Abstract
PurposeTo determine the pharmacokinetics of radiolabeled copanlisib (BAY 80-6946) in healthy male volunteers and to investigate the disposition and biotransformation of copanlisib.MethodsA single dose of 12 mg copanlisib containing 2.76 MBq [14C]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.ResultsCopanlisib 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.ConclusionsCopanlisib 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.
Highlights
Phosphatidylinositol 3-kinase (PI3K) is a valuable target for clinical treatment of various types of cancer, as its biological activity is crucial for the translation of extracellular stimulation into intracellular signaling pathway, including cell growth and survival
A total of 5 gastrointestinal treatment emergent adverse event (TEAE) (MedDRA preferred terms: abdominal pain, nausea, flatulence, frequent bowel movements and diarrhea) as well as one event each of myalgia and oropharyngeal pain, respectively. The intensity of these TEAEs was generally mild-to-moderate (CTCAE grade 1 or 2), except one case of grade 3 abdominal pain occurring in one patient 8 days after the copanlisib administration, which was not considered drug-related by the investigator and resolved within 24-h
2 subjects experienced TEAEs, which were assessed as being related to the study drug copanlisib, including abdominal pain, diarrhea and nausea
Summary
Phosphatidylinositol 3-kinase (PI3K) is a valuable target for clinical treatment of various types of cancer, as its biological activity is crucial for the translation of extracellular stimulation into intracellular signaling pathway, including cell growth and survival. Population PK analysis showed no correlation between body weight, body surface area, or other body size-related factors and copanlisib clearance, indicating that body weight-based dosing does not reduce between-subject variability in copanlisib PK. Data from this analysis along with the exposure–response analysis for safety/efficacy was the basis to support the switch from a body weight-based dosing to a flat-dose regimen of copanlisib. This study was designed to elucidate the pharmacokinetics, especially focusing on metabolism and excretion pathways, of copanlisib after intravenous (i.v.) infusion in healthy volunteers to establish the safety features of the compound for further clinical evaluation. The 12 mg dose was chosen because it was expected to be safe to be used in healthy volunteers corresponding to one of the lowest doses in the first-in-man study [10]
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