Xtandi (Page 4 of 7)

10 OVERDOSAGE

In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose.

11 DESCRIPTION

Enzalutamide is an androgen receptor inhibitor. The chemical name is 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N -methylbenzamide.

The molecular weight is 464.44 and molecular formula is C21 H16 F4 N4 O2 S. The structural formula is:

Structural formula of Enzalutamide
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Enzalutamide is a white crystalline non-hygroscopic solid. It is practically insoluble in water.

XTANDI is available as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides. The inactive ingredients are caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide.

XTANDI is also available as film-coated tablets for oral administration. Each tablet contains 40 mg or 80 mg of enzalutamide. The inactive ingredients are hypromellose acetate succinate, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate. The tablet film-coat contains hypromellose, talc, polyethylene glycol, titanium dioxide, and ferric oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors; and consequently, inhibits nuclear translocation of androgen receptors and their interaction with DNA. A major metabolite, N‑desmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide. Enzalutamide decreased proliferation and induced cell death of prostate cancer cells in vitro , and decreased tumor volume in a mouse prostate cancer xenograft model.

12.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of enzalutamide 160 mg/day at steady-state on the QTc interval was evaluated in 796 patients with metastatic CRPC. No large difference (i.e., greater than 20 ms) was observed between the mean QT interval change from baseline in patients treated with XTANDI and that in patients treated with placebo, based on the Fridericia correction method. However, small increases in the mean QTc interval (i.e., less than 10 ms) due to enzalutamide cannot be excluded due to limitations of the study design.

12.3 Pharmacokinetics

The pharmacokinetics of enzalutamide and its major active metabolite (N-desmethyl enzalutamide) were evaluated in patients with metastatic CRPC and healthy male volunteers. The plasma enzalutamide pharmacokinetics are adequately described by a linear two-compartment model with first-order absorption.

Absorption

Following oral administration of XTANDI capsules (160 mg daily) in patients with metastatic CRPC, the median time to reach maximum plasma enzalutamide concentrations (Cmax ) is 1 hour (range 0.5 to 3 hours). At steady-state, the plasma mean Cmax values for enzalutamide and N-desmethyl enzalutamide are 16.6 μg/mL (23% CV) and 12.7 μg/mL (30% CV), respectively, and the plasma mean predose trough values are 11.4 μg/mL (26% CV) and 13.0 μg/mL (30% CV), respectively. Following a single dose administration of 160 mg enzalutamide in healthy male volunteers, enzalutamide extent of absorption (AUC) was comparable between XTANDI tablet and XTANDI capsule, but the mean Cmax was 10%-28% lower than that of XTANDI capsules. The steady-state pharmacokinetic profiles (AUC and Cmax ) of enzalutamide and N-desmethyl enzalutamide are similar for XTANDI tablet and XTANDI capsule.

With the daily dosing regimen, enzalutamide steady-state is achieved by Day 28, and enzalutamide accumulates approximately 8.3-fold relative to a single dose. Daily fluctuations in enzalutamide plasma concentrations are low (mean peak-to-trough ratio of 1.25). At steady-state, enzalutamide showed approximately dose proportional pharmacokinetics over the daily dose range of 30 to 360 mg.

A single 160 mg oral dose of XTANDI was administered to healthy volunteers with a high-fat meal or in the fasted condition. A high-fat meal did not alter the AUC to enzalutamide or N-desmethyl enzalutamide. The results are summarized in Figure 1.

Distribution and Protein Binding

The mean apparent volume of distribution (V/F) of enzalutamide in patients after a single oral dose is 110 L (29% CV).

Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl enzalutamide is 95% bound to plasma proteins. In vitro , there was no protein binding displacement between enzalutamide and other highly protein bound drugs (warfarin, ibuprofen, and salicylic acid) at clinically relevant concentrations.

Metabolism

Following single oral administration of 14 C-enzalutamide 160 mg, plasma samples were analyzed for enzalutamide and its metabolites up to 77 days post dose. Enzalutamide, N-desmethyl enzalutamide, and a major inactive carboxylic acid metabolite accounted for 88% of the 14 C-radioactivity in plasma, representing 30%, 49%, and 10%, respectively, of the total 14 C-AUC0-inf .

In vitro , human CYP2C8 and CYP3A4 are responsible for the metabolism of enzalutamide. Based on in vivo and in vitro data, CYP2C8 is primarily responsible for the formation of the active metabolite (N-desmethyl enzalutamide). In vitro data suggest that carboxylesterase 1 metabolizes N-desmethyl enzalutamide and enzalutamide to the inactive carboxylic acid metabolite.

In vitro , N-desmethyl enzalutamide is not a substrate of human CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5.

Elimination

Enzalutamide is primarily eliminated by hepatic metabolism. Following single oral administration of 14 C-enzalutamide 160 mg, 85% of the radioactivity is recovered by 77 days post dose: 71% 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).

The mean apparent clearance (CL/F) of enzalutamide in patients after a single oral dose is 0.56 L/h (range 0.33 to 1.02 L/h).

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.

