AR/Androgen-receptor
N-desmethyl enzalutamide is the major active metabolite of enzalutamide. Its molecular structure is similar to enzalutamide and it demonstrates primary and secondary pharmacodynamics of similar potency to enzalutamide in all endpoints. [1]

N-desmethylenzalutamide is a benzamide obtained by formal condensation of the carboxy group of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl}-2-fluorobenzoic acid with ammonia. It has a role as an antineoplastic agent and an androgen antagonist. It is a member of benzamides, an imidazolidinone, a nitrile, a thiocarbonyl compound, a member of (trifluoromethyl)benzenes and a member of monofluorobenzenes.

Because it is more effective than enzalutamide and shows similar primary efficacy and secondary pharmacodynamics, N-Desmethylenzalutamide is an active adjuvant that may have a role in the clinical effects of enzalutamide. Enzalutamide's glucosamine metabolite is pharmacologically inert and has a circulating concentration that is roughly 25% less than enzalutamide's [1].

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Coadministration of gemfibrozil increased the composite area under the plasma concentration-time curve from time zero to infinity (AUC∞) of enzalutamide plus active metabolite by 2.2-fold, and coadministration of itraconazole increased the composite AUC∞ by 1.3-fold. Enzalutamide did not affect exposure to oral pioglitazone. Enzalutamide reduced the AUC∞ of oral S-warfarin, omeprazole, and midazolam by 56, 70, and 86 %, respectively; therefore, enzalutamide is a moderate inducer of CYP2C9 and CYP2C19 and a strong inducer of CYP3A4.
Conclusions: If a patient requires coadministration of a strong CYP2C8 inhibitor with enzalutamide, then the enzalutamide dose should be reduced to 80 mg/day. It is recommended to avoid concomitant use of enzalutamide with narrow therapeutic index drugs metabolized by CYP2C9, CYP2C19, or CYP3A4, as enzalutamide may decrease their exposure.[1]

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In healthy male subjects receiving a single oral dose of enzalutamide (160 mg) alone, the terminal elimination half-life of N-desmethyl enzalutamide is approximately 8 days. [1]
Coadministration of enzalutamide with the strong CYP2C8 inhibitor gemfibrozil significantly altered the pharmacokinetics of N-desmethyl enzalutamide. Based on simulated data, the area under the plasma concentration-time curve from time zero to infinity (AUC∞) of N-desmethyl enzalutamide decreased by 25% (geometric mean ratio 0.75, 90% CI 0.64–0.87), and the maximum plasma concentration (Cmax) decreased by 44% (geometric mean ratio 0.56, 90% CI 0.49–0.65). The AUC from time zero to 18 days post-dose (AUC18d) decreased by 67% (geometric mean ratio 0.33, 90% CI 0.28–0.38). [1]
Coadministration of enzalutamide with the strong CYP3A4 inhibitor itraconazole resulted in a 21% increase in the AUC∞ of N-desmethyl enzalutamide (geometric mean ratio 1.21, 90% CI 1.08–1.36) and a 14% decrease in Cmax (geometric mean ratio 0.86, 90% CI 0.75–0.99). The AUC18d was not significantly changed (geometric mean ratio 0.96, 90% CI 0.83–1.11). [1]
In patients with metastatic castration-resistant prostate cancer (mCRPC) receiving enzalutamide 160 mg once daily to steady state (49 days), the mean minimum (pre-dose) plasma concentration (Ctrough) of N-desmethyl enzalutamide was 10.6 ± 3.27 μg/mL, and the mean maximum plasma concentration (Cmax) was 12.7 ± 3.77 μg/mL. The median time to reach Cmax (tmax) was 4.0 hours (range 0.0–24.0 hours). The mean area under the plasma concentration-time curve for one 24-hour dosing interval at steady state (AUCτ) was 278 ± 85.5 μg·h/mL. [1]

Study with CYP2C8, CYP2C9, CYP2C19, and CYP3A4 Substrates The pharmacokinetic parameters for enzalutamide and its major metabolites (Table 4) confirmed that plasma exposures in this study were similar to those observed in other studies in which enzalutamide was administered at 160 mg once daily to steady state [4]. The mean Ctrough values for enzalutamide, N-desmethyl enzalutamide, the carboxylic acid metabolite, and the sum of enzalutamide plus N-desmethyl enzalutamide were 12.0, 10.6, 6.32, and 23.0 μg/mL, respectively.[1]

A parallel-treatment design (n = 41) was used to evaluate the effects of a strong cytochrome P450 (CYP) 2C8 inhibitor (oral gemfibrozil 600 mg twice daily) or strong CYP3A4 inhibitor (oral itraconazole 200 mg once daily) on the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide after a single dose of enzalutamide (160 mg). A single-sequence crossover design (n = 14) was used to determine the effects of enzalutamide 160 mg/day on the pharmacokinetics of a single oral dose of sensitive substrates for CYP2C8 (pioglitazone 30 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), or CYP3A4 (midazolam 2 mg).[1]

Studies with potent CYP2C8 and CYP3A4 inhibitors have shown, as shown in Figure 2, that gemfibrozil reduces the elimination rate of enzalutamide and the formation rate of N-desmethylenzalutamide, while increasing the formation rate of carboxylic acid metabolites; these rates change abruptly when gemfibrozil is discontinued on day 22. Given the significant changes in the pharmacokinetics of N-desmethylenzalutamide after gemfibrozil discontinuation, it is impossible to extrapolate the effect of gemfibrozil on AUC∞ using concentration-time data observed in the terminal phase. To address this issue, we used pharmacokinetic models to simulate the concentration-time profiles of enzalutamide and its metabolites under monotherapy and continuous co-administration with gemfibrozil (i.e., without discontinuation on day 22) (Electronic Supplement 1). Subsequently, simulated concentration-time data from 41 subjects in the study were analyzed using non-component analysis (NCA) to estimate AUC∞ values. Since AUC18d and Cmax were defined by plasma concentration-time data prior to discontinuation of gemfibrozil on day 22, these parameters were estimated by NCA analysis of the observed data. [1]

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As shown in the geometric mean ratios (GMR; Table 3), the effects of gemfibrozil on enzalutamide and its active metabolites were as follows: for enzalutamide, AUC18d and AUC∞ increased by 2.53-fold and 4.26-fold, respectively, while Cmax decreased by 18%; for N-desmethylenzalutamide, AUC18d, AUC∞, and Cmax decreased by 67%, 25%, and 44%, respectively; for the combined total of enzalutamide and N-desmethylenzalutamide, AUC18d and AUC∞ increased by 1.39-fold and 2.17-fold, respectively, while Cmax decreased by 16%. It is noteworthy that the effect of gemfibrozil on the total exposure of the active ingredient (enzalutamide plus N-desmethylenzalutamide) was smaller in the observational AUC term (AUC18d) than in the modeling and simulation-based AUC term (AUC∞). [1]

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The effect of itraconazole on the elimination of enzalutamide and the rate of formation of N-desmethylenzalutamide and carboxylic acid metabolites appears to be small (Figure 2); therefore, all pharmacokinetic parameters used to assess itraconazole drug interactions were based on observational data. According to the GMR values (Table 3), itraconazole had the following effects on enzalutamide and its active metabolites: for enzalutamide, AUC18d and AUC∞ increased by 1.34 times and 1.41 times, respectively, while Cmax decreased by 2%; for N-desmethylenzalutamide, AUC18d decreased by 4%, AUC∞ increased by 1.21 times, and Cmax decreased by 14%; for the sum of enzalutamide and N-desmethylenzalutamide, AUC18d and AUC∞ increased by 1.14 times and 1.28 times, respectively, while Cmax decreased by 3%. [1]

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N-desmethylenzalutamide is the main metabolite of enzalutamide, which is produced by the cytochrome P450 (CYP) enzymes CYP2C8 and CYP3A4. [1] In healthy male subjects, the terminal elimination half-life of N-desmethylenzalutamide was approximately 8 days after a single oral dose of enzalutamide. [1] In patients with mCRPC, the apparent oral clearance (CL/F) of N-desmethylenzalutamide was not applicable at steady state after a once-daily dose of 160 mg of enzalutamide because N-desmethylenzalutamide is a metabolite. [1] The plasma concentrations of N-desmethylenzalutamide were approximately the same as those of enzalutamide. [1] Combined pharmacokinetic analysis (representing the sum of enzalutamide and N-desmethylenzalutamide (the active ingredient)) was used to assess clinical relevance. The combined AUC∞ increased 2.17-fold when enzalutamide was used in combination with gemfibrozil and 1.28-fold when used in combination with itraconazole. [1]

