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Xenobiotica
the fate of foreign compounds in biological systems
Volume 49, 2019 - Issue 8
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Clinical Pharmacokinetics and Metabolism

19F-NMR-based determination of the absorption, metabolism and excretion of the oral phosphatidylinositol-3-kinase (PI3K) delta inhibitor leniolisib (CDZ173) in healthy volunteers

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Pages 953-960 | Received 23 Jul 2018, Accepted 11 Sep 2018, Published online: 29 Nov 2018

References

  • Bauer C, Tong L, Eggimann F, et al. (2018). Design of a metabolically stable tritium-tracer of the PI3Kδ-inhibitor CDZ173 (leniolisib) as a tool to study liver metabolites. Helv Chim Acta. 101:e1800044.
  • Beaumont C, Young GC, Cavalier T, Young MA. (2014). Human absorption, distribution, metabolism and excretion properties of drug molecules: a plethora of approaches. Br J Clin Pharmacol 78:1185–200.
  • Bolleddula J, DeMent K, Driscoll JP, et al. (2014). Biotransformation and bioactivation reactions of alicyclic amines in drug molecules. Drug Metab Rev 46:379–419.
  • De Buck S, Kucher K, Hara H, et al. (2018). CYP3A but not P-gp plays a relevant role in the in vivo intestinal and hepatic clearance of the delta-specific phosphoinositide-3 kinase inhibitor leniolisib. Biopharm Drug Dispos doi: 10.1002/bdd.2157.
  • Duckett CJ, Lindon JC, Walker H, et al. (2006). Metabolism of 3-chloro-4-fluoroaniline in rat using [14C]-radiolabelling, 19F-NMR spectroscopy, HPLC-MS/MS, HPLC-ICPMS and HPLC-NMR. Xenobiotica 36:59–77.
  • European Medicines Agency Committee for Human Medicinal Products (EMA) (2012). Guideline on the Investigation of Drug Interactions [Final]. London: EMA.
  • Food and Drug Administration Center for Drug Evaluation and Research (FDA). (2016). Guidance for Industry: Safety Testing of Drug Metabolites. Silver Spring: FDA.
  • Food and Drug Administration Center for Drug Evaluation and Research (FDA). (2012). Guidance for Industry: Drug Interaction Studies --Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations [Draft Guidance]. Rockville: FDA.
  • Gao H, Jacobs A, White RE, et al. (2013). Meeting report: metabolites in safety testing (MIST) symposium-safety assessment of human metabolites: what's REALLY necessary to ascertain exposure coverage in safety tests? AAPS J 15:970–3.
  • Hamilton RA, Garnett WR, Kline BJ. (1981). Determination of mean valproic acid serum level by assay of a single pooled sample. Clin Pharmacol Ther 29:408–13.
  • Hoegenauer K, Soldermann N, Zecri F, et al. (2017). Discovery of CDZ173 (leniolisib), representing a structurally novel class of PI3K delta-selective inhibitors. ACS Med Chem Lett 8:975–80.
  • Hu H, Huang N, Yi P, et al. (2015). Utilizing 19F NMR to investigate drug disposition early in drug discovery. Xenobiotica 45:1081–91.
  • Conference on Harmonisation (ICH). (2009). Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals M3(R2). ICH Harmonised Tripartite Guideline. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M3_R2/Step4/M3_R2__Guideline.pdf.
  • James AD, Marvalin C, Luneau A, et al. (2017). Comparison of 19F NMR and 14C measurements for the assessment of ADME of BYL719 (Alpelisib) in humans. Drug Metab Dispos 45:900–7.
  • Lenz EM, Wilson ID, Wright B, et al. (2002). A comparison of quantitative NMR and radiolabelling studies of the metabolism and excretion of Statil (3-(4-bromo-2-fluorobenzyl)-4-oxo-3H-phthalazin-1-ylacetic acid) in the rat. J Pharm Biomed Anal 28:31–43.
  • Lozach F, Fahrni S, De Maria D, et al. (2018). Evaluation of cAMS for 14C microtracer ADME studies: opportunities to change the current drug development paradigm. Bioanalysis 10:321–39.
  • Malet-Martino M, Gilard V, Desmoulin F, Martino R. (2006). Fluorine nuclear magnetic resonance spectroscopy of human biofluids in the field of metabolic studies of anticancer and antifungal fluoropyrimidine drugs. Clin Chim Acta 366:61–73.
  • Mutlib A, Espina R, Atherton Wang J, et al. (2012). Alternate strategies to obtain mass balance without the use of radiolabeled compounds: application of quantitative fluorine (19F) nuclear magnetic resonance (NMR) spectroscopy in metabolism studies. Chem Res Toxicol 25:572–83.
  • Pearson D, Weiss HM, Jin Y, et al. (2017). Absorption, distribution, metabolism and excretion of the oral prostaglandin D2 receptor 2 (DP2) antagonist fevipiprant (QAW039) in healthy volunteers and in vitro. Drug Metab Dispos 45:817–825.
  • Penner N, Klunk LJ, Prakash C. (2009). Human radiolabeled mass balance studies: objectives, utilities and limitations. Biopharm. Drug Dispos 30:185–203.
  • Rao VK, Webster S, Dalm VASH, et al. (2017). Effective “activated PI3Kd syndrome”–targeted therapy with the PI3Kδ inhibitor leniolisib. Blood 130:2307–16.
  • 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 39:17–43.
  • Scarf GB, Wright B, Clayton E, et al. (1998). 19F-NMR and directly coupled HPLC-NMR-MS investigations into the metabolism of 2-bromo-4-trifluoromethylaniline in rat: a urinary excretion balance study without the use of radiolabelling. Xenobiotica 28:373–88.
  • Sylvia LA, Gerig JT. (1993). Fluorine NMR studies of the metabolism of flumecinol (3-trifluoromethyl-alpha-ethylbenzhydrol). Drug Metab Dispos 21:105–13.

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