PI-100 - THE DRUG-DRUG INTERACTION (DDI) EFFECT OF STEADY STATE ITRACONAZOLE EXPOSURE ON SINGLE DOSE PHARMACOKINETICS (PK) OF LAZERTINIB.

J. Mehta¹, N. Haddish-Berhane¹, P. Hellemans², J. Jiao³, C. Thompson¹, S. Jang⁴, D. Kim⁴; ¹Janssen Pharmaceuticals, Spring House, PA, USA, ²Janssen Pharmaceuticals, Beerse, Belgium, ³Janssen Pharmaceuticals, Raritan, NJ, USA, ⁴Yuhan Corporation, Seoul, Republic of Korea.

Background: Lazertinib is a mutant selective irreversible epidermal growth factor receptor tyrosine kinase inhibitor. Invitro studies indicate that cytochrome-mediated metabolism of lazertinib is mainly mediated by CYP3A4, 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, fixed sequence healthy adult participant study NCT04410094. Here we present findings from itraconazole and lazertinib DDI evaluation.

Methods: Sixteen participants received oral 160 mg dose of lazertinib on day 1, oral itraconazole 200 mg from days 8 to 16 with 160 mg lazertinib and 200 mg itraconazole co-administered on day 12. Serial lazertinib blood PK samples were collected over 120 hours postdose on days 1 and 12. Lazertinib PK parameters were estimated by non-compartmental analysis and statistical analysis was performed to determine geometric mean ratios (GMR). The safety of participants was monitored throughout study.

Results: The mean (SD) plasma Cmax, AUC0-120h and t1/2 of lazertinib administered without vs. with itraconazole were 238 (75) vs. 281 (85) ng/ml, 2574 (721) vs. 3787 (1235) h*ng/mL and 54.4 (4.7) vs. 48.8 (2.1) hours respectively. The overall GMR of lazertinib with lazertinib and itraconazole as test treatment and lazertinib as reference treatment for Cmax and AUC0-120h were 119% (90% CI 108, 130) and 146% (90% CI 138, 153) respectively.

Conclusion: The co-administration of lazertinib with strong CYP3A4 inhibitor itraconazole, increased mean plasma AUC0-120h of lazertinib by 47% however the 90% CI of GMR for Cmax and AUC0-120h were below the commonly used no-effect upper limit of 200% suggesting a lack of clinically relevant DDI.