N-Desmethyl-Apalutamide
(Synonyms: ARN-509杂质) 目录号 : GC61117
N-DesmethylApalutamide是Apalutamide的活性代谢产物，是一种低活性的雄激素受体拮抗剂，其作用力是Apalutamide活性的三分之一。N-DesmethylApalutamide的形成主要由CYP2C8和CYP3A4介导。N-DesmethylApalutamide是中等至强的CYP3A4和CYP2B6诱导剂，并具有优异的血浆蛋白结合浓度。
Cas No.:1332391-11-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >97.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
N-Desmethyl Apalutamide is an active metabolite of Apalutamide. N-Desmethyl Apalutamide is a less potent antagonist of the androgen receptor and is responsible for one-third of the activity of Apalutamide. The formation of N-Desmethyl Apalutamide mediated predominantly by CYP2C8 and CYP3A4. N-Desmethyl Apalutamide is moderate to strong CYP3A4 and CYP2B6 inducer and has an excellent plasma-proteins bound concentration[1][2][3].
[1]. PÉrez-Ruixo C, et al. Population Pharmacokinetics of Apalutamide and its Active Metabolite N-Desmethyl-Apalutamide in Healthy and Castration-Resistant Prostate Cancer Subjects. Clin Pharmacokinet. 2019 Aug 20. [2]. Smith MR, et al. Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort. Eur Urol. 2016 May 6. pii: S0302-2838(16)30133 [3]. May MB, et al. Apalutamide: A new agent in the management of prostate cancer. J Oncol Pharm Pract. 2019 Dec;25(8):1968-1978.
| Cas No. | 1332391-11-3 | SDF | |
| 别名 | ARN-509杂质 | ||
| Canonical SMILES | O=C(N)C1=CC=C(N(C(N(C2=CC(C(F)(F)F)=C(C#N)N=C2)C3=O)=S)C43CCC4)C=C1F | ||
| 分子式 | C20H13F4N5O2S | 分子量 | 463.41 |
| 溶解度 | 储存条件 | Store at -20°C | |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1579 mL | 10.7896 mL | 21.5792 mL |
| 5 mM | 0.4316 mL | 2.1579 mL | 4.3158 mL |
| 10 mM | 0.2158 mL | 1.079 mL | 2.1579 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Population Pharmacokinetics of Apalutamide and its Active Metabolite N-Desmethyl-Apalutamide in Healthy and Castration-Resistant Prostate Cancer Subjects
Clin Pharmacokinet 2020 Feb;59(2):229-244.PMID:31432469DOI:10.1007/s40262-019-00808-7.
Background: Apalutamide is a next-generation androgen receptor inhibitor approved for treatment of subjects with high-risk, non-metastatic, castration-resistant prostate cancer (NM-CRPC). Objective: The objective of this study was to characterize the population pharmacokinetics of apalutamide and its metabolite N-Desmethyl-Apalutamide in healthy male and castration-resistant prostate cancer subjects. Methods: Plasma concentration data for apalutamide and N-Desmethyl-Apalutamide from 1092 subjects (seven clinical studies) receiving oral apalutamide (30-480 mg) once daily were pooled for a population pharmacokinetic analysis using a non-linear mixed-effect modelling approach. The impact of clinically relevant covariates was also assessed. Results: Apalutamide absorption was rapid, and the apparent steady-state volume of distribution was large (276 L), reflecting a wide body distribution. Apalutamide was eliminated slowly, with its apparent clearance increasing from 1.31 L/h after the first dose to 2.04 L/h at steady state. No evidence of time-dependent disposition was observed for N-Desmethyl-Apalutamide, which was also widely distributed and slowly cleared (1.5 L/h). After 4 weeks of treatment, more than 95% of steady-state exposure of apalutamide and N-Desmethyl-Apalutamide was reached. At a dose of apalutamide 240 mg/day, apalutamide and N-Desmethyl-Apalutamide exposure exhibited 5.3- and 85.2-fold accumulation in plasma, respectively. Inter-individual variability in apalutamide apparent clearance is low (< 20%). Among the covariates evaluated, apalutamide and N-Desmethyl-Apalutamide exposure were statistically associated only with health status, body weight, and albumin concentration, and the effect was low (< 25%). Conclusions: A population pharmacokinetic modelling approach was successfully applied to describe the pharmacokinetics of apalutamide and N-Desmethyl-Apalutamide. No clinically relevant covariates were identified as predictors of apalutamide and N-Desmethyl-Apalutamide pharmacokinetics.
