Gerisch Michael, Schwarz Thomas, Lang Dieter, Rohde Gabriele, Reif Stefanie, Genvresse Isabelle, Reschke Susanne, van der Mey Dorina, Granvil Camille
Bayer Aktiengesellschaft, DMPK, 42096, Wuppertal, Germany.
Bayer Aktiengesellschaft, Clinical Sciences, Berlin, Germany.
Cancer Chemother Pharmacol. 2017 Sep;80(3):535-544. doi: 10.1007/s00280-017-3383-9. Epub 2017 Jul 11.
To determine the pharmacokinetics of radiolabeled copanlisib (BAY 80-6946) in healthy male volunteers and to investigate the disposition and biotransformation of copanlisib.
A single dose of 12 mg copanlisib containing 2.76 MBq [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.
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.
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.
测定放射性标记的库潘尼西（BAY 80 - 6946）在健康男性志愿者体内的药代动力学，并研究库潘尼西的处置和生物转化情况。
向6名志愿者静脉输注1小时含2.76 MBq [C]库潘尼西的12 mg单剂量库潘尼西，随后在长达34天的时间内进行采样。收集血液、血浆、尿液和粪便以监测总放射性、母体化合物和代谢物。
库潘尼西治疗耐受性良好。库潘尼西迅速分布至全身，分布容积为1870 L，消除半衰期为52.1小时（范围40.4 - 67.5小时）。库潘尼西是人体血浆中的主要成分（占总放射性AUC的84%），吗啉酮代谢物M1是唯一的循环代谢物（约5%）。基于所有6名受试者，在20 - 34天的收集期内，药物衍生放射性的排泄量为剂量的86%，其中64%以粪便为主要排泄途径，22%以尿液为排泄途径。未变化的库潘尼西是排泄到尿液（剂量的15%）和粪便（剂量的30%）中的主要成分。库潘尼西的排泄代谢物（剂量的41%）源于氧化生物转化。
与尿液相比，库潘尼西主要通过粪便以及肝脏生物转化消除，这表明库潘尼西的清除更可能受肝功能损害影响，而非肾功能不全。通过库潘尼西的未变化排泄和氧化代谢的双重消除模式降低了临床上与药代动力学相关的药物 - 药物相互作用的风险。
