Pharmacokinetics of intravenous pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor [14C]copanlisib (BAY 80-6946) in a mass balance study in healthy male volunteers

• Published in: Cancer chemotherapy and pharmacology 2017-09, Vol.80 (3), p.535-544
• Main Authors: Gerisch, Michael, Schwarz, Thomas, Lang, Dieter, Rohde, Gabriele, Reif, Stefanie, Genvresse, Isabelle, Reschke, Susanne, van der Mey, Dorina, Granvil, Camille
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Administration, Intravenous; Biotransformation; Blood plasma; Cancer Research; Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Class I Phosphatidylinositol 3-Kinases - pharmacokinetics; Class I Phosphatidylinositol 3-Kinases - therapeutic use; Drug dosages; Enzyme inhibitors; Excretion; Feces; Half-life; Healthy Volunteers; Humans; Intravenous administration; Intravenous infusion; Male; Medicine; Medicine & Public Health; Metabolism; Metabolites; Middle Aged; Oncology; Original; Original Article; Oxidative metabolism; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Pyrimidines - administration & dosage; Pyrimidines - pharmacokinetics; Pyrimidines - therapeutic use; Quinazolines - administration & dosage; Quinazolines - pharmacokinetics; Quinazolines - therapeutic use; Radioactive half-life; Radioactivity; Renal function; Urine
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-017-3383-9

Purpose To determine the pharmacokinetics of radiolabeled copanlisib (BAY 80-6946) in healthy male volunteers and to investigate the disposition and biotransformation of copanlisib. Methods A single dose of 12 mg copanlisib containing 2.76 MBq [ 14 C]copanlisib was administered as a 1-h intravenous infusion to 6 volunteers with subsequent sampling up to 34 days. Blood, plasma, urine and feces were collected to monitor total radioactivity, parent compound and metabolites. Results Copanlisib treatment was well tolerated. Copanlisib was rapidly distributed throughout the body with a volume distribution of 1870 L and an elimination half-life of 52.1-h (range 40.4–67.5-h). Copanlisib was the predominant component in human plasma (84% of total radioactivity AUC) and the morpholinone metabolite M1 was the only circulating metabolite (about 5%). Excretion of drug-derived radioactivity based on all 6 subjects was 86% of the dose within a collection interval of 20–34 days with 64% excreted into feces as major route of elimination and 22% into urine. Unchanged copanlisib was the main component excreted into urine (15% of dose) and feces (30% of dose). Excreted metabolites (41% of dose) of copanlisib resulted from oxidative biotransformation. Conclusions Copanlisib was eliminated predominantly in the feces compared to urine as well as by hepatic biotransformation, suggesting that the clearance of copanlisib would more likely be affected by hepatic impairment than by renal dysfunction. The dual mode of elimination via unchanged excretion of copanlisib and oxidative metabolism decreases the risk of clinically relevant PK-related drug–drug interactions.