Peringatan Keamanan

There is no known specific antidote for apalutamide overdose. In the event of an overdose, stop apalutamide, undertake general supportive measures until clinical toxicity has been diminished or resolved.L45538

The safety and efficacy of apalutamide have not been established in females. Based on findings from animals and its mechanism of action, apalutamide can cause fetal harm and loss of pregnancy when administered to a pregnant female. There are no
available data on apalutamide use in pregnant women to inform a drug-associated risk. In an animal reproduction study, oral administration of apalutamide to pregnant rats during and after organogenesis resulted in fetal abnormalities and embryo-fetal lethality at maternal exposures ? 2 times the human clinical exposure (AUC) at the recommended dose.L45538

In a 2-year carcinogenicity study in male rats, apalutamide was administered by oral gavage at doses of 5, 15 and 50 mg/kg/day. Apalutamide increased the incidence of Leydig interstitial cell adenoma in the testes at doses ? 5 mg/kg/day (0.2 times the human exposure based on AUC). The findings in the testes are considered to be related to the pharmacological activity of apalutamide. Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Oral administration of apalutamide to male rasH2 transgenic mice for 6 months did not result in increased incidence of neoplasms at doses up to 30 mg/kg/day.L45538

Apalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either in vitro chromosome aberration assay or the in vivo rat bone marrow micronucleus assay or the in vivo rat Comet assay. In repeat-dose toxicity studies in male rats (up to 26 weeks) and dogs (up to 39 weeks), atrophy of the prostate gland and seminal vesicles, aspermia/hypospermia, tubular degeneration and/or hyperplasia or hypertrophy of the interstitial cells in the reproductive system were observed at ? 25 mg/kg/day in rats (1.4 times the human exposure based on AUC) and ? 2.5 mg/kg/day in dogs (0.9 times the human exposure based on AUC).L45538

In a fertility study in male rats, a decrease in sperm concentration and motility, increased abnormal sperm morphology, lower copulation and fertility rates (upon pairing with untreated females) along with reduced weights of the secondary sex glands and epididymis were observed following 4 weeks of dosing at ? 25 mg/kg/day (0.8 times the human exposure based on AUC). A reduced number of live fetuses due to increased pre- and/or post-implantation loss was observed following 4 weeks of 150 mg/kg/day administration (5.7 times the human exposure based on AUC). Effects on male rats were reversible after 8 weeks from the last apalutamide administration.L45538

Apalutamide

DB11901

small molecule approved investigational

Deskripsi

Apalutamide is a potent androgen receptor (AR) antagonist that selectively binds to the ligand-binding domain of AR and blocks AR nuclear translocation or binding to androgen response elements A31846. It has been used in trials studying the treatment of Prostate Cancer, Hepatic Impairment, Prostatic Neoplasms, Castration-Resistant Prostate Cancer, and Prostatic Neoplasms, Castration-Resistant, among others. Exerting an antitumor action, apalutamide blocking the effect of androgens that promote tumor growth. It targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets in prostate tumors A31846. In mice bearing human CRPC xenograft models, apalutamide treatment produced tumor regressions in a dose-dependent manner that was more effective than that of DB01128 or DB08899. Unlike bicalutamide, apalutamide antagonized AR-mediated signaling in AR overexpressing human CRPC cell lines A31846.

Androgen-deprivation therapy, or hormone therapy, can be used as part of maintenance therapy for patients with non-metastatic prostate cancer. Although most patients achieve therapeutic responses at the initial hormone therapy, many patients progress to non-metastatic castration-resistant (resistance to hormone therapy) prostate cancer which is the second-most common cause of cancer-related deaths in American males A31852. Castration-resistant prostate cancer is often incurable, which poses significant clinical challenges for patients. Approximately 10 to 20 % of prostate cancer cases are castration-resistant, and up to 16% of these patients show no evidence of cancer metastasis at the time of castration-resistant diagnosis L1295. Higher prostate-specific antigen (PSA) and shorter PSA doubling time (PSA DT) are associated with a higher risk for metastases and death A31846. In a phase-2 multicenter open-label study, 89% of patients with non-metastatic, castration-resistant prostate cancer had ?50% PSA decline at week 12 of apalutamide treatment A31846. In a randomized trial, the median metastasis-free survival for patients taking apalutamide was 40.5 months compared to 16.2 months for patients taking a placebo L1295. Apalutamide displayed good tolerability and safety profile in clinical studies.

Apalutamide was approved in February 2018 by the FDA as Erleada for the treatment of patients with non-metastatic prostate cancer that is resistant to treatment with hormone therapy (castration-resistant). It is available as oral tablets. Apalutamide is the first FDA-approved treatment for non-metastatic, castration-resistant prostate cancer L1295.

