024: The Drug-Drug Interaction Effect of Steady State Rifampin Exposure on Single Dose Pharmacokinetics of Lazertinib

Lazertinib is a mutant selective irreversible epidermal growth factor receptor tyrosine kinase inhibitor. Lazertinib is primarily metabolized by glutathione S-transferase mu1 (GSTM1) mediated glutathione conjugation with a relatively minor contribution from CYP3A4 mediated oxidative metabolic pathway and hence lazertinib systemic exposure may be affected by concomitant administration of strong CYP3A4 inhibitors (eg. itraconazole) or inducers (eg. rifampin). The clinical relevance of CYP3A4 mediated DDI with lazertinib as victim was evaluated in phase 1, open-label, 2-period and fixed sequence healthy adult participant study NCT04410094. Here we present findings from rifampin and lazertinib DDI evaluation.   

Description of Methods & Materials:

Sixteen participants received oral 240 mg dose of lazertinib on day 1 and oral rifampin 600 mg once daily from days 8 to 22 with 240 mg lazertinib co-administered on day 19. Serial blood samples for lazertinib PK evaluation were collected over 120 hours postdose on days 1 and 19. Lazertinib PK parameters were estimated by non-compartmental analysis and statistical analysis was performed to determine geometric mean ratios (GMR) and associated 90% confidence interval (90% CI). The safety of participants was monitored throughout study. 

Data & Results:

The mean (SD) plasma C_max, AUC_0-120h and t_1/2 of lazertinib administered without vs. with rifampin were 303 (136) vs. 85.5 (35.3) ng/ml, 3379 (1239) vs. 562 (211) h*ng/mL and 47.5 (8.52) vs. 28.6 (18.4) hours respectively. The overall GMR (90% CI) of lazertinib with lazertinib and rifampin as test treatment and lazertinib only as reference treatment for C_max and AUC_0-120h were 28.16% (23.16% – 34.25%) and 16.52% (14.05% – 19.43%) respectively. 

Overall, single dose of lazertinib with or without coadministration of rifampin was safe and well tolerated. Adverse events reported were known effects of lazertinib and rifampin. No new safety findings were observed during study conduct.

Interpretation, Conclusion or Significance:

The co-administration of lazertinib with strong CYP3A4 inducer rifampin, significantly decreased lazertinib plasma exposure. The co-administration of lazertinib with strong CYP3A4 inducers should be avoided.

Disclosures:

Citations/References:

Additional Information/Authors: Not applicable