A Drug–Drug Interaction Study of Mobocertinib and Midazolam, a Cytochrome P450 3A Substrate, in Patients With Advanced Non–Small Cell Lung Cancer

• Published in: Clinical pharmacology in drug development Vol. 14; no. 3; pp. 252 - 262
• Main Authors: Hanley, Michael J., Zhang, Steven, Pavlakis, Nick, Soo, Ross A., Wekken, Anthonie J., Ganju, Vinod, Piña, Adela, Dong, Qi, Gupta, Neeraj
• Format: Journal Article
• Language: English
• Published: United States 01.03.2025
• Subjects: Administration, Intravenous; Administration, Oral; Adult; Aged; Aged, 80 and over; Aniline Compounds; Area Under Curve; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Cytochrome P-450 CYP3A - metabolism; cytochrome P450 (CYP) 3A; Drug Interactions; drug–drug interaction; epidermal growth factor receptor; Female; Humans; Indoles; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Male; midazolam; Midazolam - administration & dosage; Midazolam - adverse effects; Midazolam - pharmacokinetics; Middle Aged; mobocertinib; non‐small cell lung cancer; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Pyrimidines; drug–drug interaction; midazolam; mobocertinib; cytochrome P450 (CYP) 3A; epidermal growth factor receptor; non‐small cell lung cancer
• ISSN: 2160-763X; 2160-7648
• DOI: 10.1002/cpdd.1500

Mobocertinib is a kinase inhibitor designed to selectively target epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations in non‐small cell lung cancer. This drug–drug interaction study assessed the effect of multiple‐dose administration of mobocertinib on the pharmacokinetics (PK) of midazolam, a sensitive cytochrome P450 3A substrate. Patients with locally advanced or metastatic non‐small cell lung cancer refractory/intolerant to standard available therapy were enrolled. In Cycle 1 (Part A; PK cycle), a single 3‐mg oral dose of midazolam was administered on Days 1 and 24, and a single 1‐mg intravenous dose of midazolam was administered on Days 2 and 25. Mobocertinib 160 mg once daily was administered orally on Days 3‐30. After Cycle 1, patients could continue receiving mobocertinib in 28‐day cycles in Part B of the study. The study objective was to characterize the effect of mobocertinib on the single oral‐ and intravenous‐dose PK of midazolam. Safety and exploratory efficacy were also assessed. Twenty‐six patients were enrolled, and 13 patients were PK‐evaluable. Safety findings were consistent with the known safety profile of mobocertinib, and diarrhea was the only Grade 3 or higher treatment‐related adverse event observed in more than 2 patients. Two of 16 patients with EGFR exon 20 insertion mutations were confirmed responders per investigator. Coadministration of mobocertinib decreased the area under the plasma concentration–time curve from time zero to infinity of oral and intravenous midazolam by approximately 32% and 16%, respectively (geometric least‐squares mean ratios of 0.676 and 0.837, respectively).