Lanzotred Mechanism of Action

ATC: L02BB04.
Pharmacology: Pharmacodynamics: Mechanism of action: Prostate cancer is known to be androgen-sensitive and responds to inhibition of androgen receptor signalling. Despite low or even undetectable levels of serum androgen, androgen receptor signalling continues to promote disease progression. Stimulation of tumour cell growth via the androgen receptor requires nuclear localization and DNA binding. Enzalutamide is a potent androgen receptor signalling inhibitor that blocks several steps in the androgen receptor signalling pathway.
Enzalutamide competitively inhibits androgen binding to androgen receptors, and consequently; inhibits nuclear translocation of activated receptors and inhibits the association of the activated androgen receptor with DNA even in the setting of androgen receptor overexpression and in prostate cancer cells resistant to anti-androgens. Enzalutamide treatment decreases the growth of prostate cancer cells and can induce cancer cell death and tumour regression. In preclinical studies enzalutamide lacks androgen receptor agonist activity.
Pharmacokinetics: Enzalutamide is poorly water-soluble. In this product, the solubility of enzalutamide is increased by caprylocaproyl macrogolglycerides as emulsifier/surfactant. In preclinical studies, the absorption of enzalutamide was increased when dissolved in caprylocaproyl macrogolglycerides.
The pharmacokinetics of enzalutamide have been evaluated in prostate cancer patients and in healthy male subjects. The mean terminal half-life (t½) for enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 days), and steady state is achieved in approximately one month. With daily oral administration, enzalutamide accumulates approximately 8.3-fold relative to a single dose. Daily fluctuations in plasma concentrations are low (peak-to-trough ratio of 1.25). Clearance of enzalutamide is primarily via hepatic metabolism, producing an active metabolite that is equally as active as enzalutamide and circulates at approximately the same plasma concentration as enzalutamide.
Absorption: Maximum plasma concentrations (Cmax) of enzalutamide in patients are observed 1 to 2 hours after administration. Oral absorption of enzalutamide is estimated to be at least 84.2%. Enzalutamide is not a substrate of the efflux transporters P-gp or BCRP. At steady state, the mean Cmax values for enzalutamide and its active metabolite are 16.6 μg/mL. Food has no clinically significant effect on the extent of absorption. In available data, Enzalutamide was administered without regard to food.
Distribution: The mean apparent volume of distribution (V/F) of enzalutamide in patients after a single oral dose is 110 L (29% CV). The volume of distribution of enzalutamide is greater than the volume of total body water, indicative of extensive extravascular distribution. Data in rodents indicate that enzalutamide and its active metabolite can cross the blood brain barrier.
Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. The active metabolite (N-desmethyl enzalutamide) is 95% bound to plasma proteins. There is no protein binding displacement between enzalutamide and other highly bound medicinal products (warfarin, ibuprofen and salicylic acid).
Biotransformation: Enzalutamide is extensively metabolized. There are two major metabolites in human plasma: N-desmethyl enzalutamide (active) and a carboxylic acid derivative (inactive). Enzalutamide is metabolized by CYP2C8 and to a lesser extent by CYP3A4/5, both of which play a role in the formation of the active metabolite. N-desmethyl enzalutamide is metabolized to the carboxylic acid metabolite by carboxylesterase 1, which also plays a minor role in the metabolism of enzalutamide to the carboxylic acid metabolite. N-desmethyl enzalutamide was not metabolized by CYPs.
Enzalutamide is a strong inducer of CYP3A4, a moderate inducer of CYP2C9 and CYP2C19, and has no clinically relevant effect on CYP2C8.
Elimination: The mean apparent clearance (CL/F) of enzalutamide in patients ranges from 0.520 and 0.564 L/h.
Following oral administration of 14C-enzalutamide, 84.6% of the radioactivity is recovered by 77 days post dose: 71.0% is recovered in urine (primarily as the inactive metabolite, with trace amounts of enzalutamide and the active metabolite), and 13.6% is recovered in faeces (0.39% of dose as unchanged enzalutamide).
Data indicates that enzalutamide is not a substrate for OATP1B1, OATP1B3, or OCT1; and N-desmethyl enzalutamide is not a substrate for P-gp or BCRP.
Data indicate that enzalutamide and its major metabolites do not inhibit the following transporters at clinically relevant concentrations: OATP1B1, OATP1B3, OCT2, or OAT1.
Linearity: No major deviations from dose proportionality are observed over the dose range 40 to 160 mg. The steady-state Cmin values of enzalutamide and the active metabolite in individual patients remained constant during more than one year of chronic therapy, demonstrating time-linear pharmacokinetics once steady-state is achieved.
Renal impairment: No formal renal impairment data for enzalutamide is available. Patients with serum creatinine >177 μmol/L (2 mg/dL) were excluded from available date. Based on a population pharmacokinetic analysis, no dose adjustment is necessary for patients with calculated creatinine clearance (CrCL) values ≥30 mL/min (estimated by the Cockcroft and Gault formula). Enzalutamide has not been evaluated in patients with severe renal impairment (CrCL <30 mL/min) or end-stage renal disease, and caution is advised when treating these patients. It is unlikely that enzalutamide will be significantly removed by intermittent haemodialysis or continuous ambulatory peritoneal dialysis.
Hepatic impairment: Hepatic impairment did not have a pronounced effect on the total exposure to enzalutamide or its active metabolite. Drug half-life was however doubled in patients with severe hepatic impairment compared with healthy controls (10.4 days compared to 4.7 days), possibly related to an increased tissue distribution.
Following a single oral 160 mg dose of enzalutamide, the AUC and Cmax for enzalutamide in subjects with mild impairment increased, the AUC and Cmax of enzalutamide in subjects with moderate impairment increased, and the AUC and Cmax of enzalutamide in subjects with severe impairment increased and decreased, respectively. For the sum of unbound enzalutamide plus the unbound active metabolite, the AUC and Cmax in subjects with mild impairment increased, the AUC and Cmax in subjects with moderate impairment increased and decreased, respectively, and the AUC and Cmax in subjects with severe hepatic impairment increased and decreased, respectively.
Race: Most patients in the available data (>74%) were Caucasian. Based on pharmacokinetic data from data in Japanese and Chinese patients with prostate cancer, there were no clinically relevant differences in exposure among the populations. There are insufficient data to evaluate potential differences in the pharmacokinetics of enzalutamide in other races.
Elderly: No clinically relevant effect of age on enzalutamide pharmacokinetics was seen in the population pharmacokinetic analysis.