Login Register Cart 0
Anti-Cancer Agents in Medicinal Chemistry

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Copanlisib: Novel PI3K Inhibitor for the Treatment of Lymphoma

Author(s): Anshul Kumar, Rohit Bhatia, Pooja Chawla , Durgadas Anghore , Vipin Saini and Ravindra K. Rawal *

Volume 20, Issue 10, 2020

Page: [1158 - 1172] Pages: 15

DOI: 10.2174/1871520620666200317105207

Price: $65

Become a Editorial Board Member
Become a Reviewer
Become a Editor
Become a Section Editor

Abstract

Lymphoma refers to a specialized category of blood cancers, which is characterized by lymph node enlargement, reduced body weight, prolonged tiredness, and fever associated with sweats. Traditional treatment strategies involve chemotherapy, radiation therapy, targeted therapy, and surgery. Copanlisib has emerged as a very potent drug which acts through inhibiting PI3K enzyme. The FDA has approved it for specific treatment of follicular Lymphoma in September 2017. Copanlisib induces tumor cell death along with the prevention of proliferation of dominant malignant β-cells. Copanlisib has a large volume of distribution i.e., 871L (%CV 47.4), plasma protein binding up to 15.8%, plasma half-life(t1/2) of 39.1h and the mean systemic plasma clearance 18.9 L/h (%CV 51.2). In the present review, various aspects related to Copanlisib have been summarized, which include pathophysiology, synthetic strategy, pharmacokinetics, pharmacodynamics and clinical studies. A special emphasis is paid on various reported adverse effects and in silico/in vivo studies conducted on Copanlisib.

Keywords: Lymphoma, PI3K, copanlisib, systemic plasma clearance, lymph node enlargement, blood cancer.

« Previous Next »

