دورية أكاديمية
Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Xenograft.
| العنوان: | Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Xenograft. |
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| المؤلفون: | Raub TJ; Drug Disposition, Lilly Research Laboratories (T.J.R., G.N.W., P.K., B.A.S., R.T.A., G.A.S.), Division of Cancer Research (L.M.G., H.E.S.), and Discovery Chemistry Research and Technologies (A.D.D.), Eli Lilly and Company, Indianapolis, Indiana; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Alcobendas, Madrid, Spain (C.S.-M.); and Covance Laboratories, Greenfield, Indiana (H.E.S.) raubtj@lilly.com., Wishart GN; Drug Disposition, Lilly Research Laboratories (T.J.R., G.N.W., P.K., B.A.S., R.T.A., G.A.S.), Division of Cancer Research (L.M.G., H.E.S.), and Discovery Chemistry Research and Technologies (A.D.D.), Eli Lilly and Company, Indianapolis, Indiana; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Alcobendas, Madrid, Spain (C.S.-M.); and Covance Laboratories, Greenfield, Indiana (H.E.S.)., Kulanthaivel P; Drug Disposition, Lilly Research Laboratories (T.J.R., G.N.W., P.K., B.A.S., R.T.A., G.A.S.), Division of Cancer Research (L.M.G., H.E.S.), and Discovery Chemistry Research and Technologies (A.D.D.), Eli Lilly and Company, Indianapolis, Indiana; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Alcobendas, Madrid, Spain (C.S.-M.); and Covance Laboratories, Greenfield, Indiana (H.E.S.)., Staton BA; Drug Disposition, Lilly Research Laboratories (T.J.R., G.N.W., P.K., B.A.S., R.T.A., G.A.S.), Division of Cancer Research (L.M.G., H.E.S.), and Discovery Chemistry Research and Technologies (A.D.D.), Eli Lilly and Company, Indianapolis, Indiana; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Alcobendas, Madrid, Spain (C.S.-M.); and Covance Laboratories, Greenfield, Indiana (H.E.S.)., Ajamie RT; Drug Disposition, Lilly Research Laboratories (T.J.R., G.N.W., P.K., B.A.S., R.T.A., G.A.S.), Division of Cancer Research (L.M.G., H.E.S.), and Discovery Chemistry Research and Technologies (A.D.D.), Eli Lilly and Company, Indianapolis, Indiana; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Alcobendas, Madrid, Spain (C.S.-M.); and Covance Laboratories, Greenfield, Indiana (H.E.S.)., Sawada GA; Drug Disposition, Lilly Research Laboratories (T.J.R., G.N.W., P.K., B.A.S., R.T.A., G.A.S.), Division of Cancer Research (L.M.G., H.E.S.), and Discovery Chemistry Research and Technologies (A.D.D.), Eli Lilly and Company, Indianapolis, Indiana; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Alcobendas, Madrid, Spain (C.S.-M.); and Covance Laboratories, Greenfield, Indiana (H.E.S.)., Gelbert LM; Drug Disposition, Lilly Research Laboratories (T.J.R., G.N.W., P.K., B.A.S., R.T.A., G.A.S.), Division of Cancer Research (L.M.G., H.E.S.), and Discovery Chemistry Research and Technologies (A.D.D.), Eli Lilly and Company, Indianapolis, Indiana; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Alcobendas, Madrid, Spain (C.S.-M.); and Covance Laboratories, Greenfield, Indiana (H.E.S.)., Shannon HE; Drug Disposition, Lilly Research Laboratories (T.J.R., G.N.W., P.K., B.A.S., R.T.A., G.A.S.), Division of Cancer Research (L.M.G., H.E.S.), and Discovery Chemistry Research and Technologies (A.D.D.), Eli Lilly and Company, Indianapolis, Indiana; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Alcobendas, Madrid, Spain (C.S.-M.); and Covance Laboratories, Greenfield, Indiana (H.E.S.)., Sanchez-Martinez C; Drug Disposition, Lilly Research Laboratories (T.J.R., G.N.W., P.K., B.A.S., R.T.A., G.A.S.), Division of Cancer Research (L.M.G., H.E.S.), and Discovery Chemistry Research and Technologies (A.D.D.), Eli Lilly and Company, Indianapolis, Indiana; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Alcobendas, Madrid, Spain (C.S.-M.); and Covance Laboratories, Greenfield, Indiana (H.E.S.)., De Dios A; Drug Disposition, Lilly Research Laboratories (T.J.R., G.N.W., P.K., B.A.S., R.T.A., G.A.S.), Division of Cancer Research (L.M.G., H.E.S.), and Discovery Chemistry Research and Technologies (A.D.D.), Eli Lilly and Company, Indianapolis, Indiana; Discovery Chemistry Research and Technologies, Eli Lilly and Company, Alcobendas, Madrid, Spain (C.S.-M.); and Covance Laboratories, Greenfield, Indiana (H.E.S.). |
