Apalutamide was first described in 2007, and was approved for the treatment of prostate cancer in February 2018.[8][9][10][15] It is the first medication to be approved specifically for the treatment of non-metastatic castration-resistant prostate cancer.[2][10][9]
Apalutamide isindicated for the treatment of people with metastatic castration-sensitive prostate cancer and the treatment of people with non-metastatic castration-resistant prostate cancer.[2][6]
There is no knownantidote foroverdose of apalutamide.[2] General supportive measures should be undertaken until clinicaltoxicity, if any, diminishes or resolves.[2]
Apalutamide has a high potential fordrug interactions.[2] In terms of effects of apalutamide on other drugs, the exposure ofsubstrates of CYP3A4,CYP2C19,CYP2C9,UDP-glucuronosyltransferase,P-glycoprotein,ABCG2, orOATP1B1 may be reduced to varying extents.[2] In terms of effects of other drugs on apalutamide, strong CYP2C8 or CYP3A4 inhibitors may increase levels of apalutamide or its major active metaboliteN-desmethylapalutamide, while mild to moderate CYP2C8 or CYP3A4 inhibitors are not expected to affect their exposure.[2]
The acquired F876L mutation of the AR identified in advanced prostate cancer cells has been found to confer resistance to both enzalutamide and apalutamide.[27][28] A newer NSAA,darolutamide, is not affected by this mutation, nor has it been found to be affected by any other tested/well-known AR mutations.[29] Apalutamide may be effective in a subset of prostate cancer patients with acquired resistance toabiraterone acetate.[20]
Apalutamide binds weakly to andinhibits theGABAA receptorin vitro similarly to enzalutamide (IC50Tooltip half-maximal inhibitory concentration = 3.0 and 2.7 μM, respectively),[14] but due to its relatively lower central concentrations, may have a lower risk ofseizures in comparison.[14][11][21]
Apalutamide has been found to significantly and concentration-dependently increaseQT interval.[2]
The meanabsoluteoralbioavailability of apalutamide is 100%.[2] Meanpeak levels of apalutamide occur 2 hours following administration, with a range of 1 to 5 hours.[2] Food delays the median time to peak levels of apalutamide by approximately 2 hours, with no significant changes in the peak levels themselves or inarea-under-curve levels.[2]Steady-state levels of apalutamide are achieved following 4 weeks of administration, with an approximate 5-fold accumulation.[2]Peak concentrations for 160 mg/day apalutamide at steady-state are 6.0 μg/mL (12.5 μmol/L),[2] relative to peak levels of 16.6 μg/mL (35.7 μmol/L) for 160 mg/dayenzalutamide and mean (R)-bicalutamide levels of 21.6 μg/mL (50.2 μmol/L) for 150 mg/daybicalutamide.[32][33] The meanvolume of distribution of apalutamide at steady-state is approximately 276 L.[2] Theplasma protein binding of apalutamide is 96%, while that of its majormetaboliteN-desmethylapalutamide is 95%, both irrespective of concentration.[2]
Apalutamide ismetabolized in theliver byCYP2C8 andCYP3A4.[2] A majoractive metabolite, N-desmethylapalutamide, is formed by theseenzymes, with similar contribution of each of these enzymes to its formation at steady-state.[2] Following a single oral dose of 200 mg apalutamide, apalutamide represented 45% and N-desmethylapalutamide 44% of total area-under-curve levels.[2] The meanelimination half-life of apalutamide at steady-state is 3 to 4 days.[2][7] Fluctuations in apalutamide exposure are low and levels are stable throughout the day, with mean peak-to-trough ratios of 1.63 for apalutamide and 1.27–1.3 for N-desmethylapalutamide.[2] After a single dose of apalutamide, itsclearance rate (CL/F) was 1.3 L/h, while its clearance rate increased to 2.0 L/h at steady-state.[10] This change is considered to be likely due to CYP3A4auto-induction.[10] Approximately 65% of apalutamide isexcreted inurine (1.2% as unchanged apalutamide and 2.7% as N-desmethylapalutamide) while 24% is excreted infeces (1.5% as unchanged apalutamide and 2% as N-desmethylapalutamide).[2]
Apalutamide was originated by theUniversity of California system and was developed primarily byJanssen Research & Development, a division ofJohnson & Johnson.[36] It was first described in the literature in a United Statespatent application that was published in November 2007 and in another that was submitted in July 2010.[15][37] A March 2012 publication described the discovery and development of apalutamide.[14] Aphase Iclinical trial of apalutamide was completed by March 2012, and the results of this study were published in 2013.[14][38] Information onphase III clinical studies, including ATLAS, SPARTAN, and TITAN, was published between 2014 and 2016.[39][40][41] Positive results for phase III trials were first described in 2017, and Janssen submitted aNew Drug Application for apalutamide to the United States Food and Drug Administration on 11 October 2017.[42] Apalutamide was approved by the Food and Drug Administration in the United States, under the brand name Erleada, for the treatment of non-metastatic castration-resistant prostate cancer in February 2018.[8][9] It was subsequently approved in Canada, the European Union, and Australia.[43][6]
^abDellis AE, Papatsoris AG (June 2018). "Apalutamide: The established and emerging roles in the treatment of advanced prostate cancer".Expert Opin Investig Drugs.27 (6):553–559.doi:10.1080/13543784.2018.1484107.PMID29856649.S2CID46925616.
^abWO 2007126765, Jung ME, Sawyers CL, Ouk S, Tran C, Wongvipat J, "Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases", published 8 November 2007, assigned to The Regents Of The University Of California.Archived 4 November 2021 at theWayback Machine
^Kobe H, Tachikawa R, Masuno Y, Matsunashi A, Murata S, Hagimoto H, et al. (September 2021). "Apalutamide-induced severe interstitial lung disease: A report of two cases from Japan".Respir Investig.59 (5):700–705.doi:10.1016/j.resinv.2021.05.006.PMID34144936.S2CID235481675.
^Wu B, Shen P, Yin X, Yu L, Wu F, Chen C, et al. (March 2022). "Analysis of adverse event of interstitial lung disease in men with prostate cancer receiving hormone therapy using the Food and Drug Administration Adverse Event Reporting System".Br J Clin Pharmacol.89 (2):440–448.doi:10.1111/bcp.15336.PMID35349180.S2CID247777754.
^US 20100190991, Ouerfelli O, Dilhas A, Yang G, Zhao H, "Synthesis of thiohydantoins", issued 11 June 2013, assigned to Sloan Kettering Institute for Cancer Research.Archived 5 November 2021 at theWayback Machine
^Smith MR, Liu G, Shreeve SM, Matheny S, Sosa A, Kheoh TS, et al.A randomized double-blind, comparative study of ARN-509 plus androgen deprivation therapy (ADT) versus ADT alone in nonmetastatic castration-resistant prostate cancer (M0-CRPC): The SPARTAN trial. 2014 ASCO Annual Meeting.doi:10.1200/jco.2014.32.15_suppl.tps5100.
^World Health Organization (2016). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75".WHO Drug Information.30 (1).hdl:10665/331046.
