Comprehensive clinical pharmacology characterization of AZD4635 in healthy participants to support dosing considerations.
A2AR antagonist
AZD4635
healthy participants
pharmacokinetics
relative bioavailability
Journal
British journal of clinical pharmacology
ISSN: 1365-2125
Titre abrégé: Br J Clin Pharmacol
Pays: England
ID NLM: 7503323
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
revised:
10
03
2023
received:
14
11
2022
accepted:
13
03
2023
medline:
16
8
2023
pubmed:
15
4
2023
entrez:
14
4
2023
Statut:
ppublish
Résumé
Two phase 1 studies characterized the oral bioavailability of AZD4635 (potential anticancer therapy) and factors that may influence its pharmacokinetics (PKs; food, smoking, proton-pump inhibitors [PPIs] and CYP1A2 inhibitors) to support continued clinical development of AZD4635. Study 1 (comparative PK study; nonsmokers) consists of Part A and Part B. Participants (fasted) in Part A were administered 50 mg of AZD4635 either as nanosuspension or capsule. In Part B, these participants were administered a 50-mg capsule either following a high-fat meal or with a PPI in the fasted state. In Study 2 (CYP1A2 mediated drug-drug interaction study), a 25-mg AZD4635 capsule was administered to smokers and nonsmokers (fasted) with or without 100 mg of fluvoxamine. In Study 1 (N = 21), AZD4635 exposure was comparable between the capsule and nanosuspension. The high-fat meal produced a 12% decrease in AUC The high-fat meal reduced the rate but not the extent of AZD4635 absorption. The effect of gastric pH on AZD4635 was minimal. Smoking had no effect on the exposure (C
Substances chimiques
Fluvoxamine
O4L1XPO44W
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2775-2787Informations de copyright
© 2023 British Pharmacological Society.
Références
Chhabra P, Linden J, Lobo P, Okusa MD, Brayman KL. The immunosuppressive role of adenosine A2A receptors in ischemia reperfusion injury and islet transplantation. Curr Diabetes Rev. 2012;8(6):419-433. doi:10.2174/157339912803529878
Fishman P, Bar-Yehuda S, Synowitz M, et al. Adenosine receptors and cancer. Handb Exp Pharmacol. 2009;193:399-441. doi:10.1007/978-3-540-89615-9_14
Sek K, Molck C, Stewart GD, Kats L, Darcy PK, Beavis PA. Targeting adenosine receptor signaling in cancer immunotherapy. Int J Mol Sci. 2018;19(12):3837. doi:10.3390/ijms19123837
Blay J, White TD, Hoskin DW. The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res. 1997;57(13):2602-2605.
Ohta A. A metabolic immune checkpoint: adenosine in tumor microenvironment. Front Immunol. 2016;7:109. doi:10.3389/fimmu.2016.00109
Leone RD, Lo YC, Powell JD. A2aR antagonists: next generation checkpoint blockade for cancer immunotherapy. Comput Struct Biotechnol J. 2015;13:265-272. doi:10.1016/j.csbj.2015.03.008
Young A, Mittal D, Stagg J, Smyth MJ. Targeting cancer-derived adenosine: new therapeutic approaches. Cancer Discov. 2014;4(8):879-888. doi:10.1158/2159-8290.CD-14-0341
Lim EA, Bendell JC, Falchook GS, et al. Phase 1a/b, open-label, multicenter study of AZD4635 (an adenosine A2A receptor antagonist) as monotherapy or combined with durvalumab, in patients with solid tumors. Clin Cancer Res. 2022;28(22):4871-4884. doi:10.1158/1078-0432.CCR-22-0612
Smelick GS, Heffron TP, Chu L, et al. Prevalence of acid-reducing agents (ARA) in cancer populations and ARA drug-drug interaction potential for molecular targeted agents in clinical development. Mol Pharm. 2013;10(11):4055-4062. doi:10.1021/mp400403s
US Food and Drug Administration. Evaluation of gastric pH-dependent drug interactions with acid-reducing agents: study design, data analysis, and clinical implications guidance for industry. 2002. Accessed August 15, 2022. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/evaluation-gastric-ph-dependent-drug-interactions-acid-reducing-agents-study-design-data-analysis
Boulton DW, Kasichayanula S, Keung CF, et al. Simultaneous oral therapeutic and intravenous 14C-microdoses to determine the absolute oral bioavailability of saxagliptin and dapagliflozin. Br J Clin Pharmacol. 2013;75(3):763-768. doi:10.1111/j.1365-2125.2012.04391.x
US Food and Drug Administration. Food-Effect Bioavailability and Fed Bioequivalence Studies guidance for industry. 2002. Accessed March 15, 2022. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/food-effect-bioavailability-and-fed-bioequivalence-studies
Kaartinen TJK, Tornio A, Tapaninen T, et al. Effect of high-dose esomeprazole on CYP1A2, CYP2C19, and CYP3A4 activities in humans: evidence for substantial and long-lasting inhibition of CYP2C19. Clin Pharmacol Ther. 2020;108(6):1254-1264. doi:10.1002/cpt.1949
Fluvoxamine maleate [package insert]. ANI Pharmaceuticals, Inc.; 2012.
Alexander SP, Fabbro D, Kelly E, et al. The concise guide to pharmacology 2021/22: Enzymes. Br J Pharmacol. 2021;178(Suppl 1):S313-S411. doi:10.1111/bph.15542
Alexander SP, Christopoulos A, Davenport AP, et al. The concise guide to pharmacology 2021/22: G protein-coupled receptors. Br J Pharmacol. 2021;178(Suppl 1):S27-S156. doi:10.1111/bph.15538
Koziolek M, Alcaro S, Augustijns P, et al. The mechanisms of pharmacokinetic food-drug interactions-a perspective from the UNGAP group. Eur J Pharm Sci. 2019;134:31-59. doi:10.1016/j.ejps.2019.04.003
Uchiyama AAT, Silva P, Lopes MSM, et al. Proton pump inhibitors and oncologic treatment efficacy: a practical review of the literature for oncologists. Curr Oncol. 2021;28(1):783-799. doi:10.3390/curroncol28010076
Lappin G, Stevens L. Biomedical accelerator mass spectrometry: recent applications in metabolism and pharmacokinetics. Expert Opin Drug Metab Toxicol. 2008;4(8):1021-1033. doi:10.1517/17425255.4.8.1021
US Food and Drug Administration. Clinical drug interaction studies-cytochrome P450 enzyme- and transporter-mediated drug interactions guidance for industry. 2020. Accessed August 30, 2022. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. Accessed August 30, 2022.
van der Weide J, Steijns LS, van Weelden MJ. The effect of smoking and cytochrome P450 CYP1A2 genetic polymorphism on clozapine clearance and dose requirement. Pharmacogenetics. 2003;13(3):169-172. doi:10.1097/00008571-200303000-00006