Metabolism and disposition of the anticancer quinolone derivative vosaroxin, a novel inhibitor of topoisomerase II

• Published in: Investigational new drugs Vol. 35; no. 4; pp. 478 - 490
• Main Authors: Nijenhuis, C.M., Lucas, L., Rosing, H., Huitema, A.D.R., Mergui-Roelvink, M., Jamieson, G. C., Fox, J.A., Mould, D.R., Schellens, J.H.M., Beijnen, J.H.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-08-2017; Springer Nature B.V
• Subjects: Acute myeloid leukemia; Adult; Aged; Biotransformation; Cancer; Carbon Radioisotopes; Conjugation; Decarboxylation; Demethylation; DNA topoisomerase (ATP-hydrolysing); Excretion; Feces; Feces - chemistry; Female; Humans; Hydrogenation; Inhibitors; Injection; Injections, Intravenous; Intravenous administration; Leukemia; Male; Matrices (mathematics); Medicine; Medicine & Public Health; Metabolism; Metabolites; Middle Aged; Myeloid leukemia; Naphthyridines - adverse effects; Naphthyridines - blood; Naphthyridines - pharmacokinetics; Naphthyridines - urine; Neoplasms - blood; Neoplasms - metabolism; Neoplasms - urine; Oncology; Patients; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Phase I Studies; Radioactivity; Solid tumors; Studies; Thiazoles - adverse effects; Thiazoles - blood; Thiazoles - pharmacokinetics; Thiazoles - urine; Topoisomerase II Inhibitors - adverse effects; Topoisomerase II Inhibitors - blood; Topoisomerase II Inhibitors - pharmacokinetics; Topoisomerase II Inhibitors - urine; Tumors; Urine; Mass balance; Anti-cancer; Vosaroxin; Pharmacokinetics; ADME; Metabolite profiling
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-017-0428-1

Summary
Background
Vosaroxin is a first-in-class anticancer quinolone derivative that is being investigated for patients with relapsed or refractory acute myeloid leukemia (AML). The primary objective of this study was to quantitatively determine the pharmacokinetics of vosaroxin and its metabolites in patients with advanced solid tumors.
Methods
This mass balance study investigated the pharmacokinetics (distribution, metabolism, and excretion) of vosaroxin in cancer patients after a single dose of 60 mg/m
2 14
C–vosaroxin, administered as short intravenous injection. Blood, urine and feces were collected over 168 h after injection or until recovered radioactivity over 24 h was less than 1% of the administered dose (whichever was earlier). Total radioactivity (TRA), vosaroxin and metabolites were studied in all matrices.
Results
Unchanged vosaroxin was the major species identified in plasma, urine, and feces. N-desmethylvosaroxin was the only circulating metabolite detected in plasma, accounting for <3% of the administered dose. However, in plasma, the combined vosaroxin + N-desmethylvosaroxin AUC
0-∞
was 21% lower than the TRA AUC
0-∞
, suggesting the possible formation of protein bound metabolites after 48 h when the concentration-time profiles diverged. The mean recovery of TRA in excreta was 81.3% of the total administered dose; 53.1% was excreted through feces and 28.2% through urine.
Conclusions
Unchanged vosaroxin was the major compound found in the excreta, although 10 minor metabolites were detected. The biotransformation reactions were demethylation, hydrogenation, decarboxylation and phase II conjugation including glucuronidation.