Struktur Molekul 2D

Berat 477.44
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) The mean effective half-life for apalutamide in patients with NM-CRPC was approximately 3 days at steady-state.[L45538]
Volume Distribusi The mean apparent volume of distribution at steady state of apalutamide was approximately 276 L.[L45538]
Klirens (Clearance) The CL/F of apalutamide was 1.3 L/h after single dosing and increased to 2.0 L/h at steady-state after once-daily dosing likely due to CYP3A4 auto-induction.[L45538] The auto-induction effect likely reached its maximum at the recommended dosage because exposure to apalutamide across the dose range of 30 to 480 mg is dose-proportional.[L45538]

Absorpsi

Mean absolute oral bioavailability was approximately 100%. The median time to achieve peak plasma concentration (tmax) was 2 hours (range: 1 to 5 hours). The major active metabolite N-desmethyl apalutamide Cmax was 5.9 mcg/mL (1.0) and AUC was 124 mcg·h/mL (23) at steady-state after the recommended dosage. Administration of apalutamide to healthy subjects under fasting conditions and with a high-fat meal (approximately 500 to 600 fat calories, 250 carbohydrate calories, and 150 protein calories) resulted in no clinically relevant changes in Cmax and AUC. The median time to reach tmax was delayed approximately 2 hours with food.L45538 Following administration of the recommended dosage, apalutamide steady-state was achieved after 4 weeks and the mean accumulation ratio was approximately 5-fold. Apalutamide Cmax was 6.0 mcg/mL (1.7) and AUC was 100 mcg·h/mL (32) at steady-state. Daily fluctuations in apalutamide plasma concentrations were low, with the mean peak-to-trough ratio of 1.63.L45538 Oral administration of four 60 mg apalutamide tablets dispersed in applesauce resulted in no clinically relevant changes in Cmax and AUC compared to the administration of four intact 60 mg tablets under fasting conditions.L45538

Metabolisme

Metabolism is the main route of elimination of apalutamide. Apalutamide is primarily metabolized by CYP2C8 and CYP3A4 to form active metabolite, N-desmethyl apalutamide. The contribution of CYP2C8 and CYP3A4 in the metabolism of apalutamide is estimated to be 58% and 13% following single dose but changes to 40% and 37%, respectively at steady-state.L45538 The auto-induction of CYP3A4-mediated metabolism by apalutamide may explain the increase in CYP3A4 enzymatic activity at steady-state.L45538

Rute Eliminasi

Apalutamide and its main active metabolite are subject to both renal and focal elimination. Up to 70 days following a single oral administration of radiolabeled apalutamide, 65% of the dose was recovered in urine (1.2% of dose as unchanged apalutamide and 2.7% as N-desmethyl apalutamide) and 24% was recovered in feces (1.5% of dose as unchanged apalutamide and 2% as N-desmethyl apalutamide).L45538