In studies of healthy subjects using CYP2C8 and CYP3A4 inhibitors, no deaths, serious adverse events, or adverse events leading to discontinuation of treatment occurred. Thirteen subjects (3 in group 1, 6 in group 2, and 4 in group 3) experienced at least one treatment-interventional adverse event (TEAE). All events were classified as NCI-CTCAE Grade 1, except for one subject (group 2) who experienced Grade 2 flatulence (possibly related to gemfibrozil). Four additional subjects experienced at least one TEAE, possibly related to the study drug. All TEAEs resolved by the end of the study. In CYP substrate patient studies, the most common TEAEs (occurring in at least 3 of 14 patients, ≥21.4%) were nausea, constipation, dizziness, arthropod bites, fatigue, and hot flashes. Most reported treatment-interventional adverse events (TEAEs) were NCI-CTCAE Grade 1 or 2. One patient experienced a brief generalized tonic-clonic seizure that was assessed as potentially associated with enzalutamide, leading to the patient discontinuing enzalutamide treatment. Safety laboratory tests or electrocardiograms showed no clinically significant changes. [1]

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Exposure to N-desmethylenzalutamide is considered to have significant clinical implications for the efficacy and safety of enzalutamide. An exposure-response analysis of a phase III clinical trial showed no difference in clinical efficacy or safety between enzalutamide and N-desmethylenzalutamide. [1]
In vitro human liver microsomal studies suggest that N-desmethylenzalutamide may act as an inhibitor of CYP2C8 and CYP2C19, with less inhibitory activity against CYP2B6 and CYP2C9. [1]

[1]. Pharmacokinetic Drug Interaction Studies with Enzalutamide. Clin Pharmacokinet. 2015 Oct;54(10):1057-69.

N-Desmethylenzalutamide is a benzamide compound formed by the condensation of the carboxyl group and ammonia of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl}-2-fluorobenzoic acid. It is an antitumor drug and androgen antagonist. It belongs to the benzamide class, imidazolidine ketone class, nitrile class, thiocarbonyl class, (trifluoromethyl)benzene class and monofluorobenzene class.

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N-Desmethylenzalutamide is the active metabolite of enzalutamide and contributes to the clinical efficacy of enzalutamide. [1]
To interpret the clinical relevance (including efficacy and safety), the conclusions are based on the sum of enzalutamide and N-Desmethylenzalutamide, which corresponds to the exposure of the active ingredient of enzalutamide. [1]
An exposure-response analysis of plasma concentration data for enzalutamide and N-desmethylenzalutamide from a Phase III clinical trial (AFFIRM) showed no difference in clinical efficacy or safety between the two. [1]
In vitro studies suggest that N-desmethylenzalutamide may act as an inhibitor of CYP2C8 and CYP2C19. [1]

C₂₀H₁₄F₄N₄O₂S

450.41

450.077

C, 53.33; H, 3.13; F, 16.87; N, 12.44; O, 7.10; S, 7.12

1242137-16-1

Enzalutamide;915087-33-1;N-desmethyl Enzalutamide-d6;Enzalutamide carboxylic acid;1242137-15-0

70678916

White to off-white solid powder

4.562

1

8

3

31

824

0

JSFOGZGIBIQRPU-UHFFFAOYSA-N

InChI=1S/C20H14F4N4O2S/c1-19(2)17(30)27(11-4-3-10(9-25)14(7-11)20(22,23)24)18(31)28(19)12-5-6-13(16(26)29)15(21)8-12/h3-8H,1-2H3,(H2,26,29)

4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl]-2-fluorobenzamide

N-desmethyl MDV 3100; N-desmethyl MDV-3100; N-desmethyl enzalutamide; 1242137-16-1; N-desmethylenzalutamide; 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzamide; CHEMBL5171907; N-desmethyl MDV3100

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~222.02 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.55 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.55 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)