Enzalutamide

464.4359528

464.44

1592732-453-0

93T0T9GKNU

C71744

L02BB04|L - Antineoplastic and immunomodulating agents

2933990090

109

3.6

1.5±0.1 g/cm3

1.630

Insoluble

|Danger|H302 (75%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P264, P270, P273, P281, P301+P312, P308+P313, P314, P330, P391, P405, and P501|Aggregated GHS information provided by 8 companies from 8 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The most common adverse reactions (≥ 5%) are asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension.

In preregistration controlled trials, serum aminotransferase elevations occurred in up to 10% patients treated with enzalutamide, but similar somewhat high rates occurred in patients receiving placebo (~9%). The liver test abnormalities were generally mild, transient and not associated with symptoms or jaundice. ALT elevations above 5 times the ULN were rare (0.2%) and also no more frequent than with placebo therapy. In addition, clinically apparent liver injury with jaundice was not reported in the preregistration trials of enzalutamide, and clinically apparent liver injury and hepatitis are not mentioned in the product label. Since the approval and more wide scale use of enzalutamide, there have been no publications or descriptions of the clinical features of hepatotoxicity with jaundice associated with its use. Thus, clinically apparent liver injury due to enzalutamide must be rare, if it occurs at all.

Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl enzalutamide is 95% bound to plasma proteins.

Enzalutamide is indicated for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.|FDA Label|Xtandi is indicated for:the treatment of adult men with metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy (see section 5.1).the treatment of adult men with high-risk non-metastatic castration-resistant prostate cancer (CRPC) (see section 5.1).the treatment of adult men with metastatic CRPC who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated (see section 5.1).the treatment of adult men with metastatic CRPC whose disease has progressed on or after docetaxel therapy.|Drug: Enzalutamide

Enzalutamide is a nonsteroidal antiandrogen used to treat metastatic castration-resistant prostate cancer. Enzalutamide is associated with a low rate of serum enzyme elevation during therapy, but has not been linked to cases of clinically apparent liver injury with jaundice.

Antineoplastic Agents

Resitance to enzalutamide therapy has been observed. This may occurred due to an upregulation of NF-κB2/p52.

The pharmacokinetic profile of enzalutamide and N-desmethyl enzalutamide (its major active metabolite) is described by a linear two-compartment model with first-order absorption. Enzalutamide also accumulates. Food does not affect its absorption. Tmax, prostate cancer patients = 1 hour (range of 0.5-3 hours); Cmax, steady state, enzalutamide = 16.6 μg/mL; Cmax, steady state, N-desmethyl enzalutamide = 12.7 μg/mL; Time to steady state, daily dosing = 28 days;|Enzalutamide is primarily eliminated by hepatic metabolism. 71% of the dose is recovered in urine (including only trace amounts of enzalutamide and N-desmethyl enzalutamide), and 14% is recovered in feces (0.4% of dose as unchanged enzalutamide and 1% as N-desmethyl enzalutamide).|Apparent volume of distribution (Vd/F), single oral dose = 110 L|Apparent clearance (CL/F), single oral dose = 0.56 L/h (range of 0.33 - 1.02 L/h)

Enzalutamide is hepatically metabolized, primarily by CYP2C8 and CYP3A4. The enzyme that converts enzalutamide to its active metabolite, N-desmethyl enzalutamide, is CYP2C8. The activity of N-desmethyl-enzalutamide is similar to that of the parent compound.

The mean terminal half-life (t1/2) for enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 days). Following a single 160 mg oral dose of enzalutamide in healthy volunteers, the mean terminal t1/2 for N-desmethyl enzalutamide is approximately 7.8 to 8.6 days.

Enzalutamide is a competitive androgen receptor inhibitor that effects multiple stages of the signalling pathway. It is able to inhibit androgen binding to its receptor, androgen receptor nuclear translocation, and subsequent interaction with DNA. As a result, proliferation of prostate cancer cells decreases which ultimately leads to apoptosis and decreased tumour volume.

4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl)-2-fluoro-N-(methyl-d3)benzamide

Human drugs -> Xtandi -> EMA Drug Category|Endocrine therapy -> Human pharmacotherapeutic group|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients