Apalutamide was first described in 2007, and was approved for the treatment of prostate cancer in February 2018.[12][13][8][16] It was the first medication to be approved specifically for the treatment of NM-CRPC.[2][8][13]
Apalutamide is provided in the form of 60 mg oral tablets.[2] It is taken at a dosage of 240 mg once per day (four tablets) when used in the treatment of NM-CRPC.[2]
There is no known
antidote for
overdose of apalutamide.[2] General supportive measures should be undertaken until clinical
toxicity, if any, diminishes or resolves.[2]
Interactions
Apalutamide has a high potential for
drug interactions.[2] In terms of effects of apalutamide on other drugs, the exposure of
substrates of CYP3A4,
CYP2C19,
CYP2C9,
UDP-glucuronosyltransferase,
P-glycoprotein,
ABCG2, or
OATP1B1 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 metabolite
N-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 to
abiraterone acetate.[20]
Apalutamide binds weakly to and
inhibits the
GABAA receptorin vitro similarly to enzalutamide (
IC50Tooltip half-maximal inhibitory concentration = 3.0 and 2.7 μM, respectively),[32] but due to its relatively lower central concentrations, may have a lower risk of
seizures in comparison.[11][14][21]
Apalutamide has been found to significantly and concentration-dependently increase
QT interval.[2]
Pharmacokinetics
The mean
absoluteoralbioavailability of apalutamide is 100%.[2] Mean
peak 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 in
area-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/day
enzalutamide and mean (R)-bicalutamide levels of 21.6 μg/mL (50.2 μmol/L) for 150 mg/day
bicalutamide.[33][34] The mean
volume of distribution of apalutamide at steady-state is approximately 276 L.[2] The
plasma protein binding of apalutamide is 96%, while that of its major
metaboliteN-desmethylapalutamide is 95%, both irrespective of concentration.[2]
Apalutamide is
metabolized in the
liver by
CYP2C8 and
CYP3A4.[2] A major
active metabolite, N-desmethylapalutamide, is formed by these
enzymes, 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 mean
elimination 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, its
clearance rate (CL/F) was 1.3 L/h, while its clearance rate increased to 2.0 L/h at steady-state.[8] This change is considered to be likely due to CYP3A4
auto-induction.[8] Approximately 65% of apalutamide is
excreted in
urine (1.2% as unchanged apalutamide and 2.7% as N-desmethylapalutamide) while 24% is excreted in
feces (1.5% as unchanged apalutamide and 2% as N-desmethylapalutamide).[2]
Apalutamide was originated by the
University of California system and was developed primarily by
Janssen Research & Development, a division of
Johnson & Johnson.[37] It was first described in the literature in a United States
patent application that was published in November 2007 and in another that was submitted in July 2010.[16][38] A March 2012 publication described the discovery and development of apalutamide.[11] A
phase Iclinical trial of apalutamide was completed by March 2012, and the results of this study were published in 2013.[11][39] Information on
phase III clinical studies, including ATLAS, SPARTAN, and TITAN, was published between 2014 and 2016.[40][41][42] Positive results for phase III trials were first described in 2017, and Janssen submitted a
New Drug Application for apalutamide to the United States Food and Drug Administration on 11 October 2017.[43] Apalutamide was approved by the Food and Drug Administration in the United States, under the brand name Erleada, for the treatment of NM-CRPC on 14 February 2018.[12][13] It was subsequently approved in
Canada, the
European Union, and
Australia.[44][6]
Society and culture
Generic names
Apalutamide is the
generic name of the drug and its
INNTooltip International Nonproprietary Name.[45][44] It is also known by its developmental code names ARN-509 and JNJ-56021927.[37][8]
Brand names
Apalutamide is marketed under the brand names Erleada and Erlyand.[2][12][13][44]
Availability
Apalutamide is available in the United States, Canada, the European Union, and Australia.[2][12][13][44][6]
^
abcDellis 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.
^Kobe H, Tachikawa R, Masuno Y, Matsunashi A, Murata S, Hagimoto H, Tomii K (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.
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^Wu B, Shen P, Yin X, Yu L, Wu F, Chen C, Li J, Xu T (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.
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^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.
^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.
Dellis 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.