Absorption, metabolism and excretion of [
Mass balance
Metabolites
Oncology
Pharmacokinetics
Sotorasib
Journal
Cancer chemotherapy and pharmacology
ISSN: 1432-0843
Titre abrégé: Cancer Chemother Pharmacol
Pays: Germany
ID NLM: 7806519
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
received:
14
07
2022
accepted:
22
08
2022
pubmed:
6
9
2022
medline:
17
9
2022
entrez:
5
9
2022
Statut:
ppublish
Résumé
The objectives of this study were to characterize the absorption, metabolism, and excretion of sotorasib and determine the metabolites present in plasma, urine, and feces in healthy male subjects following a single oral 720 mg dose containing approximately 1 μCi of [ Urine, feces, and plasma were collected post-dose and assayed for total radioactivity and profiled for sotorasib metabolites. Urine and plasma were also assayed for sotorasib pharmacokinetics. In addition, in vitro studies were performed to determine the enzymes responsible for formation of major circulating metabolites and protein adducts in human plasma. Sotorasib was rapidly absorbed, with a median time to peak concentration of 0.75 h. Mean t Sotorasib metabolism involves nonenzymatic glutathione conjugation, GGT-mediated hydrolysis of glutathione adduct, and direct CYP3A and CYP2C8-mediated oxidation. Elimination of sotorasib is predominantly fecal excretion, suggesting dose reduction is not necessary with renal impairment.
Identifiants
pubmed: 36063185
doi: 10.1007/s00280-022-04470-y
pii: 10.1007/s00280-022-04470-y
doi:
Substances chimiques
Albumins
0
Carbon Radioisotopes
0
Piperazines
0
Pyridines
0
Pyrimidines
0
sotorasib
2B2VM6UC8G
Glutathione
GAN16C9B8O
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
357-367Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, Gaida K, Holt T, Knutson CG, Koppada N, Lanman BA, Werner J, Rapaport AS, San Miguel T, Ortiz R, Osgood T, Sun JR, Zhu X, McCarter JD, Volak LP, Houk BE, Fakih MG, O’Neil BH, Price TJ, Falchook GS, Desai J, Kuo J, Govindan R, Hong DS, Ouyang W, Henary H, Arvedson T, Cee VJ, Lipford JR (2019) The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575(7781):217–223. https://doi.org/10.1038/s41586-019-1694-1 (Epub 2019 Oct 30 PMID: 31666701)
doi: 10.1038/s41586-019-1694-1
pubmed: 31666701
Lanman BA, Allen JR, Allen JG, Amegadzie AK, Ashton KS, Booker SK, Chen JJ, Chen N, Frohn MJ, Goodman G, Kopecky DJ, Liu L, Lopez P, Low JD, Ma V, Minatti AE, Nguyen TT, Nishimura N, Pickrell AJ, Reed AB, Shin Y, Siegmund AC, Tamayo NA, Tegley CM, Walton MC, Wang HL, Wurz RP, Xue M, Yang KC, Achanta P, Bartberger MD, Canon J, Hollis LS, McCarter JD, Mohr C, Rex K, Saiki AY, San Miguel T, Volak LP, Wang KH, Whittington DA, Zech SG, Lipford JR, Cee VJ (2020) Discovery of a covalent inhibitor of KRAS
doi: 10.1021/acs.jmedchem.9b01180
pubmed: 31820981
LUMAKRAS [package insert] Thousand Oaks, CA: Amgen Inc. 2021
Hamilton RA, Garnett WR, Kline BJ (1981) Determination of mean valproic acid serum level by assay of a single pooled sample. Clin Pharmacol Ther 29(3):408–413. https://doi.org/10.1038/clpt.1981.56 (PMID: 6781809)
doi: 10.1038/clpt.1981.56
pubmed: 6781809
Penner N, Klunk LJ, Prakash C (2009) Human radiolabeled mass balance studies: objectives, utilities and limitations. Biopharm Drug Dispos 30(4):185–203. https://doi.org/10.1002/bdd.661 (PMID: 19544285)
doi: 10.1002/bdd.661
pubmed: 19544285
Dahal UP, Rock BM, Rodgers J, Shen X, Wang Z, Wahlstrom JL (2022) Absorption, distribution, metabolism and excretion of [
Ishida K, Werner JA, Davies R, Fan F, Thomas B, Wahlstrom J, Lipford JR, Monticello T (2021) Nonclinical safety profile of sotorasib, a KRASG12C-specific covalent inhibitor for the treatment of KRAS p.G12C-mutated cancer. Int J Toxicol. 40(5):427–441. https://doi.org/10.1177/10915818211022965 (Epub 2021 Jun 17 PMID: 34137282)
doi: 10.1177/10915818211022965
pubmed: 34137282
