Introduction
Zaluta Tablet 40 mg is an androgen receptor inhibitor for the treatment of castration-resistant prostate cancer. FDA approved on August 31, 2012.
Uses
Zaluta Tablet 40 mg is an androgen receptor inhibitor used to treat castration-resistant prostate cancer.
Zaluta Tablet 40 mg is indicated for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.
Associated Conditions
Pharmacodynamics
Resitance to enzalutamide therapy has been observed. This may occurred due to an upregulation of NF-κB2/p52.
Mechanism of Action
Zaluta Tablet 40 mg 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.
Absorption
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. Zaluta Tablet 40 mg 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;
Volume of Distribution
Apparent volume of distribution (Vd/F), single oral dose = 110 L
Protein Binding
Zaluta Tablet 40 mg is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl enzalutamide is 95% bound to plasma proteins.
Route of Elimination
Zaluta Tablet 40 mg 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).
Half Life
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.
Clearance
Apparent clearance (CL/F), single oral dose = 0.56 L/h (range of 0.33 - 1.02 L/h)
Toxicity
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.
Food Interactions
- Avoid St. John's Wort. This herb induces the CYP3A4 metabolism of enzalutamide and may reduce its serum concentration.
- Take with or without food.
Dosage
Dosage Modifications for Adverse Reactions: If a patient experiences a ≥Grade 3 or an intolerable adverse reaction, withhold Zaluta Tablet 40 mg for one week or until symptoms improve to ≤Grade 2, then resume at the same or a reduced dose (120 mg or 80 mg) if warranted.
Strong CYP2C8 Inhibitors: Avoid the coadministration of strong CYP2C8 inhibitors. If the coadministration of a strong CYP2C8 inhibitor cannot be avoided, reduce the Zaluta Tablet 40 mg dosage to 80 mg once daily. If the coadministration of the strong inhibitor is discontinued, increase the Zaluta Tablet 40 mg dosage to the dosage used prior to initiation of the strong CYP2C8 inhibitor.
Strong CYP3A4 Inducers: Avoid the coadministration of strong CYP3A4 inducers. If the coadministration of a strong CYP3A4 inducer cannot be avoided, increase the Zaluta Tablet 40 mg dosage from 160 mg to 240 mg orally once daily. If the coadministration of the strong CYP3A4 inducer is discontinued, decrease the Zaluta Tablet 40 mg dosage to the dosage used prior to initiation of the strong CYP3A4 induce.
Pediatric Use: Safety and effectiveness of Zaluta Tablet 40 mg in pediatric patients have not been established.
Renal Impairment: No dosage modification is recommended for patients with mild to moderate renal impairment.
Hepatic Impairment: No dosage modification is recommended for patients with mild, moderate, or severe hepatic impairment.
