Inactive metabolite of Enzalutamide (AR antagonist)

By means of cytochrome P450 (CYP) 3A4/5 and CYP2C8, enzalutamide is transformed into its principal metabolites, N-desmethylenzalutamide and enzalutamide carboxylate, respectively. While enzalutamide carboxylate is inactive, N-desmethylenzalutamide exhibits clinically significant antiandrogenic activity that is comparable to enzalutamide [1].

[1]. Exposure-Response Assessment of Enzalutamide and Its Major Metabolites in a Real-World Cohort of Patients with Metastatic Castration-Resistant Prostate Cancer. Pharmacotherapy. 2019 Dec;39(12):1137-1145.

Study Objective: Enzalutamide is an oral medication used to treat metastatic castration-resistant prostate cancer (mCRPC). N-Desmethylenzalutamide is its active metabolite, possessing clinically relevant anti-androgenic activity similar to enzalutamide, while carboxylic acid enzalutamide is an inactive metabolite. This study aimed to investigate the relationship between enzalutamide and N-desmethylenzalutamide exposure and treatment response in a real-world cohort of mCRPC patients. Design: Retrospective, observational, pharmacokinetic study. Location: Outpatient clinic of a tertiary cancer center in Amsterdam, Netherlands. Patients: 65 mCRPC patients treated with 160 mg enzalutamide daily between May 2015 and June 2018, with at least one steady-state enzalutamide plasma concentration measurement; among these patients, 38 were prostate-specific antigen (PSA) responders and 27 were non-responders. Measurement Methods and Main Results: Plasma drug concentrations were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and plasma drug concentrations were compared between PSA responders and non-responders. This study assessed three clinical endpoints: PSA-independent progression-free survival (PFS), time to PSA progression (TTPP), and PSA response rate (defined as a ≥50% decrease in PSA level from baseline). Enzalutamide toxicity was defined as discontinuation, dose reduction, or temporary interruption of treatment due to adverse events. In these analyses, plasma concentrations of enzalutamide and N-desmethylenzalutamide were quartiles. The mean plasma concentrations ± standard deviations for the 65 patients were as follows: enzalutamide 11.2 ± 2.8 μg/ml, N-desmethylenzalutamide 9.9 ± 2.9 μg/ml, and enzalutamide carboxylate 6.1 ± 4.3 μg/ml. There were no statistically significant differences in plasma concentrations of enzalutamide (11.5 vs 10.6 μg/ml, p=0.20), N-desmethylenzalutamide (10.1 vs 9.6 μg/ml, p=0.48), and carboxylic acid enzalutamide (6.5 vs 5.5 μg/ml, p=0.34) between the PSA-responsive and non-responsive groups. Univariate and multivariate analyses did not find any correlation between plasma concentration and PSA-independent progression-free survival (PFS), time to disease progression (TTPP), or toxicity. Conclusion: This study confirms that in patients with metastatic castration-resistant prostate cancer (mCRPC), plasma concentrations of enzalutamide are not associated with PSA-independent progression-free survival (PFS), time to treatment progression (TTPP), or toxicity, and the plasma concentrations of its main metabolite are also not associated with treatment response. Based on these findings, in routine clinical practice, there is no need for monitoring enzalutamide treatment in mCRPC patients. [1]

C₂₀H₁₃F₄N₃O₃S

451.39

451.061

1242137-15-0

Enzalutamide;915087-33-1;N-desmethyl Enzalutamide;1242137-16-1;Enzalutamide carboxylic acid-d6

46898522

White to off-white solid powder

4.461

1

9

3

31

824

0

MECDPCCFIDQBBP-UHFFFAOYSA-N

InChI=1S/C20H13F4N3O3S/c1-19(2)17(30)26(11-4-3-10(9-25)14(7-11)20(22,23)24)18(31)27(19)12-5-6-13(16(28)29)15(21)8-12/h3-8H,1-2H3,(H,28,29)

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

Enzalutamide carboxylic acid; MDV3100 carboxylic acid; 1242137-15-0; Enzalutamide Carboxylic Acid; 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzoic acid; Enzalutamide Carboxylic Acid Metabolite (M1); YF8MAL2HDY; Enzalutamide metabolite M1; 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl]-2-fluorobenzoic acid; 4-[3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl]-2-fluoro-benzoic Acid; MDV-3100 carboxylic acid

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 : ~125 mg/mL (~276.92 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.61 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 20.8 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: ≥ 2.08 mg/mL (4.61 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.61 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 20.8 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.)