Graphical Abstract

Graphical abstract illustrating key findings of the study

[1]
Taylor, E.J. Dorland’s illustrated medical dictionary, 29th ed; Saunders: Philadelphia, 2000.
[2]
Bower, M.; Waxman, J. Lecture Notes: Oncology, 2nd ed; Wiley- Blackwell: United States, 2011.
[3]
SEER, Stat Fact Sheets : Hodgkin Lymphoma. NCI., 2016 April; Archived from the original on 17 October 2012. Retrieved 13 August 2016.
[4]
Patnaik, A.; Appleman, L.J.; Tolcher, A.W.; Papadopoulos, K.P.; Beeram, M.; Rasco, D.W.; Weiss, G.J.; Sachdev, J.C.; Chadha, M.; Fulk, M.; Ejadi, S.; Mountz, J.M.; Lotze, M.T.; Toledo, F.G.; Chu, E.; Jeffers, M.; Peña, C.; Xia, C.; Reif, S.; Genvresse, I.; Ramanathan, R.K. First-in-human phase I study of copanlisib (BAY 80- 6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin’s lymphomas. Ann. Oncol., 2016, 27(10), 1928-1940.
[http://dx.doi.org/10.1093/annonc/mdw282] [PMID: 27672108]
[5]
Dreyling, M.; Morschhauser, F.; Bron, D.; Bouabdallah, K.; Vitolo, M.; Linton, K. Preliminary results of a phase II study of single agent Bay 80-6946, a Novel PI3 K inhibitor, in patients with relapsed/ refractory, indolent or aggressive lymphoma. Clin. Adv. Hematol. Oncol., 2014, 2014(12), 14-16.
[6]
Chalhoub, N.; Baker, S.J. PTEN and the PI3-kinase pathway in cancer. Annu. Rev. Pathol., 2009, 4, 127-150.
[http://dx.doi.org/10.1146/annurev.pathol.4.110807.092311] [PMID: 18767981]
[7]
Curran, E.; Smith, S.M. Phosphoinositide 3-kinase inhibitors in lymphoma. Curr. Opin. Oncol., 2014, 26(5), 469-475.
[http://dx.doi.org/10.1097/CCO.0000000000000113] [PMID: 25024054]
[8]
Bala Krishnan, K.; Peluso, M.; Fu, M.; Rosin, N.Y.; Burger, J.A.; Wierda, W.G.; Keating, M.J. The phosphoinositide-3-kinase (PI3 K)-delta and gamma inhibitor, IPI-145 (Duvelisib), overcomes signals from the PI3 K/ AKT/S6 pathway and promotes apoptosis in CLL. Leukaemia, 2015, 29(9), 1811-1822.
[http://dx.doi.org/10.1038/leu.2015.105]
[9]
Herman, S.E.; Johnson, A.J. Molecular pathways: Targeting phosphoinositide 3-kinase p110-delta in chronic lymphocytic leukemia. Clin. Cancer Res., 2012, 18(15), 4013-4018.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-1402] [PMID: 22711705]
[10]
Scott, W.J.; Hentemann, M.F.; Rowley, R.B.; Bull, C.O.; Jenkins, S.; Bullion, A.M.; Johnson, J.; Redman, A.; Robbins, A.H.; Esler, W.; Fracasso, R.P.; Garrison, T.; Hamilton, M.; Michels, M.; Wood, J.E.; Wilkie, D.P.; Xiao, H.; Levy, J.; Stasik, E.; Liu, N.; Schaefer, M.; Brands, M.; Lefranc, J. Discovery and SAR of novel 2,3-Dihydroimidazo[1,2-c] quinazoline PI3 K inhibitors: Identification of copanlisib (BAY 80-6946). ChemMedChem, 2016, 11(14), 1517-1530.
[http://dx.doi.org/10.1002/cmdc.201600148] [PMID: 27310202]
[11]
Liu, N.; Rowley, B.R.; Bull, C.O.; Schneider, C.; Haegebarth, A.; Schatz, C.A.; Fracasso, P.R.; Wilkie, D.P.; Hentemann, M.; Wilhelm, S.M.; Scott, W.J.; Mumberg, D.; Ziegelbauer, K. BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110α and p110δ activities in tumor cell lines and xenograft models. Mol. Cancer Ther., 2013, 12(11), 2319-2330.
[http://dx.doi.org/10.1158/1535-7163.MCT-12-0993-T] [PMID: 24170767]
[12]
Doi, T.; Fuse, N.; Yoshino, T.; Kojima, T.; Bando, H.; Miyamoto, H.; Kaneko, M.; Osada, M.; Ohtsu, A. A Phase I study of intravenous PI3K inhibitor copanlisib in Japanese patients with advanced or refractory solid tumors. Cancer Chemother. Pharmacol., 2017, 79(1), 89-98.
