Metabolism and disposition of the anticancer quinolone derivative vosaroxin, a novel inhibitor of topoisomerase II (2023)

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. (2017). Metabolism and disposition of the anticancer quinolone derivative vosaroxin, a novel inhibitor of topoisomerase II. Investigational New Drugs, 35(4), 478-490. https://doi.org/10.1007/s10637-017-0428-1

Nijenhuis, C. M. ; Lucas, L. ; Rosing, H. et al. / Metabolism and disposition of the anticancer quinolone derivative vosaroxin, a novel inhibitor of topoisomerase II. In: Investigational New Drugs. 2017 ; Vol. 35, Nr. 4. blz. 478-490.

@article{ccf264d6ff5548c7b6e4daa22af911d1,

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

abstract = "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 60mg/m2 14C–vosaroxin, administered as short intravenous injection. Blood, urine and feces were collected over 168h after injection or until recovered radioactivity over 24h 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 AUC0-∞ was 21% lower than the TRA AUC0-∞ , suggesting the possible formation of protein bound metabolites after 48h 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.",

keywords = "ADME, Anti-cancer, Mass balance, Metabolite profiling, Pharmacokinetics, Vosaroxin",

author = "Nijenhuis, {C. M.} and L. Lucas and H. Rosing and Huitema, {A. D.R.} and M. Mergui-Roelvink and Jamieson, {G. C.} and Fox, {J. A.} and Mould, {D. R.} and Schellens, {J. H.M.} and Beijnen, {J. H.}",

note = "Publisher Copyright: {\textcopyright} 2017, Springer Science+Business Media New York.",

year = "2017",

month = aug,

day = "1",

doi = "10.1007/s10637-017-0428-1",

language = "English",

volume = "35",

pages = "478--490",

journal = "Investigational New Drugs",

issn = "0167-6997",

publisher = "Kluwer Academic Publishers",

number = "4",

}

Nijenhuis, CM, Lucas, L, Rosing, H, Huitema, ADR, Mergui-Roelvink, M, Jamieson, GC, Fox, JA, Mould, DR, Schellens, JHM & Beijnen, JH 2017, 'Metabolism and disposition of the anticancer quinolone derivative vosaroxin, a novel inhibitor of topoisomerase II', Investigational New Drugs, vol. 35, nr. 4, blz. 478-490. https://doi.org/10.1007/s10637-017-0428-1

Metabolism and disposition of the anticancer quinolone derivative vosaroxin, a novel inhibitor of topoisomerase II. / Nijenhuis, C. M.; Lucas, L.; Rosing, H. et al.
In: Investigational New Drugs, Vol. 35, Nr. 4, 01.08.2017, blz. 478-490.

Onderzoeksoutput: Bijdrage aan tijdschrift › Artikel › peer review

TY - JOUR

T1 - Metabolism and disposition of the anticancer quinolone derivative vosaroxin, a novel inhibitor of topoisomerase II

AU - Nijenhuis, C. M.

AU - Lucas, L.

AU - Rosing, H.

AU - Huitema, A. D.R.

AU - Mergui-Roelvink, M.

AU - Jamieson, G. C.

AU - Fox, J. A.

AU - Mould, D. R.

AU - Schellens, J. H.M.

AU - Beijnen, J. H.

N1 - Publisher Copyright:© 2017, Springer Science+Business Media New York.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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 60mg/m2 14C–vosaroxin, administered as short intravenous injection. Blood, urine and feces were collected over 168h after injection or until recovered radioactivity over 24h 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 AUC0-∞ was 21% lower than the TRA AUC0-∞ , suggesting the possible formation of protein bound metabolites after 48h 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.

AB - 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 60mg/m2 14C–vosaroxin, administered as short intravenous injection. Blood, urine and feces were collected over 168h after injection or until recovered radioactivity over 24h 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 AUC0-∞ was 21% lower than the TRA AUC0-∞ , suggesting the possible formation of protein bound metabolites after 48h 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.

KW - ADME

KW - Anti-cancer

KW - Mass balance

KW - Metabolite profiling

KW - Pharmacokinetics

KW - Vosaroxin

UR - http://www.scopus.com/inward/record.url?scp=85010991092&partnerID=8YFLogxK

U2 - 10.1007/s10637-017-0428-1

DO - 10.1007/s10637-017-0428-1

M3 - Article

C2 - 28138829

AN - SCOPUS:85010991092

SN - 0167-6997

VL - 35

SP - 478

EP - 490

JO - Investigational New Drugs

JF - Investigational New Drugs

IS - 4

ER -

Nijenhuis CM, Lucas L, Rosing H, Huitema ADR, Mergui-Roelvink M, Jamieson GC et al. Metabolism and disposition of the anticancer quinolone derivative vosaroxin, a novel inhibitor of topoisomerase II. Investigational New Drugs. 2017 aug. 1;35(4):478-490. doi: 10.1007/s10637-017-0428-1