patients with advanced EGFR mutation-positive non-small-cell lung cancer.

Methods: In a total of 234 patients with lazertinib pharmacokinetics observed at steady state, dose-normalized (DN) area under the concentration-time curve (AUC_ss), maximum concentration (C_max,ss), and/or trough concentration on day 15 (C_D15) were compared between a group receiving ARA concomitantly for at least 4 days (ARA group) and another group not receiving ARA (non-ARA group) in a dose-proportional range. Additionally, a comparison of pharmacokinetic parameters at a therapeutic dose of 240 mg once daily was evaluated.

Results: Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) of ARA group to non-ARA group for DNAUC_ss, DNC_max,ss, and DNC_D15 at 40 mg to 320 mg once daily showing the dose proportionality were 0.8743 (0.7285-1.0493), 0.9035 (0.7482-1.0910), and 0.9126 (0.7364-1.1311), respectively. GMRs with 90% CIs for AUC_ss, C_max,ss, and C_D15 at 240 mg were 0.9136 (0.6637-1.2576), 0.9012 (0.6703-1.2116), and 0.8850 (0.6463-1.2118), respectively.

Conclusion: All pharmacokinetic parameters were not significantly different between the two groups (p values > 0.05), indicating that co-administered ARAs did not significantly affect the steady state pharmacokinetics of lazertinib. Therefore, no dose adjustment of lazertinib is required in patients receiving concomitant ARAs.

Gov identifiers: NCT03046992, NCT04075396.

Keywords: Acid-reducing agent; Drug–drug interactions; Lazertinib; Pharmacokinetics; Tyrosine kinase inhibitor.

Fig. 1

Dose proportionality of lazertinib in the dose range of 40 to 320 mg. The circles represent the observed values, the black straight line represents the linear regression line, and the red and blue dashed lines represent the 90% confidence limits and 90% prediction limits, respectively: a ln(AUC_ss) versus ln(dose); b ln(C_max,ss) versus ln(dose); c ln(C_D15) versus ln(dose)

Fig. 2

Comparison of the dose-normalized pharmacokinetic parameters of lazertinib between the ARA and non-ARA groups in the dose range of 40 to 320 mg. The dashed and solid lines across each box represent the median and arithmetic mean of the dose-normalized pharmacokinetic parameters, respectively. The upper and lower whiskers represent the maximum and minimum values within 1.5-fold interquartile range: a dose-normalized AUC_ss; b dose-normalized C_max,ss; c dose-normalized C_D15

Fig. 3

Comparison of the pharmacokinetic parameters of lazertinib between the ARA and non-ARA groups at 240 mg. The dashed and solid lines across each box represent the median and arithmetic mean of the pharmacokinetic parameters, respectively. The upper and lower whiskers represent the maximum and minimum values within 1.5-fold interquartile range: a AUC_ss; b C_max,ss; c C_D15

Fig. 4

Geometric mean ratios of ARA group to non-ARA group with 90% confidence intervals of pharmacokinetic parameters of lazertinib: empty circle, square, and triangle represent the geometric mean ratio of the dose-normalized AUC_ss, C_max,ss, and C_D15 of ARA group to non-ARA group, respectively, in the dose range of 40 to 320 mg. Filled circle, square, and triangle represent the geometric mean ratio of the dose-normalized AUC_ss, C_max,ss, and C_D15 of ARA group to non-ARA group, respectively, at 240 mg. The line extending from the point represents the 90% confidence interval for each geometric mean ratio