Apalutamide

Apalutamide, sold under the brand name Erleada, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer.[1][3][4][5][6] It is specifically indicated for use in conjunction with castration in the treatment of non-metastatic castration-resistant prostate cancer (NM-CRPC).[1][7][8] It is taken by mouth.[1][3]

Apalutamide
Clinical data
Trade namesErleada
Other namesARN-509; JNJ-56021927; JNJ-927; A52
Pregnancy
category
  • X (Contraindicated)
Routes of
administration		By mouth[1]
Drug classNonsteroidal antiandrogen
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability100%[1]
Protein bindingApalutamide: 96%[1]
NDMA: 95%[1]
MetabolismLiver (CYP2C8, CYP3A4)[1]
Metabolites• NDMA[1]
Elimination half-lifeApalutamide: 3–4 days (at steady-state)[2][1]
ExcretionUrine: 65%[1]
Feces: 24%[1]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.235.115
Chemical and physical data
FormulaC21H15F4N5O2S
Molar mass477.435 g/mol g·mol−1
3D model (JSmol)

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.[1][9][10][3][5] Rarely, it can cause seizures.[1][3] The medication has a high potential for drug interactions.[1][3] Apalutamide is an antiandrogen, and acts as an antagonist of the androgen receptor, the biological target of androgens like testosterone and dihydrotestosterone.[1][3][6] In doing so, it prevents the effects of these hormones in the prostate gland and elsewhere in the body.[1][3][6]

Apalutamide was first described in 2007, and was approved for the treatment of prostate cancer in February 2018.[7][8][3][11] It was the first medication to be approved specifically for the treatment of NM-CRPC.[1][3][8]

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.[1][12][13][14] 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.[5]

Available forms

Apalutamide is provided in the form of 60 mg oral tablets.[1] It is taken at a dosage of 240 mg once per day (four tablets) when used in the treatment of NM-CRPC.[1]

Contraindications

Contraindications of apalutamide include pregnancy and a history of or susceptibility to seizures.[1]

Side effects

Apalutamide has been found to be well-tolerated in clinical trials,[15][12] with the most common side effects reported when added to surgical or medical castration including fatigue, nausea, abdominal pain, and diarrhea.[9][10][16] Other side effects have included rash, falls and bone fractures, and hypothyroidism, as well as seizures (in 0.2%), among others.[1][3][8] Apalutamide is an expected teratogen and has a theoretical risk of birth defects in male infants if taken by women during pregnancy.[1] It may impair male fertility.[1] 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.[17] 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.[1]

Overdose

There is no known antidote for overdose of apalutamide.[1] General supportive measures should be undertaken until clinical toxicity, if any, diminishes or resolves.[1]

Interactions

Apalutamide has a high potential for drug interactions.[1] 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.[1] 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.[1]

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.[3][6][9][12] It is similar both structurally and pharmacologically to the second-generation NSAA enzalutamide,[15][18] but shows some advantages, including higher antiandrogenic activity as well as several-fold reduced central nervous system distribution.[6][9][12] The latter difference may reduce its comparative risk of seizures and other central side effects.[6][9][12] Apalutamide has 5- to 10-fold greater affinity for the AR than bicalutamide, a first-generation NSAA.[14][13]

The acquired F876L mutation of the AR identified in advanced prostate cancer cells has been found to confer resistance to both enzalutamide and apalutamide.[19][20] 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.[21] Apalutamide may be effective in a subset of prostate cancer patients with acquired resistance to abiraterone acetate.[15]

Other activities

Apalutamide shows potent induction potential of cytochrome P450 enzymes similarly to enzalutamide.[1][22][23] It is a strong inducer of CYP3A4 and CYP2C19 and a weak inducer of CYP2C9, as well as an inducer of UDP-glucuronosyltransferase.[1] In addition, apalutamide is an inducer of P-glycoprotein, ABCG2, and OATP1B1.[1]

Apalutamide binds weakly to and inhibits the GABAA receptor in vitro similarly to enzalutamide (IC50 = 3.0 and 2.7 μM, respectively),[24] but due to its relatively lower central concentrations, may have a lower risk of seizures in comparison.[6][9][16]

Apalutamide has been found to significantly and concentration-dependently increase QT interval.[1]

Pharmacokinetics

The mean absolute oral bioavailability of apalutamide is 100%.[1] Mean peak levels of apalutamide occur 2 hours following administration, with a range of 1 to 5 hours.[1] 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.[1] Steady-state levels of apalutamide are achieved following 4 weeks of administration, with an approximate 5-fold accumulation.[1] Peak concentrations for 160 mg/day apalutamide at steady-state are 6.0 µg/mL (12.5 µmol/L),[1] 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.[25][26] The mean volume of distribution of apalutamide at steady-state is approximately 276 L.[1] The plasma protein binding of apalutamide is 96%, while that of its major metabolite N-desmethylapalutamide is 95%, both irrespective of concentration.[1]

Apalutamide is metabolized in the liver by CYP2C8 and CYP3A4.[1] 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.[1] Following a single oral dose of 200 mg apalutamide, apalutamide represented 45% and N-desmethylapalutamide 44% of total area-under-curve levels.[1] The mean elimination half-life of apalutamide at steady-state is 3 to 4 days.[1][2] 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.[1] 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.[3] This change is considered to be likely due to CYP3A4 auto-induction.[3] 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 apalutmaide and 2% as N-desmethylapalutamide).[1]

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

Apalutamide is a structural analogue of enzalutamide and RD-162.[14][27] 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.[28]

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.[29] 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.[11][30] A March 2012 publication described the discovery and development of apalutamide.[6] A phase I clinical trial of apalutamide was completed by March 2012, and the results of this study were published in 2013.[6][31] Information on phase III clinical studies, including ATLAS, SPARTAN, and TITAN, was published between 2014 and 2016.[32][33][34] 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.[35] 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.[7][8]

Society and culture

Generic names

Apalutamide is the generic name of the drug and its INN.[36][37] It is also known by its developmental code names ARN-509 and JNJ-56021927.[29][3]

Brand names

Apalutamide is marketed under the brand name Erleada.[1][7][8][37]

Availability

As of present, apalutamide is available only in the United States and Canada.[1][7][8][37]

References
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  2. Rathkopf DE, Morris MJ, Fox JJ, Danila DC, Slovin SF, Hager JH, et al. (October 2013). "Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer". Journal of Clinical Oncology. 31 (28): 3525–30. doi:10.1200/JCO.2013.50.1684. PMC 3782148. PMID 24002508.
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  33. Bossi, A.; Dearnaley, D.; McKenzie, M.; Baskin-Bey, E.; Tyler, R.; Tombal, B.; Freedland, S.J.; Roach, M.; Widmark, A.; Dicker, A.P.; Wiegel, T.; Shore, N.; Smith, M.; Yu, M.; Kheoh, T.; Thomas, S.; Sandler, H.M. (2016). "ATLAS: A phase 3 trial evaluating the efficacy of apalutamide (ARN-509) in patients with high-risk localized or locally advanced prostate cancer receiving primary radiation therapy". Annals of Oncology. 27 (suppl_6). doi:10.1093/annonc/mdw372.52. ISSN 0923-7534.
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