| المصدر: | Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2015 Sep; Vol. 43 (9), pp. 1360-71. Date of Electronic Publication: 2015 Jul 06. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics, etc.] Country of Publication: United States NLM ID: 9421550 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-009X (Electronic) Linking ISSN: 00909556 NLM ISO Abbreviation: Drug Metab Dispos Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [Bethesda, Md., etc., American Society for Pharmacology and Experimental Therapeutics, etc.] |
| مواضيع طبية MeSH: | Aminopyridines/*pharmacology , Benzimidazoles/*pharmacology , Brain/*drug effects , Brain Neoplasms/*drug therapy , Cyclin-Dependent Kinase 4/*antagonists & inhibitors , Cyclin-Dependent Kinase 6/*antagonists & inhibitors , Glioblastoma/*drug therapy , Piperazines/*pharmacology , Protein Kinase Inhibitors/*pharmacology , Pyridines/*pharmacology, Aminopyridines/administration & dosage ; Aminopyridines/therapeutic use ; Animals ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Benzimidazoles/administration & dosage ; Benzimidazoles/therapeutic use ; Brain Neoplasms/pathology ; Dacarbazine/administration & dosage ; Dacarbazine/analogs & derivatives ; Dogs ; Female ; Glioblastoma/pathology ; Madin Darby Canine Kidney Cells ; Male ; Mice ; Piperazines/administration & dosage ; Piperazines/therapeutic use ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/therapeutic use ; Pyridines/administration & dosage ; Pyridines/therapeutic use ; Rats ; Temozolomide ; Xenograft Model Antitumor Assays |
| مستخلص: | Effective treatments for primary brain tumors and brain metastases represent a major unmet medical need. Targeting the CDK4/CDK6-cyclin D1-Rb-p16/ink4a pathway using a potent CDK4 and CDK6 kinase inhibitor has potential for treating primary central nervous system tumors such as glioblastoma and some peripheral tumors with high incidence of brain metastases. We compared central nervous system exposures of two orally bioavailable CDK4 and CDK6 inhibitors: abemaciclib, which is currently in advanced clinical development, and palbociclib (IBRANCE; Pfizer), which was recently approved by the U.S. Food and Drug Administration. Abemaciclib antitumor activity was assessed in subcutaneous and orthotopic glioma models alone and in combination with standard of care temozolomide (TMZ). Both inhibitors were substrates for xenobiotic efflux transporters P-glycoprotein and breast cancer resistant protein expressed at the blood-brain barrier. Brain Kp,uu values were less than 0.2 after an equimolar intravenous dose indicative of active efflux but were approximately 10-fold greater for abemaciclib than palbociclib. Kp,uu increased 2.8- and 21-fold, respectively, when similarly dosed in P-gp-deficient mice. Abemaciclib had brain area under the curve (0-24 hours) Kp,uu values of 0.03 in mice and 0.11 in rats after a 30 mg/kg p.o. dose. Orally dosed abemaciclib significantly increased survival in a rat orthotopic U87MG xenograft model compared with vehicle-treated animals, and efficacy coincided with a dose-dependent increase in unbound plasma and brain exposures in excess of the CDK4 and CDK6 Ki values. Abemaciclib increased survival time of intracranial U87MG tumor-bearing rats similar to TMZ, and the combination of abemaciclib and TMZ was additive or greater than additive. These data show that abemaciclib crosses the blood-brain barrier and confirm that both CDK4 and CDK6 inhibitors reach unbound brain levels in rodents that are expected to produce enzyme inhibition; however, abemaciclib brain levels are reached more efficiently at presumably lower doses than palbociclib and are potentially on target for a longer period of time. (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.) |
| المشرفين على المادة: | 0 (Aminopyridines) 0 (Benzimidazoles) 0 (Piperazines) 0 (Protein Kinase Inhibitors) 0 (Pyridines) 60UAB198HK (abemaciclib) 7GR28W0FJI (Dacarbazine) EC 2.7.11.22 (Cyclin-Dependent Kinase 4) EC 2.7.11.22 (Cyclin-Dependent Kinase 6) G9ZF61LE7G (palbociclib) YF1K15M17Y (Temozolomide) |
| تواريخ الأحداث: | Date Created: 20150708 Date Completed: 20160517 Latest Revision: 20191210 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1124/dmd.114.062745 |
| PMID: | 26149830 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1521-009X |
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| DOI: | 10.1124/dmd.114.062745 |