Pharmacokinetics, mass balance, and metabolism of [C]SAF-189s, a potent anaplastic lymphoma kinase/c-ROS proto-oncogene 1 inhibitor in humans: Metabolism potentially affected by interaction of cytochrome P450 enzymes and intestinal microbiota.

SAF-189s is a promising highly selective, brain-penetrant, next-generation inhibitor of anaplastic lymphoma kinase (ALK) and c-ROS proto-oncogene 1 (ROS1). The pharmacokinetics, mass balance, and metabolism of SAF-189s were measured in 6 healthy Chinese male participants after receiving a single oral dose of 160 mg [C]SAF-189s (150 μCi). SAF-189s was rapidly absorbed with a median T of 4.0 hours. The arithmetic mean half-life of total radioactivity in plasma was approximately 32.1 hours. The ratio of mean total drug-related substance concentration in whole blood to that in plasma (B/P) was 3.06, indicating that the drug was predominantly distributed in blood cells. After 336 hours of drug administration, the average cumulative excretion of radioactivity accounted for 96.98% of the total dose, with 6.24% of the drug excreted in urine and 90.74% of the drug excreted in feces. In total, 14 metabolites were identified. SAF-189s was the predominant component in plasma but was scarcely detected in urine and feces. Oxidative metabolism mediated by CYP3A4 was determined to be the primary metabolic pathway for SAF-189s, with the isopropyl group being the most susceptible metabolizing site. M543 was identified as the main oxidative metabolite of SAF-189s in humans, and its production was likely affected by both CYP3A and intestinal microbiota. After a single oral dose of [C]SAF-189s, SAF-189s and its principal metabolites were primarily excreted via feces. The main metabolic pathway was oxidation, likely catalyzed by both CYP3A and intestinal microbiota. SIGNIFICANCE STATEMENT: This study investigated the absorption and disposition of SAF-189s, a promising next-generation inhibitor of ALK/ROS1 administered for the treatment of ALK+/ROS1+ non-small cell lung cancer. The results demonstrated that SAF-189s and its metabolites were primarily excreted via feces, with metabolism likely mediated by both the cytochrome P450 system and gut microbiota. These findings provide essential pharmacokinetic and safety data, encourage further studies on drug interactions and dose adjustments, and support the involvement of gut microbiota, thereby guiding future research.