[http://dx.doi.org/10.1007/s00280-016-3198-0] [PMID: 27915408]
[13]
Guilherme, R.S.; Caputto, L.Z.; Fonseca, A.L.; Pereira, J.; Fonseca, F.L. Exames laboratoriais complementares indicados no apoio ao diagnóstico do Linfoma Difuso de Grandes Células B (LDGCB). Arq Bras Ciênc. Saúde., 2008, 33(3), 186-194.
[14]
Kahl, B.S.; Yang, D.T. Follicular lymphoma: Evolving therapeutic strategies. Blood, 2016, 127(17), 2055-2063.
[http://dx.doi.org/10.1182/blood-2015-11-624288] [PMID: 26989204]
[15]
Klumb, C.E. Biology and pathogenesis on non-Hodgkin’s Lymphomas of B origin in childhood: A review. Rev. Bras. Cancerol., 2001, 43(3), 291-301.
[16]
Cantley, L.C. The phosphoinositide 3-kinase pathway. Science, 2002, 296(5573), 1655-1657.
[http://dx.doi.org/10.1126/science.296.5573.1655] [PMID: 12040186]
[17]
Vanhaesebroeck, B.; Whitehead, M.A.; Piñeiro, R. Molecules in medicine mini-review: Isoforms of PI3K in biology and disease. J. Mol. Med. (Berl.), 2016, 94(1), 5-11.
[http://dx.doi.org/10.1007/s00109-015-1352-5] [PMID: 26658520]
[18]
Bauer, T.M.; Patel, M.R.; Infante, J.R. Targeting PI3 kinase in cancer. Pharmacol. Ther., 2015, 146, 53-60.
[http://dx.doi.org/10.1016/j.pharmthera.2014.09.006] [PMID: 25240910]
[19]
Shimada, M.; Murata, T.; Fuchikami, K.; Tsujishita, H.; Omori, N.; Kato, I. Fused azole-pyrimidine derivatives (Bayer Pharmaceuticals Corp.)., WO 2004029055 (20030918). 2004.
[20]
https://www.drugbank.ca/drugs/DB12483Mechanism of action of copanlisib.
[21]
Busaidy, N.L.; Farooki, A.; Dowlati, A.; Perentesis, J.P.; Dancey, J.E.; Doyle, L.A.; Brell, J.M.; Siu, L.L. Management of metabolic effects associated with anticancer agents targeting the PI3K-AktmTOR pathway. J. Clin. Oncol., 2012, 30(23), 2919-2928.
[http://dx.doi.org/10.1200/JCO.2011.39.7356] [PMID: 22778315]
[22]
Byrd, J.C.; Furman, R.R.; Coutre, S.E.; Flinn, I.W.; Burger, J.A.; Blum, K.A.; Grant, B.; Sharman, J.P.; Coleman, M.; Wierda, W.G.; Jones, J.A.; Zhao, W.; Heerema, N.A.; Johnson, A.J.; Sukbuntherng, J.; Chang, B.Y.; Clow, F.; Hedrick, E.; Buggy, J.J.; James, D.F.; O’Brien, S. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N. Engl. J. Med., 2013, 369(1), 32-42.
[http://dx.doi.org/10.1056/NEJMoa1215637] [PMID: 23782158]
[23]
Quaschning, T.; Voss, F.; Relle, K.; Kalk, P.; Vignon-Zellweger, N.; Pfab, T.; Bauer, C.; Theilig, F.; Bachmann, S.; Kraemer-Guth, A.; Wanner, C.; Theuring, F.; Galle, J.; Hocher, B. Lack of endothelial nitric oxide synthase promotes endothelin-induced hypertension: lessons from endothelin-1 transgenic/endothelial nitric oxide synthase knockout mice. J. Am. Soc. Nephrol., 2007, 18(3), 730-740.
[http://dx.doi.org/10.1681/ASN.2006050541] [PMID: 17287431]
[24]
Gopal, A.K.; Kahl, B.S.; de Vos, S.; Wagner-Johnston, N.D.; Schuster, S.J.; Jurczak, W.J.; Flinn, I.W.; Flowers, C.R.; Martin, P.; Viardot, A.; Blum, K.A.; Goy, A.H.; Davies, A.J.; Zinzani, P.L.; Dreyling, M.; Johnson, D.; Miller, L.L.; Holes, L.; Li, D.; Dansey, R.D.; Godfrey, W.R.; Salles, G.A. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N. Engl. J. Med., 2014, 370(11), 1008-1018.
[http://dx.doi.org/10.1056/NEJMoa1314583] [PMID: 24450858]