Roffel AF, van Marle SP, van Lier JJ, Hartstra J, van Hoogdalem EJ (2016) An evaluation of human ADME and mass balance studies using regular or low doses of radiocarbon. J Labelled Comp Radiopharm 59(14):619–626. https://doi.org/10.1002/jlcr.3473 (PMID: 28000265)
doi: 10.1002/jlcr.3473
pubmed: 28000265
Lozac’h F, Fahrni S, Maria D, Welte C, Bourquin J, Synal HA, Pearson D, Walles M, Camenisch G (2018) Evaluation of cAMS for 14C microtracer ADME studies: opportunities to change the current drug development paradigm. Bioanalysis 10(5):321–339. https://doi.org/10.4155/bio-2017-0216 (Epub 2018 Feb 16 PMID: 29451392)
doi: 10.4155/bio-2017-0216
pubmed: 29451392
Stopfer P, Marzin K, Narjes H, Gansser D, Shahidi M, Uttereuther-Fischer M, Ebner T (2012) Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers. Cancer Chemother Pharmacol 69(4):1051–1061. https://doi.org/10.1007/s00280-011-1803-9 (Epub 2011 Dec 27 PMID: 22200729)
doi: 10.1007/s00280-011-1803-9
pubmed: 22200729
Scheers E, Leclercq L, de Jong J, Bode N, Bockx M, Laenen A, Cuyckens F, Skee D, Murphy J, Sukbuntherng J, Mannens G (2015) Absorption, metabolism, and excretion of oral
doi: 10.1124/dmd.114.060061
pubmed: 25488930
Dickinson PA, Cantarini MV, Collier J, Frewer P, Martin S, Pickup K, Ballard P (2016) Metabolic disposition of osimertinib in rats, dogs, and humans: insights into a drug designed to bind covalently to a cysteine residue of epidermal growth factor receptor. Drug Metab Dispos 44(8):1201–1212. https://doi.org/10.1124/dmd.115.069203 (Epub 2016 May 25 PMID: 27226351)
doi: 10.1124/dmd.115.069203
pubmed: 27226351
Sabbioni G, Turesky RJ (2017) Biomonitoring human albumin adducts: the past, the present, and the future. Chem Res Toxicol 30(1):332–366. https://doi.org/10.1021/acs.chemrestox.6b00366 . Epub 2016 Dec 18. PMID: 27989119; PMCID: PMC5241710.
Liu X, Feng D, Zheng M, Cui Y, Zhong D (2020) Characterization of covalent binding of tyrosine kinase inhibitors to plasma proteins. Drug Metab Pharmacokinet 35(5):456–465. https://doi.org/10.1016/j.dmpk.2020.07.002 (Epub 2020 Jul 24 PMID: 32847720)
doi: 10.1016/j.dmpk.2020.07.002
pubmed: 32847720
Molins-Molina O, Pérez-Ruiz R, Lence E, González-Bello C, Miranda MA, Jiménez MC (2019) Photobinding of triflusal to human serum albumin investigated by fluorescence, proteomic analysis, and computational studies. Front Pharmacol 10:1028. https://doi.org/10.3389/fphar.2019.01028 (PMID: 31616294; PMCID: PMC6764118)
doi: 10.3389/fphar.2019.01028
pubmed: 31616294
pmcid: 6764118
Roffey SJ, Obach RS, Gedge JI, Smith DA (2007) What is the objective of the mass balance study? A retrospective analysis of data in animal and human excretion studies employing radiolabeled drugs. Drug Metab Rev 39(1):17–43. https://doi.org/10.1080/03602530600952172 (PMID: 17364879)
doi: 10.1080/03602530600952172
pubmed: 17364879
Gardell SJ, Tate SS (1980) Affinity labeling of gamma-glutamyl transpeptidase by glutamine antagonists. Effects of the gamma-glutamyl transferase and proteinase activities. FEBS Lett 122(2):171–174. https://doi.org/10.1016/0014-5793(80)80430-3 (PMID: 6110564)
doi: 10.1016/0014-5793(80)80430-3
pubmed: 6110564
VandenBrink BM, Foti RS, Rock DA, Wienkers LC, Wahlstrom JL (2011) Evaluation of CYP2C8 inhibition in vitro: utility of montelukast as a selective CYP2C8 probe substrate. Drug Metab Dispos 39(9):1546–1554. https://doi.org/10.1124/dmd.111.039065 (Epub 2011 Jun 22 PMID: 21697463)
doi: 10.1124/dmd.111.039065
pubmed: 21697463
Foti RS, Rock DA, Wienkers LC, Wahlstrom JL (2010) Selection of alternative CYP3A4 probe substrates for clinical drug interaction studies using in vitro data and in vivo simulation. Drug Metab Dispos 38(6):981–987. https://doi.org/10.1124/dmd.110.032094 (Epub 2010 Mar 4 PMID: 20203109)
doi: 10.1124/dmd.110.032094
pubmed: 20203109
U.S. Food and Drug Administration, Center for Drug Evaluation and Research (2022) Lumakras NDA 214665 multidisciplinary review and evaluation. Retrieved August 12, 2022 from https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214665Orig1s000MultidisciplineR.pdf