Interaksi Makanan

2 Data
  • 1. Take at the same time every day.
  • 2. Take with or without food.

Interaksi Obat

1603 Data
Aripiprazole The serum concentration of Aripiprazole can be decreased when it is combined with Apalutamide.
Brentuximab vedotin The serum concentration of Brentuximab vedotin can be decreased when it is combined with Apalutamide.
Dabigatran etexilate The serum concentration of Dabigatran etexilate can be decreased when it is combined with Apalutamide.
Sofosbuvir The serum concentration of Sofosbuvir can be decreased when it is combined with Apalutamide.
Mifepristone The serum concentration of Apalutamide can be increased when it is combined with Mifepristone.
Succinic acid The excretion of Succinic acid can be decreased when combined with Apalutamide.
Citrulline The excretion of Citrulline can be decreased when combined with Apalutamide.
Aminohippuric acid The excretion of Aminohippuric acid can be decreased when combined with Apalutamide.
Cefdinir The excretion of Cefdinir can be decreased when combined with Apalutamide.
Leucovorin The excretion of Leucovorin can be decreased when combined with Apalutamide.
Fluorescein The excretion of Fluorescein can be decreased when combined with Apalutamide.
Quinapril The excretion of Quinapril can be decreased when combined with Apalutamide.
Dinoprostone The serum concentration of Dinoprostone can be decreased when it is combined with Apalutamide.
Famotidine The excretion of Famotidine can be decreased when combined with Apalutamide.
Benzylpenicillin The serum concentration of Benzylpenicillin can be decreased when it is combined with Apalutamide.
Captopril The excretion of Captopril can be decreased when combined with Apalutamide.
Tazobactam The excretion of Tazobactam can be decreased when combined with Apalutamide.
Cyclic adenosine monophosphate The excretion of Cyclic adenosine monophosphate can be decreased when combined with Apalutamide.
Cholic Acid The serum concentration of Cholic Acid can be decreased when it is combined with Apalutamide.
Glutaric Acid The excretion of Glutaric Acid can be decreased when combined with Apalutamide.
Oxalic Acid The excretion of Oxalic Acid can be decreased when combined with Apalutamide.
Ellagic acid The excretion of Ellagic acid can be decreased when combined with Apalutamide.
Avibactam The excretion of Avibactam can be decreased when combined with Apalutamide.
Eluxadoline The serum concentration of Eluxadoline can be decreased when it is combined with Apalutamide.
Silibinin The excretion of Silibinin can be decreased when combined with Apalutamide.
Relebactam The excretion of Relebactam can be decreased when combined with Apalutamide.
Cefotiam The excretion of Cefotiam can be decreased when combined with Apalutamide.
Valaciclovir The excretion of Valaciclovir can be decreased when combined with Apalutamide.
Acyclovir The excretion of Acyclovir can be decreased when combined with Apalutamide.
Cefaclor The excretion of Cefaclor can be decreased when combined with Apalutamide.
Hydrochlorothiazide The excretion of Hydrochlorothiazide can be decreased when combined with Apalutamide.
Cefazolin The excretion of Cefazolin can be decreased when combined with Apalutamide.
Ceftizoxime The excretion of Ceftizoxime can be decreased when combined with Apalutamide.
Cefacetrile The excretion of Cefacetrile can be decreased when combined with Apalutamide.
Ceftibuten The excretion of Ceftibuten can be decreased when combined with Apalutamide.
Cefaloridine The excretion of Cefaloridine can be decreased when combined with Apalutamide.
Oseltamivir The excretion of Oseltamivir can be decreased when combined with Apalutamide.
Piperacillin The excretion of Piperacillin can be decreased when combined with Apalutamide.
Trifluridine The excretion of Trifluridine can be decreased when combined with Apalutamide.
Allopurinol The serum concentration of Allopurinol can be decreased when it is combined with Apalutamide.
Levocarnitine The excretion of Levocarnitine can be decreased when combined with Apalutamide.
Doripenem The excretion of Doripenem can be decreased when combined with Apalutamide.
Indomethacin The serum concentration of Indomethacin can be decreased when it is combined with Apalutamide.
Ranitidine The excretion of Ranitidine can be decreased when combined with Apalutamide.
Taurocholic acid The serum concentration of Taurocholic acid can be decreased when it is combined with Apalutamide.
Cimetidine The excretion of Cimetidine can be decreased when combined with Apalutamide.
Oxytetracycline The excretion of Oxytetracycline can be decreased when combined with Apalutamide.
Ifosfamide The metabolism of Ifosfamide can be increased when combined with Apalutamide.
Ledipasvir The serum concentration of Ledipasvir can be decreased when it is combined with Apalutamide.
Perampanel The metabolism of Perampanel can be increased when combined with Apalutamide.
R,S-Warfarin alcohol The metabolism of R,S-Warfarin alcohol can be increased when combined with Apalutamide.
S,R-Warfarin alcohol The metabolism of S,R-Warfarin alcohol can be increased when combined with Apalutamide.
Warfarin The serum concentration of Warfarin can be decreased when it is combined with Apalutamide.
Doxorubicin The serum concentration of Doxorubicin can be decreased when it is combined with Apalutamide.
Vincristine The serum concentration of Vincristine can be decreased when it is combined with Apalutamide.
Choline C 11 Apalutamide may decrease effectiveness of Choline C 11 as a diagnostic agent.
Capromab pendetide Apalutamide may decrease effectiveness of Capromab pendetide as a diagnostic agent.
Secobarbital The metabolism of Apalutamide can be increased when combined with Secobarbital.
Rifampin The metabolism of Apalutamide can be increased when combined with Rifampicin.
Troglitazone The serum concentration of Troglitazone can be decreased when it is combined with Apalutamide.
Spironolactone Spironolactone may increase the excretion rate of Apalutamide which could result in a lower serum level and potentially a reduction in efficacy.
Nabilone The serum concentration of Nabilone can be decreased when it is combined with Apalutamide.
Irbesartan The serum concentration of Irbesartan can be decreased when it is combined with Apalutamide.
Genistein The metabolism of Apalutamide can be decreased when combined with Genistein.
Topiroxostat The metabolism of Apalutamide can be decreased when combined with Topiroxostat.
Eltrombopag The metabolism of Apalutamide can be decreased when combined with Eltrombopag.
Teriflunomide The serum concentration of Teriflunomide can be decreased when it is combined with Apalutamide.
Levothyroxine The metabolism of Apalutamide can be decreased when combined with Levothyroxine.
Tipiracil The excretion of Tipiracil can be decreased when combined with Apalutamide.
Sorafenib The metabolism of Sorafenib can be increased when combined with Apalutamide.
Fluticasone propionate The serum concentration of Apalutamide can be increased when it is combined with Fluticasone propionate.
Clopidogrel The serum concentration of Apalutamide can be increased when it is combined with Clopidogrel.
Candesartan cilexetil The serum concentration of Apalutamide can be increased when it is combined with Candesartan cilexetil.
Salmeterol The serum concentration of Apalutamide can be increased when it is combined with Salmeterol.
Felodipine The serum concentration of Apalutamide can be increased when it is combined with Felodipine.
Gemfibrozil The serum concentration of Apalutamide can be increased when it is combined with Gemfibrozil.
Fluticasone furoate The serum concentration of Fluticasone furoate can be decreased when it is combined with Apalutamide.
Trametinib Trametinib may decrease the excretion rate of Apalutamide which could result in a higher serum level.
Dabrafenib The serum concentration of Apalutamide can be increased when it is combined with Dabrafenib.
Fluticasone The serum concentration of Apalutamide can be increased when it is combined with Fluticasone.
Mometasone furoate The serum concentration of Apalutamide can be increased when it is combined with Mometasone furoate.
Pantoprazole The serum concentration of Pantoprazole can be increased when it is combined with Apalutamide.
Citalopram The serum concentration of Citalopram can be increased when it is combined with Apalutamide.
Phenytoin The serum concentration of Phenytoin can be increased when it is combined with Apalutamide.
Pentobarbital The serum concentration of Pentobarbital can be increased when it is combined with Apalutamide.
Amitriptyline The serum concentration of Amitriptyline can be increased when it is combined with Apalutamide.
Methadone The serum concentration of Methadone can be increased when it is combined with Apalutamide.
Omeprazole The serum concentration of Omeprazole can be increased when it is combined with Apalutamide.
Trimethadione The serum concentration of Trimethadione can be increased when it is combined with Apalutamide.
Carisoprodol The serum concentration of Carisoprodol can be increased when it is combined with Apalutamide.
Progesterone The serum concentration of Progesterone can be increased when it is combined with Apalutamide.
Zolpidem The serum concentration of Zolpidem can be increased when it is combined with Apalutamide.
Lansoprazole The serum concentration of Lansoprazole can be increased when it is combined with Apalutamide.
Imipramine The serum concentration of Imipramine can be increased when it is combined with Apalutamide.
Quinine The serum concentration of Quinine can be increased when it is combined with Apalutamide.
Fluoxetine The serum concentration of Fluoxetine can be increased when it is combined with Apalutamide.
Albendazole The serum concentration of Albendazole can be increased when it is combined with Apalutamide.
Cyclophosphamide The serum concentration of Cyclophosphamide can be increased when it is combined with Apalutamide.
Doxazosin The serum concentration of Doxazosin can be increased when it is combined with Apalutamide.
Thiopental The serum concentration of Thiopental can be increased when it is combined with Apalutamide.

