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Clinical data | |
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Trade names | Erleada, others |
Other names | ARN-509; JNJ-56021927; JNJ-927; A52 |
AHFS/ Drugs.com | Monograph |
MedlinePlus | a618018 |
License data | |
Pregnancy category |
|
Routes of administration | By mouth [2] |
Drug class | Nonsteroidal antiandrogen |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | 100% [2] |
Protein binding | Apalutamide: 96%
[2] NDMA: 95% [2] |
Metabolism | Liver ( CYP2C8, CYP3A4) [2] |
Metabolites | • NDMA [2] |
Elimination half-life | Apalutamide: 3–4 days (at steady-state) [7] [2] |
Excretion |
Urine: 65%
[2] Feces: 24% [2] |
Identifiers | |
| |
CAS Number |
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PubChem CID | |
DrugBank | |
ChemSpider | |
UNII | |
KEGG | |
ChEMBL | |
CompTox Dashboard ( EPA) | |
ECHA InfoCard | 100.235.115 |
Chemical and physical data | |
Formula | C21H15F4N5O2S |
Molar mass | 477.44 g·mol−1 |
3D model ( JSmol) | |
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|
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] [8] [9] [10] [11] It is specifically indicated for use in conjunction with castration in the treatment of non- metastatic castration-resistant prostate cancer (NM-CRPC). [2] [12] [13] It is taken by mouth. [2] [8]
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] [14] [15] [8] [10] Rarely, it can cause seizures. [2] [8] The medication has a high potential for drug interactions. [2] [8] Apalutamide is an antiandrogen, and acts as an antagonist of the androgen receptor, the biological target of androgens like testosterone and dihydrotestosterone. [2] [8] [11] In doing so, it prevents the effects of these hormones in the prostate gland and elsewhere in the body. [2] [8] [11]
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 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] [17] [18] [19] 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. [10]
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 of apalutamide include pregnancy and a history of or susceptibility to seizures. [2]
Apalutamide has been found to be well tolerated in clinical trials, [20] [17] with the most common side effects reported when added to surgical or medical castration including fatigue, nausea, abdominal pain, and diarrhea. [14] [15] [21] Other side effects have included rash, falls and bone fractures, and hypothyroidism, as well as seizures (in 0.2%), among others. [2] [8] [13] 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. [22] 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. [23] [24] [25]
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]
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]
Apalutamide acts as a selective competitive silent antagonist of the androgen receptor (AR), via the ligand-binding domain, and hence is an antiandrogen. [8] [11] [14] [17] It is similar both structurally and pharmacologically to the second-generation NSAA enzalutamide, [20] [26] but shows some advantages, including higher antiandrogenic activity as well as several-fold reduced central nervous system distribution. [11] [14] [17] The latter difference may reduce its comparative risk of seizures and other central side effects. [11] [14] [17] Apalutamide has 5- to 10-fold greater affinity for the AR than bicalutamide, a first-generation NSAA. [19] [18]
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 shows potent induction potential of cytochrome P450 enzymes similarly to enzalutamide. [2] [30] [31] 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 ( IC50 = 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]
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. [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 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] [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 is a structural analogue of enzalutamide and RD-162. [19] [35] 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. [36]
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 I clinical 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]
Apalutamide is the generic name of the drug and its INN . [45] [44] It is also known by its developmental code names ARN-509 and JNJ-56021927. [37] [8]
Apalutamide is marketed under the brand names Erleada and Erlyand. [2] [12] [13] [44]
Apalutamide is available in the United States, Canada, the European Union, and Australia. [2] [12] [13] [44] [6]
ARN-509 is related structurally to enzalutamide with greater in vivo activity in CRPC xenograft models (Clegg et al., 2012).
![]() | |
![]() | |
Clinical data | |
---|---|
Trade names | Erleada, others |
Other names | ARN-509; JNJ-56021927; JNJ-927; A52 |
AHFS/ Drugs.com | Monograph |
MedlinePlus | a618018 |
License data | |
Pregnancy category |
|
Routes of administration | By mouth [2] |
Drug class | Nonsteroidal antiandrogen |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | 100% [2] |
Protein binding | Apalutamide: 96%
[2] NDMA: 95% [2] |
Metabolism | Liver ( CYP2C8, CYP3A4) [2] |
Metabolites | • NDMA [2] |
Elimination half-life | Apalutamide: 3–4 days (at steady-state) [7] [2] |
Excretion |
Urine: 65%
[2] Feces: 24% [2] |
Identifiers | |
| |
CAS Number |
|
PubChem CID | |
DrugBank | |
ChemSpider | |
UNII | |
KEGG | |
ChEMBL | |
CompTox Dashboard ( EPA) | |
ECHA InfoCard | 100.235.115 |
Chemical and physical data | |
Formula | C21H15F4N5O2S |
Molar mass | 477.44 g·mol−1 |
3D model ( JSmol) | |
| |
|
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] [8] [9] [10] [11] It is specifically indicated for use in conjunction with castration in the treatment of non- metastatic castration-resistant prostate cancer (NM-CRPC). [2] [12] [13] It is taken by mouth. [2] [8]
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] [14] [15] [8] [10] Rarely, it can cause seizures. [2] [8] The medication has a high potential for drug interactions. [2] [8] Apalutamide is an antiandrogen, and acts as an antagonist of the androgen receptor, the biological target of androgens like testosterone and dihydrotestosterone. [2] [8] [11] In doing so, it prevents the effects of these hormones in the prostate gland and elsewhere in the body. [2] [8] [11]
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 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] [17] [18] [19] 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. [10]
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 of apalutamide include pregnancy and a history of or susceptibility to seizures. [2]
Apalutamide has been found to be well tolerated in clinical trials, [20] [17] with the most common side effects reported when added to surgical or medical castration including fatigue, nausea, abdominal pain, and diarrhea. [14] [15] [21] Other side effects have included rash, falls and bone fractures, and hypothyroidism, as well as seizures (in 0.2%), among others. [2] [8] [13] 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. [22] 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. [23] [24] [25]
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]
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]
Apalutamide acts as a selective competitive silent antagonist of the androgen receptor (AR), via the ligand-binding domain, and hence is an antiandrogen. [8] [11] [14] [17] It is similar both structurally and pharmacologically to the second-generation NSAA enzalutamide, [20] [26] but shows some advantages, including higher antiandrogenic activity as well as several-fold reduced central nervous system distribution. [11] [14] [17] The latter difference may reduce its comparative risk of seizures and other central side effects. [11] [14] [17] Apalutamide has 5- to 10-fold greater affinity for the AR than bicalutamide, a first-generation NSAA. [19] [18]
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 shows potent induction potential of cytochrome P450 enzymes similarly to enzalutamide. [2] [30] [31] 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 ( IC50 = 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]
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. [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 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] [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 is a structural analogue of enzalutamide and RD-162. [19] [35] 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. [36]
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 I clinical 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]
Apalutamide is the generic name of the drug and its INN . [45] [44] It is also known by its developmental code names ARN-509 and JNJ-56021927. [37] [8]
Apalutamide is marketed under the brand names Erleada and Erlyand. [2] [12] [13] [44]
Apalutamide is available in the United States, Canada, the European Union, and Australia. [2] [12] [13] [44] [6]
ARN-509 is related structurally to enzalutamide with greater in vivo activity in CRPC xenograft models (Clegg et al., 2012).