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

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.

Validated LC–MS/MS method for the determination of copanlisib in mouse dried blood spots

“…This data suggests that copanlisib has selective uptake/binding by/to red blood cells. Gerisch et al (2017) also reported the selective uptake of copanlisib by human red blood cells. Because of this, the blood concentrations were higher than in plasma in humans.…”

Copanlisib in the Treatment of Relapsed Follicular Lymphoma: Utility and Experience from the Clinic

“…Elimination of copanlisib and its metabolites is predominantly through hepatic metabolism and biliary excretion with more than 90% of in vitro metabolism mediated by cytochrome P450 (CYP) 3A4 and less than 1% by CYP1A1. 24 Aforementioned exposure and other PK parameters remained similar following multiple administrations (every second day × 5), signifying lack of compound accumulation of compound or metabolic process alterations. An alternative dosing schedule of intravenous copanlisib twice a day once weekly for also showed equivalent antitumor activity.…”

“…Given the predominant hepatic elimination of copanlisib, 24 concomitant use of copanlisib with a strong CYP3A inducer should be avoided and the package insert recommends a dose decrement to 45 mg in this setting. Manufacturers also recommend a dose decrease to 45 mg in case with moderate hepatic impairment (Child Pugh Class B).…”

Spotlight on copanlisib and its potential in the treatment of relapsed/refractory follicular lymphoma: evidence to date

“…In a smaller Phase I study by Gerisch et al, six healthy volunteers were observed with similar pharmacokinetics to the above studies. 50 All volunteers were healthy males and received a single dose of 12 mg of copanlisib. Using radioactivity, the primary means of elimination of the drug was in the feces (64%) and urine (22%).…”