Target Protein

Androgen receptor AR
GABA(A) Receptor GABRA1

Referensi & Sumber

Artikel (PubMed)
  • PMID: 27160947
    Smith MR, Antonarakis ES, Ryan CJ, Berry WR, Shore ND, Liu G, Alumkal JJ, Higano CS, Chow Maneval E, Bandekar R, de Boer CJ, Yu MK, Rathkopf DE: Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort. Eur Urol. 2016 Dec;70(6):963-970. doi: 10.1016/j.eururo.2016.04.023. Epub 2016 May 6.
  • PMID: 22266222
    Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, Chen Y, Grillot K, Bischoff ED, Cai L, Aparicio A, Dorow S, Arora V, Shao G, Qian J, Zhao H, Yang G, Cao C, Sensintaffar J, Wasielewska T, Herbert MR, Bonnefous C, Darimont B, Scher HI, Smith-Jones P, Klang M, Smith ND, De Stanchina E, Wu N, Ouerfelli O, Rix PJ, Heyman RA, Jung ME, Sawyers CL, Hager JH: ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. 2012 Mar 15;72(6):1494-503. doi: 10.1158/0008-5472.CAN-11-3948. Epub 2012 Jan 20.
  • PMID: 30101644
    Rathkopf DE, Scher HI: Apalutamide for the treatment of prostate cancer. Expert Rev Anticancer Ther. 2018 Sep;18(9):823-836. doi: 10.1080/14737140.2018.1503954.
  • PMID: 23779130
    Joseph JD, Lu N, Qian J, Sensintaffar J, Shao G, Brigham D, Moon M, Maneval EC, Chen I, Darimont B, Hager JH: A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov. 2013 Sep;3(9):1020-9. doi: 10.1158/2159-8290.CD-13-0226. Epub 2013 Jun 18.

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