PII-110 - DRUG-DRUG INTERACTION EFFECT OF STEADY STATE LAZERTINIB EXPOSURE ON THE SINGLE-DOSE PHARMACOKINETICS OF MIDAZOLAM, ROSUVASTATIN AND METFORMIN.

J. Mehta¹, M. Sanga², N. Haddish-Berhane², P. Hellemans³, D. Jonathan², J. Jiao², C. Thompson⁴, S. Bok Jang⁵; ¹Janssen Research & Development LLC, ²Janssen Research and Development LLC, ³3Janssen Research & Development, a division of Janssen Pharmaceutica NV, ⁴Janssen Research and Development, ⁵Yuhan Corporation.

Background: Lazertinib is a mutant selective irreversible epidermal growth factor receptor tyrosine kinase inhibitor. In-vitro studies showed that lazertinib inhibits CYP3A4 enzyme, BCRP and OCT1 transporters. A clinical study was conducted to evaluate the potential for drug-drug interactions (DDIs) when lazertinib is co-administered with CYP3A4, BCRP and OCT1 substrates.

Methods: NCT05076877 was a non-randomized, open-label, multiple dose, single-center, Phase 1 PK study in 20 healthy participants. On Study Day 1 participants received a single oral dose of the probe substrates (midazolam for CYP3A4, rosuvastatin for BCRP, and metformin for OCT1) administered simultaneously under fasting conditions to assess PK of probe substrates when administered alone. Following 4 days washout , from Study Day 5 to 14, participants received lazertinib (160 mg) once daily under fed conditions (except for Study Day 13 with fasting intake) to achieve steady-state concentrations. On Study Day 13, participants received a single oral dose of the probe substrates along with lazertinib under fasting conditions to assess the PK parameters of the probe substrates when co-administered with lazertinib. The safety of participants was monitored throughout the study.

Results: Co-administration of lazertinib with probe substrates was safe and well tolerated. The co-administration of midazolam with lazertinib increased midazolam plasma exposure by < 2-fold. The midazolam geometric mean ratios (GMR, 90% CI) for Cmax and AUC0-last were 1.39 (1.23, 1.58) and 1.47 (1.34, 1.60) respectively, when co-administered with lazertinib, relative to midazolam alone. The co-administration of rosuvastatin with lazertinib increased rosuvastatin plasma exposure by >2-fold. The rosuvastatin GMR (90% CI) for Cmax and AUC0-last were 2.24 (1.82, 2.76) and 2.02 (1.70, 2.40) respectively, when co-administered with lazertinib, relative to rosuvastatin alone. The co-administration of metformin with lazertinib did not increase metformin plasma exposure. The metformin GMR (90% CI) for Cmax and AUC0-last were 0.81 (0.72, 0.91) and 0.94 (0.83, 1.06) respectively, when co-administered with lazertinib, relative to metformin alone.

Conclusion: Lazertinib is a weak inhibitor of CYP3A4 enzyme, a moderate inhibitor of BCRP transporter and not an inhibitor of OCT1 transporter.