Pharmacokinetics in Special Populations

Renal Impairment:

A population pharmacokinetic analysis (based on pre-existing renal function) was carried out with data from 59 healthy male volunteers and 926 patients with metastatic CRPC enrolled in clinical trials, including 512 with normal renal function (CrCL ≥ 90 mL/min), 332 with mild renal impairment (CrCL 60 to < 90 mL/min), 88 with moderate renal impairment (CrCL 30 to < 60 mL/min), and 1 with severe renal impairment (CrCL < 30 mL/min). The apparent clearance of enzalutamide was similar in patients with pre-existing mild and moderate renal impairment (CrCL 30 to < 90 mL/min) compared to patients and volunteers with normal renal function. The potential effect of severe renal impairment or end-stage renal disease on enzalutamide pharmacokinetics cannot be determined as clinical and pharmacokinetic data are available from only one patient [see Use in Specific Populations (8.6)].

Hepatic Impairment:

The plasma pharmacokinetics of enzalutamide and N-desmethyl enzalutamide were examined in volunteers with normal hepatic function (N = 22) and with pre-existing mild (N = 8, Child-Pugh Class A) moderate (N = 8, Child-Pugh Class B), or severe (N = 8, Child-Pugh Class C) hepatic impairment. XTANDI was administered as a single 160 mg dose. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild, moderate, or severe baseline hepatic impairment compared to volunteers with normal hepatic function. The results are summarized in Figure 1[see Use in Specific Populations (8.7)].

Body Weight and Age:

Population pharmacokinetic analyses showed that weight (range: 46 to 163 kg) and age (range: 41 to 92 yr) do not have a clinically meaningful influence on the exposure to enzalutamide.

Gender:

The effect of gender on the pharmacokinetics of enzalutamide has not been evaluated.

Race:

The majority of XTANDI-treated patients in the randomized clinical trials were Caucasian (81%). Based on pharmacokinetic data from studies 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.

Drug Interactions

Effect of Other Drugs on XTANDI:

In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of XTANDI was administered alone or after multiple oral doses of gemfibrozil (strong CYP2C8 inhibitor). Gemfibrozil increased the AUC0‑inf of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold with minimal effect on Cmax . The results are summarized in Figure 1[see Dosage and Administration (2.2) and Drug Interactions (7.1)].

In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of XTANDI was administered alone or after multiple oral doses of rifampin (strong CYP3A4 and moderate CYP2C8 inducer). Rifampin decreased the AUC0‑inf of enzalutamide plus N-desmethyl enzalutamide by 37% with no effect on Cmax . The results are summarized in Figure 1[see Dosage and Administration (2.2) and Drug Interactions (7.2)].

In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of XTANDI was administered alone or after multiple oral doses of itraconazole (strong CYP3A4 inhibitor). Itraconazole increased the AUC0‑inf of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold with no effect on Cmax . The results are summarized in Figure 1.

Figure 1. Effects of Other Drugs and Intrinsic/Extrinsic Factors on XTANDI
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Figure 1. Effects of Other Drugs and Intrinsic/Extrinsic Factors on XTANDI

# PK parameters (Cmax and AUC0-inf ) are for enzalutamide plus N-desmethyl enzalutamide, except in the food-effect trial, where they are for enzalutamide alone. * See Dosage and Administration (2.2).

Effect of XTANDI on Other Drugs:

In an in vivo phenotypic cocktail drug-drug interaction trial in patients with metastatic CRPC, a single oral dose of the CYP probe substrate cocktail (for CYP2C8, CYP2C9, CYP2C19, and CYP3A4) was administered before and concomitantly with XTANDI (following at least 55 days of dosing at 160 mg daily). The results are summarized in Figure 2. Results showed that in vivo , at steady-state, XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer [see Drug Interactions (7.3)]. XTANDI did not cause clinically meaningful changes in exposure to the CYP2C8 substrate.

In an in vivo phenotypic cocktail drug-drug interaction trial in patients with CRPC, a single oral dose of the CYP probe substrate cocktail for CYP1A2 and CYP2D6 was administered before and concomitantly with XTANDI (following at least 49 days of dosing at 160 mg daily). The results are summarized in Figure 2. Results showed that in vivo , at steady-state, XTANDI did not cause clinically meaningful changes in exposure to the CYP1A2 or CYP2D6 substrates.

Figure 2. Effect of XTANDI on Other Drugs
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Figure 2. Effect of XTANDI on Other Drugs

*See Drug Interactions (7.3).

In vitro , enzalutamide, N-desmethyl enzalutamide, and the major inactive carboxylic acid metabolite caused direct inhibition of multiple CYP enzymes including CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5; however, subsequent clinical data showed that XTANDI is an inducer of CYP2C9, CYP2C19, and CYP3A4 and had no clinically meaningful effect on CYP2C8 (see Figure 2). In vitro , enzalutamide caused time-dependent inhibition of CYP1A2.

In vitro studies showed that enzalutamide induces CYP2B6 and CYP3A4 and does not induce CYP1A2 at therapeutically relevant concentrations.

In vitro , enzalutamide, N-desmethyl enzalutamide, and the major inactive carboxylic acid metabolite are not substrates for human P-glycoprotein. In vitro , enzalutamide and N-desmethyl enzalutamide are inhibitors of human P-glycoprotein, while the major inactive carboxylic acid metabolite is not.

In vitro , enzalutamide and N-desmethyl enzalutamide do not appear to be substrates of human breast cancer resistance protein (BCRP); however, enzalutamide and N-desmethyl enzalutamide are inhibitors of human BCRP at clinically relevant concentrations.

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