[25]
Bendell, J.C.; Rodon, J.; Burris, H.A.; de Jonge, M.; Verweij, J.; Birle, D.; Demanse, D.; De Buck, S.S.; Ru, Q.C.; Peters, M.; Goldbrunner, M.; Baselga, J. Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J. Clin. Oncol., 2012, 30(3), 282-290.
[http://dx.doi.org/10.1200/JCO.2011.36.1360] [PMID: 22162589]
[26]
Shapiro, G.I.; Bell-McGuinn, K.M.; Molina, J.R.; Bendell, J.; Spicer, J.; Kwak, E.L.; Pandya, S.S.; Millham, R.; Borzillo, G.; Pierce, K.J.; Han, L.; Houk, B.E.; Gallo, J.D.; Alsina, M.; Braña, I.; Tabernero, J. First- the human study of PF-05212384 (PKI-587), a small-molecule, intravenous, dual inhibitor of PI3K and mTOR in patients with advanced cancer. Clin. Cancer Res., 2015, 21(8), 1888-1895.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-1306] [PMID: 25652454]
[27]
Flinn, I.W.; Kahl, B.S.; Leonard, J.P.; Furman, R.R.; Brown, J.R.; Byrd, J.C.; Wagner-Johnston, N.D.; Coutre, S.E.; Benson, D.M.; Peterman, S.; Cho, Y.; Webb, H.K.; Johnson, D.M.; Yu, A.S.; Ulrich, R.G.; Godfrey, W.R.; Miller, L.L.; Spurgeon, S.E. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood, 2014, 123(22), 3406-3413.
[http://dx.doi.org/10.1182/blood-2013-11-538546] [PMID: 24615776]
[28]
Yap, T.A.; Yan, L.; Patnaik, A.; Fearen, I.; Olmos, D.; Papadopoulos, K.; Baird, R.D.; Delgado, L.; Taylor, A.; Lupinacci, L.; Riisnaes, R.; Pope, L.L.; Heaton, S.P.; Thomas, G.; Garrett, M.D.; Sullivan, D.M.; de Bono, J.S.; Tolcher, A.W. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J. Clin. Oncol., 2011, 29(35), 4688-4695.
[http://dx.doi.org/10.1200/JCO.2011.35.5263] [PMID: 22025163]
[29]
Britten, C.D.; Adjei, A.A.; Millham, R.; Houk, B.E.; Borzillo, G.; Pierce, K.; Wainberg, Z.A.; LoRusso, P.M. Phase I study of PF- 04691502, a small-molecule, oral, dual inhibitor of PI3K and mTOR, in patients with advanced cancer. Invest. New Drugs, 2014, 32(3), 510-517.
[http://dx.doi.org/10.1007/s10637-013-0062-5] [PMID: 24395457]
[30]
Knight, Z.A.; Gonzalez, B.; Feldman, M.E.; Zunder, E.R.; Goldenberg, D.D.; Williams, O.; Loewith, R.; Stokoe, D.; Balla, A.; Toth, B.; Balla, T.; Weiss, W.A.; Williams, R.L.; Shokat, K.M. A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling. Cell, 2006, 125(4), 733-747.
[http://dx.doi.org/10.1016/j.cell.2006.03.035] [PMID: 16647110]
[31]
Brown, J.R.; Davids, M.S.; Rodon, J.; Abrisqueta, P.; Kasar, S.N.; Lager, J.; Jiang, J.; Egile, C.; Awan, F.T. Phase I trial of the pan- PI3K inhibitor pilaralisib (SAR245408/XL147) in patients with Chronic Lymphocytic Leukemia (CLL) or relapsed/refractory lymphoma. Clin. Cancer Res., 2015, 21(14), 3160-3169.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-3262] [PMID: 25840972]
[32]
Sarker, D.; Ang, J.E.; Baird, R.; Kristeleit, R.; Shah, K.; Moreno, V.; Clarke, P.A.; Raynaud, F.I.; Levy, G.; Ware, J.A.; Mazina, K.; Lin, R.; Wu, J.; Fredrickson, J.; Spoerke, J.M.; Lackner, M.R.; Yan, Y.; Friedman, L.S.; Kaye, S.B.; Derynck, M.K.; Workman, P.; de Bono, J.S. First-in-human phase I study of pictilisib (GDC- 0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors. Clin. Cancer Res., 2015, 21(1), 77-86.
[http://dx.doi.org/10.1158/1078-0432.CCR-14-0947] [PMID: 25370471]
[33]
