Apalutamide
Clinical data
Trade namesErleada, others
Other namesARN-509; JNJ-56021927; JNJ-927; A52
AHFS/Drugs.comMonograph
MedlinePlusa618018
License data
Pregnancy
category
Routes of
administration		By mouth[2]
Drug classNonsteroidal antiandrogen
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability100%[2]
Protein bindingApalutamide: 96%[2]
NDMA: 95%[2]
MetabolismLiver (CYP2C8, CYP3A4)[2]
Metabolites• NDMATooltip N-Desmethylapalutamide[2]
Elimination half-lifeApalutamide: 3–4 days (at steady-state)[6][2]
ExcretionUrine: 65%[2]
Feces: 24%[2]
Identifiers
  • 4-[7-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.235.115 Edit this at Wikidata
Chemical and physical data
FormulaC21H15F4N5O2S
Molar mass477.44 g·mol−1
3D model (JSmol)
  • CNC(=O)C1=C(C=C(C=C1)N2C(=S)N(C(=O)C23CCC3)C4=CN=C(C(=C4)C(F)(F)F)C#N)F
  • InChI=1S/C21H15F4N5O2S/c1-27-17(31)13-4-3-11(8-15(13)22)30-19(33)29(18(32)20(30)5-2-6-20)12-7-14(21(23,24)25)16(9-26)28-10-12/h3-4,7-8,10H,2,5-6H2,1H3,(H,27,31)
  • Key:HJBWBFZLDZWPHF-UHFFFAOYSA-N

Apalutamide, sold under the brand name Erleada among others, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer.[2][7][8][9][10] It is specifically indicated for use in conjunction with castration in the treatment of non-metastatic castration-resistant prostate cancer (NM-CRPC).[2][11][12] It is taken by mouth.[2][7]

Side effects of apalutamide when added to castration include fatigue, nausea, abdominal pain, diarrhea, high blood pressure, rash, falls, bone fractures, and an underactive thyroid.[2][13][14][7][9] Rarely, it can cause seizures.[2][7] The medication has a high potential for drug interactions.[2][7] Apalutamide is an antiandrogen, and acts as an antagonist of the androgen receptor, the biological target of androgens like testosterone and dihydrotestosterone.[2][7][10] In doing so, it prevents the effects of these hormones in the prostate gland and elsewhere in the body.[2][7][10]

Apalutamide was first described in 2007, and was approved for the treatment of prostate cancer in February 2018.[11][12][7][15] It was the first medication to be approved specifically for the treatment of NM-CRPC.[2][7][12]

Medical uses

Apalutamide is used in conjunction with castration, either via bilateral orchiectomy or gonadotropin-releasing hormone analogue (GnRH analogue) therapy, as a method of androgen deprivation therapy in the treatment of NM-CRPC.[2][16][17][18] It is also a promising potential treatment for metastatic castration-resistant prostate cancer (mCRPC), which the NSAA enzalutamide and the androgen synthesis inhibitor abiraterone acetate are used to treat.[9]

Available forms

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]

Contraindications

Contraindications of apalutamide include pregnancy and a history of or susceptibility to seizures.[2]

Side effects

Apalutamide has been found to be well tolerated in clinical trials,[19][16] with the most common side effects reported when added to surgical or medical castration including fatigue, nausea, abdominal pain, and diarrhea.[13][14][20] Other side effects have included rash, falls and bone fractures, and hypothyroidism, as well as seizures (in 0.2%), among others.[2][7][12] Apalutamide is an expected teratogen and has a theoretical risk of birth defects in male infants if taken by women during pregnancy.[2] It may impair male fertility.[2] When used as a monotherapy (i.e., without surgical or medical castration) in men, NSAAs are known to produce additional, estrogenic side effects like breast tenderness, gynecomastia, and feminization in general by increasing estradiol levels.[21] Similarly to the related second-generation NSAA enzalutamide but unlike first-generation NSAAs like flutamide and bicalutamide, elevated liver enzymes and hepatotoxicity have not been reported with apalutamide.[2] Case reports of rare interstitial lung disease with apalutamide exist similarly to with first-generation NSAAs however.[22][23][24]

Overdose

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]

Pharmacology

Pharmacodynamics

Antiandrogenic activity

Apalutamide acts as a selective competitive silent antagonist of the androgen receptor (AR), via the ligand-binding domain, and hence is an antiandrogen.[7][10][13][16] It is similar both structurally and pharmacologically to the second-generation NSAA enzalutamide,[19][25] but shows some advantages, including higher antiandrogenic activity as well as several-fold reduced central nervous system distribution.[10][13][16] The latter difference may reduce its comparative risk of seizures and other central side effects.[10][13][16] Apalutamide has 5- to 10-fold greater affinity for the AR than bicalutamide, a first-generation NSAA.[18][17]

The acquired F876L mutation of the AR identified in advanced prostate cancer cells has been found to confer resistance to both enzalutamide and apalutamide.[26][27] 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.[28] Apalutamide may be effective in a subset of prostate cancer patients with acquired resistance to abiraterone acetate.[19]

Other activities

Apalutamide shows potent induction potential of cytochrome P450 enzymes similarly to enzalutamide.[2][29][30] It is a strong inducer of CYP3A4 and CYP2C19 and a weak inducer of CYP2C9, as well as an inducer of UDP-glucuronosyltransferase.[2] In addition, apalutamide is an inducer of P-glycoprotein, ABCG2, and OATP1B1.[2]

Apalutamide binds weakly to and inhibits the GABAA receptor in vitro similarly to enzalutamide (IC50Tooltip half-maximal inhibitory concentration = 3.0 and 2.7 μM, respectively),[31] but due to its relatively lower central concentrations, may have a lower risk of seizures in comparison.[10][13][20]

Apalutamide has been found to significantly and concentration-dependently increase QT interval.[2]

Pharmacokinetics

The mean absolute oral bioavailability 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.[32][33] 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 metabolite N-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][6] 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.[7] This change is considered to be likely due to CYP3A4 auto-induction.[7] 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]

Chemistry

See also: Nonsteroidal antiandrogen and List of antiandrogens § Nonsteroidal antiandrogens

Apalutamide is a structural analogue of enzalutamide and RD-162.[18][34] It is a pyridyl variant of RD-162. Enzalutamide and RD-162 were derived from the nonsteroidal androgen RU-59063, which itself was derived from the first-generation NSAA nilutamide and by extension from flutamide.[35]

Chemical structures of apalutamide and its predecessors

History

Apalutamide was originated by the University of California system and was developed primarily by Janssen Research & Development, a division of Johnson & Johnson.[36] 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.[15][37] A March 2012 publication described the discovery and development of apalutamide.[10] A phase I clinical trial of apalutamide was completed by March 2012, and the results of this study were published in 2013.[10][38] Information on phase 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 a New 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 NM-CRPC on 14 February 2018.[11][12] It was subsequently approved in Canada, the European Union, and Australia.[43][5]

Society and culture

Generic names

Apalutamide is the generic name of the drug and its INNTooltip International Nonproprietary Name.[44][43] It is also known by its developmental code names ARN-509 and JNJ-56021927.[36][7]

Brand names

Apalutamide is marketed under the brand names Erleada and Erlyand.[2][11][12][43]

Availability

Apalutamide is available in the United States, Canada, the European Union, and Australia.[2][11][12][43][5]

References

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