Metabolism and Excretion of [14C]Mobocertinib, a Selective Covalent Inhibitor of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations, in Healthy Male Subjects

• Published in: Drug metabolism and disposition Vol. 52; no. 10; pp. 1115 - 1123
• Main Authors: Chen, Hao, Shah, Abhi, Kato, Suguru, Griffin, Robert, Zhang, Steven, Pusalkar, Sandeepraj, Cohen, Lawrence, Li, Yuexian, Chowdhury, Swapan K., Zhu, Sean Xiaochun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2024
• Subjects: absorption, distribution, metabolism, and excretion; accelerator mass spectrometry; ADME; Administration, Oral; Adult; AMS; Aniline Compounds; Carbon Radioisotopes; cDNA-expressed recombinant human cytochrome P450 (Supersomes); CYP; cytochrome P450; EGFR; epidermal growth factor receptor; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; ErbB Receptors - metabolism; ex20ins; exon 20 insertion; Exons; Feces - chemistry; Healthy Volunteers; high resolution mass spectrometry; high-performance liquid chromatography; HPLC; HRMS; HSA; HSA-Cys; HSA-cysteine conjugate; human serum albumin; Humans; Indoles; liquid scintillation counting; LSC; Male; Middle Aged; MS/MS; Mutagenesis, Insertional; non–small cell lung cancer; NSCLC; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - blood; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Pyrimidines; rhCYP; tandem mass spectrometry; TECRA; total extracted circulating radioactivity; total radioactivity; TRA; UHPLC; ultra-high performance liquid chromatography; Young Adult; TECRA; TRA; NSCLC; ADME; AMS; HSA-Cys; MS/MS; EGFR; ex20ins; HRMS; rhCYP; HSA; CYP; UHPLC; LSC; HPLC
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.124.001841

Mobocertinib (formerly known as TAK-788) is a targeted covalent tyrosine kinase inhibitor of epidermal growth factor receptor with exon 20 insertion mutations. This article describes the metabolism and excretion of mobocertinib in healthy male subjects after a single oral administration of [14C]mobocertinib. Mobocertinib-related materials were highly covalently bound to plasma proteins such as human serum albumin. The mean extraction recovery of total radioactivity was only 3.9% for six individual Hamilton pooled plasma samples. After extraction, mobocertinib was the most abundant component accounting for 7.7% of total extracted circulating radioactivity (TECRA) in the supernatant. Each of identified metabolites accounted for <10% of TECRA. Mobocertinib underwent extensive first-pass metabolism with the fraction of the dose absorbed estimated to be approximately 91.7%. Fecal excretion of mobocertinib metabolites was the major elimination route. Mobocertinib was mainly eliminated via oxidative metabolism with a fraction of approximately 88% metabolized by CYP3A4/5. The other minor elimination pathways included cysteine conjugation, metabolism by other cytochrome P450s, and renal excretion of unchanged mobocertinib. This article describes the metabolism and excretion of a targeted covalent inhibitor mobocertinib in humans after a single oral administration of [14C]mobocertinib. Mobocertinib was highly covalently bound to human plasma proteins. No metabolite accounted for >10% of total extracted circulating radioactivity in human plasma. Mobocertinib was mainly eliminated via CYP3A4/5 mediated oxidative metabolism followed by fecal excretion after approximately 91.7% of the dose was absorbed.