Symons, J.D.; McMillin, S.L.; Riehle, C.; Tanner, J.; Palionyte, M.; Hillas, E.; Jones, D.; Cooksey, R.C.; Birnbaum, M.J.; McClain, D.A.; Zhang, Q.J.; Gale, D.; Wilson, L.J.; Abel, E.D. Contribution of insulin and Akt1 signaling to endothelial nitric oxide synthase in the regulation of endothelial function and blood pressure. Circ. Res., 2009, 104(9), 1085-1094.
[http://dx.doi.org/10.1161/CIRCRESAHA.108.189316] [PMID: 19342603]
[34]
Wilson, W.H.; Young, R.M.; Schmitz, R.; Yang, Y.; Pittaluga, S.; Wright, G.; Lih, C.J.; Williams, P.M.; Shaffer, A.L.; Gerecitano, J.; de Vos, S.; Goy, A.; Kenkre, V.P.; Barr, P.M.; Blum, K.A.; Shustov, A.; Advani, R.; Fowler, N.H.; Vose, J.M.; Elstrom, R.L.; Habermann, T.M.; Barrientos, J.C.; McGreivy, J.; Fardis, M.; Chang, B.Y.; Clow, F.; Munneke, B.; Moussa, D.; Beaupre, D.M.; Staudt, L.M. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat. Med., 2015, 21(8), 922-926.
[http://dx.doi.org/10.1038/nm.3884] [PMID: 26193343]
[35]
Erdmann, T.; Klener, P.; Lynch, J.T.; Grau, M.; Vočková, P.; Molinsky, J.; Tuskova, D.; Hudson, K.; Polanska, U.M.; Grondine, M.; Mayo, M.; Dai, B.; Pfeifer, M.; Erdmann, K.; Schwammbach, D.; Zapukhlyak, M.; Staiger, A.M.; Ott, G.; Berdel, W.E.; Davies, B.R.; Cruzalegui, F.; Trneny, M.; Lenz, P.; Barry, S.T.; Lenz, G. Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL. Blood, 2017, 130(3), 310-322.
[http://dx.doi.org/10.1182/blood-2016-12-758599] [PMID: 28202458]
[36]
Paul, J.; Soujon, M.; Wengner, A.M.; Zitzmann-Kolbe, S.; Sturz, A.; Haike, K.; Keng Magdalene, K.H.; Tan, S.H.; Lange, M.; Tan, S.Y.; Mumberg, D.; Lim, S.T.; Ziegelbauer, K.; Liu, N. Simultaneous inhibition of PI3Kδ and PI3Kα induces ABCDLBCL regression by blocking BCR-dependent and -independent activation of NF-κB and AKT. Cancer Cell, 2017, 31(1), 64-78.
[http://dx.doi.org/10.1016/j.ccell.2016.12.003] [PMID: 28073005]
[37]
Kahl, B.S.; Spurgeon, S.E.; Furman, R.R.; Flinn, I.W.; Coutre, S.E.; Brown, J.R.; Benson, D.M.; Byrd, J.C.; Peterman, S.; Cho, Y.; Yu, A.; Godfrey, W.R.; Wagner-Johnston, N.D. A phase 1 study of the PI3Kδ inhibitor idelalisib in patients with relapsed/ refractory mantle cell lymphoma (MCL). Blood, 2014, 123(22), 3398-3405.
[http://dx.doi.org/10.1182/blood-2013-11-537555] [PMID: 24615778]
[38]
Wang, M.L.; Blum, K.A.; Martin, P.; Goy, A.; Auer, R.; Kahl, B.S.; Jurczak, W.; Advani, R.H.; Romaguera, J.E.; Williams, M.E.; Barrientos, J.C.; Chmielowska, E.; Radford, J.; Stilgenbauer, S.; Dreyling, M.; Jedrzejczak, W.W.; Johnson, P.; Spurgeon, S.E.; Zhang, L.; Baher, L.; Cheng, M.; Lee, D.; Beaupre, D.M.; Rule, S. Long-term follow-up of MCL patients treated with single-agent ibrutinib: Updated safety and efficacy results. Blood, 2015, 126(6), 739-745.
[http://dx.doi.org/10.1182/blood-2015-03-635326] [PMID: 26059948]
[39]
Iyengar, S.; Clear, A.; Bödör, C.; Maharaj, L.; Lee, A.; Calaminici, M.; Matthews, J.; Iqbal, S.; Auer, R.; Gribben, J.; Joel, S. P110α-mediated constitutive PI3K signaling limits the efficacy of p110δ- selective inhibition in mantle cell lymphoma, particularly with multiple relapse. Blood, 2013, 121(12), 2274-2284.
[http://dx.doi.org/10.1182/blood-2012-10-460832] [PMID: 23341541]
[40]
Horwitz, S.M.; Porcu, P.; Flinn, I. Duvelisib (IPI-145), a phosphoinositide- 3-kinase-δ,γ inhibitor, shows activity in patients with relapsed/ refractory T-cell lymphoma. Blood ASH Annual Meeting Abstracts, 2014, 124, 803.
