Apalutamide
Apalutamide Uses, Dosage, Side Effects, Food Interaction and all others data.
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 . 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 . In mice bearing human CRPC xenograft models, apalutamide treatment produced tumor regressions in a dose-dependent manner that was more effective than that of Bicalutamide or Enzalutamide. Unlike bicalutamide, apalutamide antagonized AR-mediated signaling in AR overexpressing human CRPC cell lines .
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 . 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 . Higher prostate-specific antigen (PSA) and shorter PSA doubling time (PSA DT) are associated with a higher risk for metastases and death . 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 . 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 . 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 .
| Trade Name | Apalutamide |
| Availability | Prescription only |
| Generic | Apalutamide |
| Apalutamide Other Names | Apalutamide |
| Related Drugs | estradiol, Premarin, Xtandi, Casodex, Zytiga, Lynparza |
| Weight | 60mg |
| Type | Oral tablet |
| Formula | C21H15F4N5O2S |
| Weight | Average: 477.44 Monoisotopic: 477.088258569 |
| Protein binding | Apalutamide was 96% and N-desmethyl apalutamide was 95% bound to plasma proteins with no concentration dependency . |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Apalutamide is an androgen receptor inhibitor used to treat non metastatic, castration resistant prostate cancer.
Indicated for the treatment of patients with non-metastatic, castration-resistant prostate cancer (NM-CRPC) .
Apalutamide is also used to associated treatment for these conditions: Nonmetastatic Prostate Cancer
How Apalutamide works
Persistent androgen receptor (AR) signaling is a common feature of castration-resistant prostate cancer (CRPC), attributed to AR gene-amplification, AR gene mutation, increased AR expression or increased androgen biosynthesis in prostate tumors . Apalutamide is an antagonist of AR that to the binding-site in the ligand-binding domain of the receptor with the IC50 of 16 nM. Upon binding, apalutamide disrupts AR signalling, inhibits DNA binding, and impedes AR-mediated gene transcription . Apalutamide impairs the translocation of AR from the cytoplasm to the nucleus thus reduces the concentrations of AR available to interact with the androgen response-elements (AREs) . Upon treatment with apalutamide, AR was not recruited to the DNA promoter-regions .
Its main metabolite, N-desmethyl apalutamide, is a less potent inhibitor of AR, and exhibited one-third the activity of apalutamide in an in vitro transcriptional reporter assay .
Toxicity
In the event of an overdose, discontinue apalutamide and undertake general supportive measures until clinical toxicity has been diminished or resolved . No antidote is currently known of or available for counteracting overdoses of this agent.
Apalutamide was not shown to be mutagenic 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. The carcinogenic potential of the drug has not been evaluated. In repeat-dose toxicity studies in male rats and dogs, 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 doses 0.9-1.4 times the human exposure based on AUC . In a fertility study of male rats, a decrease in sperm concentration and motility, increased abnormal sperm morphology, lower copulation and fertility rates in addition to reduced weights of the secondary sex glands and epididymis were observed following 4 weeks of dosing at ≥ 25 mg/kg/day .
Food Interaction
- Take at the same time every day.
- Take with or without food.
Apalutamide Cholesterol interaction
[Moderate] Ischemic cardiovascular events, including events leading to death, occurred in patients receiving apalutamide.
It is recommended to monitor for signs and symptoms of ischemic heart disease and to consider discontinuation of treatment for Grade 3 and 4 events.
Care should be exercised when prescribing this agent in patients at risk of an ischemic cardiovascular event, such as in those patients with hypertension, diabetes, or dyslipidemia.
Apalutamide Hypertension interaction
[Moderate] Ischemic cardiovascular events, including events leading to death, occurred in patients receiving apalutamide.
It is recommended to monitor for signs and symptoms of ischemic heart disease and to consider discontinuation of treatment for Grade 3 and 4 events.
Care should be exercised when prescribing this agent in patients at risk of an ischemic cardiovascular event, such as in those patients with hypertension, diabetes, or dyslipidemia.
Apalutamide Drug Interaction
Major: apixaban, amlodipine / hydrochlorothiazide / valsartanModerate: paclitaxel protein-bound, doxorubicin, glimepiride, aripiprazole, clarithromycin, tamsulosinUnknown: aspirin, antihemophilic factor/von willebrand factor, aminocaproic acid, insulin glargine, ubiquinone, cyclopentolate ophthalmic, tranexamic acid, etanercept, degarelix, immune globulin intravenous, fluticasone nasal, immune globulin intravenous and subcutaneous
Apalutamide Disease Interaction
Moderate: CV events, liver dysfunction, osteoporosis, renal impairment, seizure
Volume of Distribution
The mean apparent volume of distribution at steady-state of apalutamide was approximately 276 L .
Elimination Route
Mean absolute oral bioavailability was approximately 100%. Median time to achieve peak plasma concentration (tmax) was 2 hours (range: 1 to 5 hours). Median tmax may be increased with a high-fat meal. Administration of oral apalutamide at recommended dosages resulted in a steady state within 4 weeks with a maximum peak concentration (Cmax) and AUC of 6.0 mcg/mL and 100 mcg·h/mL, respectively . Cmax and AUC of apalutamide is expected to increase in a dose-proportional manner. The mean mean peak-to-trough ratio was 1.63 indicating low daily fluctuations in the plasma concentrations of the drug.
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.
Half Life
The mean effective half-life for apalutamide in patients with NM-CRPC was approximately 3 days at steady-state .
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. An increase in apparent clearance (CL/F) was observed with repeat dosing, likely due to induction of apalutamide’s own metabolism. The auto-induction effect likely reached its maximum at the recommended dosage because exposure of apalutamide across the dose range of 30 to 480 mg is dose-proportional .
Elimination Route
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) .
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