Efficacy and safety exposure-response relationships of apalutamide in patients with metastatic castration-sensitive prostate cancer: results from the phase 3 TITAN study
Cancer Chemother Pharmacol 2022 May;89(5):629-641.PMID:35366072DOI:10.1007/s00280-022-04427-1.
Purpose: Apalutamide plus androgen-deprivation therapy (ADT) has been approved for treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC) based on data from phase 3 TITAN study. This analysis was conducted to describe pharmacokinetics of apalutamide and N-Desmethyl-Apalutamide and explore relationships between apalutamide exposure and selected clinical efficacy and safety observations. Methods: 1052 patients were randomized to apalutamide + ADT (n = 525) or placebo + ADT (n = 527). A previously developed population pharmacokinetic model was applied. Cox regression analysis investigated the relationships between apalutamide exposure and overall survival (OS; n = 1004) and radiographic progression-free survival (rPFS; n = 1003). Logistic regression analysis assessed the relationships between apalutamide exposure and selected clinically relevant adverse events (n = 1051). Results: Apalutamide + ADT treatment was efficacious in extending rPFS and OS versus placebo + ADT. Within a relatively narrow apalutamide exposure range (coefficient of variation: 22%), no statistical association was detected between rPFS, OS and apalutamide exposure quartiles. Incidence of skin rash and pruritus increased significantly with increasing apalutamide exposure. Conclusions: Differences in apalutamide exposure were not associated with clinically relevant differences in rPFS or OS in patients with mCSPC. Patients with increased apalutamide exposure are more likely to develop skin rash and pruritus. Dose reductions may improve these adverse events, based on an individual risk-benefit approach.
Efficacy and Safety Exposure-Response Relationships of Apalutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer
Clin Cancer Res 2020 Sep 1;26(17):4460-4467.PMID:32561663DOI:10.1158/1078-0432.CCR-20-1041.
Purpose: To evaluate the relationship between exposure of apalutamide and its active metabolite, N-Desmethyl-Apalutamide, and selected clinical efficacy and safety parameters in men with high-risk nonmetastatic castration-resistant prostate cancer. Patients and methods: An exploratory exposure-response analysis was undertaken using data from the 1,207 patients (806 apalutamide and 401 placebo) enrolled in the SPARTAN study, including those who had undergone dose reductions and dose interruptions. Univariate and multivariate Cox regression models evaluated the relationships between apalutamide and N-Desmethyl-Apalutamide exposure, expressed as area under the concentration-time curve at steady state, and metastasis-free survival (MFS). Univariate and multivariate logistic regression models assessed the relationship between apalutamide and N-Desmethyl-Apalutamide exposure and common treatment-emergent adverse events including fatigue, fall, skin rash, weight loss, and arthralgia. Results: A total of 21% of patients in the apalutamide arm experienced dose reductions diminishing the average daily dose to 209 mg instead of 240 mg. Within the relatively narrow exposure range, no statistically significant relationship was found between MFS and apalutamide and N-Desmethyl-Apalutamide exposure. Within apalutamide-treated subjects, skin rash and weight loss had a statistically significant association with higher apalutamide exposure. Conclusions: The use of apalutamide at the recommended dose of 240 mg once daily provided a similar delay in metastases across the SPARTAN patient population, regardless of exposure. The exploratory exposure-safety analysis supports dose reductions in patients experiencing adverse events.