[http://dx.doi.org/10.1182/blood.V124.21.803.803]
[41]
Pongas, G.; Cheson, B.D. PI3K signaling pathway in normal B cells and indolent B-cell malignancies. Semin. Oncol., 2016, 43(6), 647-654.
[http://dx.doi.org/10.1053/j.seminoncol.2016.11.011] [PMID: 28061982]
[42]
Crouthamel, M.C.; Kahana, J.A.; Korenchuk, S.; Zhang, S.Y.; Sundaresan, G.; Eberwein, D.J.; Brown, K.K.; Kumar, R. Mechanism and management of AKT inhibitor-induced hyperglycemia. Clin. Cancer Res., 2009, 15(1), 217-225.
[http://dx.doi.org/10.1158/1078-0432.CCR-08-1253] [PMID: 19118049]
[43]
Zelenetz, A.D.; Barrientos, J.C.; Brown, J.R.; Coiffier, B.; Delgado, J.; Egyed, M.; Ghia, P.; Illés, Á.; Jurczak, W.; Marlton, P.; Montillo, M.; Morschhauser, F.; Pristupa, A.S.; Robak, T.; Sharman, J.P.; Simpson, D.; Smolej, L.; Tausch, E.; Adewoye, A.H.; Dreiling, L.K.; Kim, Y.; Stilgenbauer, S.; Hillmen, P. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: Interim results from a phase 3, randomised, double-blind, placebo controlled trial. Lancet Oncol., 2017, 18(3), 297-311.
[http://dx.doi.org/10.1016/S1470-2045(16)30671-4] [PMID: 28139405]
[44]
U.S. Food & Drug Administration. FDA alerts healthcare professionals about clinical trials with Zydelig (idelalisib) in combination with other cancer medicines.,
[45]
Coutré, S.E.; Barrientos, J.C.; Brown, J.R.; de Vos, S.; Furman, R.R.; Keating, M.J.; Li, D.; O’Brien, S.M.; Pagel, J.M.; Poleski, M.H.; Sharman, J.P.; Yao, N.S.; Zelenetz, A.D. Management of adverse events associated with idelalisib treatment: Expert panel opinion. Leuk. Lymphoma, 2015, 56(10), 2779-2786.
[http://dx.doi.org/10.3109/10428194.2015.1022770] [PMID: 25726955]
[46]
Weidner, A.S.; Panarelli, N.C.; Geyer, J.T.; Bhavsar, E.B.; Furman, R.R.; Leonard, J.P.; Jessurun, J.; Yantiss, R.K. Idelalisib-associated colitis: histologic findings in 14 patients. Am. J. Surg. Pathol., 2015, 39(12), 1661-1667.
[http://dx.doi.org/10.1097/PAS.0000000000000522] [PMID: 26448188]
[47]
Baohua, Y.; Xiaoyan, Z.; Tiecheng, Z.; Tao, Q.; Daren, S. Mutations of the PIK3CA gene in diffuse large B cell lymphoma. Diagn. Mol. Pathol., 2008, 17(3), 159-165.
[http://dx.doi.org/10.1097/PDM.0b013e31815d0588] [PMID: 18382359]
[48]
Marincevic, M.; Tobin, G.; Rosenquist, R. Infrequent occurrence of PIK3CA mutations in chronic lymphocytic leukemia. Leuk. Lymphoma, 2009, 50(5), 829-830.
[http://dx.doi.org/10.1080/10428190902803651] [PMID: 19330652]
[49]
Graham, R.A.; Lum, B.L.; Morrison, G.; Chang, I.; Jorga, K.; Dean, B.; Shin, Y.G.; Yue, Q.; Mulder, T.; Malhi, V.; Xie, M.; Low, J.A.; Hop, C.E. A single dose mass balance study of the Hedgehog pathway inhibitor vismodegib (GDC-0449) in humans using accelerator mass spectrometry. Drug Metab. Dispos., 2011, 39(8), 1460-1467.
[http://dx.doi.org/10.1124/dmd.111.039339] [PMID: 21602311]
[50]
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/20993 6s000lbl.pdfPharmacokinetic of copanlisib..
[51]
Roffey, S.J.; Obach, R.S.; Gedge, J.I.; Smith, D.A. 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., 2007, 39(1), 17-43.
[http://dx.doi.org/10.1080/03602530600952172] [PMID: 17364879]

Rights & Permissions Print Cite
Article Metrics
Pdf icon 88
Html icon 1
Find your institution