恩杂鲁胺杂质结构式列表
丁苯那嗪杂质经验总结分享
丁苯那嗪杂质总结分享
序号
名称
CAS
分子式
规格
用途
结构式
1
Tetrabenazine Impurity 1
19328-35-9C19H27NO3
10mg 25mg 50mg 100mg
研发申报
2
Tetrabenazine Impurity 2
164106-49-8C19H29NO3
10mg 25mg 50mg 100mg
研发申报
3
Tetrabenazine Impurity 3
862377-29-5C19H29NO3
10mg 25mg 50mg 100mg
研发申报
4
Tetrabenazine Impurity 4
862377-31-9C19H29NO3
10mg 25mg 50mg 100mg
研发申报
5
Tetrabenazine Impurity 5
85081-18-1C19H29NO3
10mg 25mg 50mg 100mg
研发申报
湖北瑞诺医药---专注杂质对照品、标准品：①伏立康唑杂质②尼莫地平杂质③阿立哌唑杂质④瑞格列奈杂质⑤培美曲塞杂质q：300-
⑥氟维司群杂质⑦地西他滨杂质⑧佐匹克隆杂质⑨长春瑞滨杂质⑩恩杂鲁胺杂质-8058-⑪醋丁洛尔杂质⑫倍他米松杂质
⑬塞来昔布杂质
⑭西酞普兰杂质
⑮氯吡格雷杂质
-303
⑯硫酸益康唑杂质......等更多项目品种
并代理：CP/EP/USP/TRC/TLC/MC/LGC/RHINO 等品牌。
二丙酸倍他米松杂质总结分享
C28H39FO7
10mg 25mg 50mg 100mg
sone 5 Dipropionate
EP Impurity E
5534-09-8
C28H37ClO7
10mg 25mg 50mg 100mg
研发申报
湖北瑞诺医药---专注杂质对照品、标准品： ①雷尼替丁杂质 ②利伐沙班杂质 ③甲泼尼龙杂质 ④依折麦布杂质 ⑤恩杂鲁胺杂质 q：300⑥文拉法辛杂质 ⑦坦索罗辛杂质 ⑧雷贝拉唑杂质 ⑨奥美拉唑杂质 ⑩诺氟沙星杂质 -8058⑪孟鲁司特杂质 ⑫美托洛尔杂质 ⑬氯雷他定杂质 ⑭兰索拉唑杂质 ⑮伊曲康唑杂质 -303 ⑯头孢孟多酯杂质 ......等更多项目品种 并代理：CP/EP/USP/TRC/TLC/MC/LGC/RHINO 等品牌。
序号
名称
二丙酸倍他米松杂质总结分享
CAS
分子式
规格 用途
Betamethasone 1 Dipropionate 5534-13-4
EP Impurity B
C25H33FO6
10mg 25mg 50mg 100mg
研发申报
10mg
Betamethasone
25mg
2 Dipropionate 1186048-33-8 C31H41FO8
研发申报
50mg
EP Impurity G
100mg
Betamethasone 3 Dipropionate 66917-44-0
EP Impurity F
C28H36O7
10mg 25mg 50mg 100mg
研发申报
Betamethasone 4 Dipropionate 80163-83-3
EP Impurity I
托拉菌素杂质总结分享
研发申报
Байду номын сангаас
A Impurity 3
50mg
100mg
湖北瑞诺医药---专注杂质对照品、标准品： ①雷尼替丁杂质 ②利伐沙班杂质 ③甲泼尼龙杂质 ④依折麦布杂质 ⑤恩杂鲁胺杂质 q：300⑥文拉法辛杂质 ⑦坦索罗辛杂质 ⑧雷贝拉唑杂质 ⑨奥美拉唑杂质 ⑩诺氟沙星杂质 -8058⑪孟鲁司特杂质 ⑫美托洛尔杂质 ⑬氯雷他定杂质 ⑭兰索拉唑杂质 ⑮伊曲康唑杂质 -303 ⑯头孢孟多酯杂质 ......等更多项目品种 并代理：CP/EP/USP/TRC/TLC/MC/LGC/RHINO 等品牌。
序号
名称
托拉菌素杂质总结分享
CAS
分子式
规格 用途
10mg
Tulathromycin
25mg
1
217500-96-4 C41H79N3O12
研发申报
A
50mg
100mg
10mg
Tulathromycin
25mg
2
280755-12-6 C41H79N3O12
研发申报
B
50mg
100mg
10mg
Tulathromycin
25mg
3
111247-94-0 C29H56N2O9
研发申报
A Impurity 1
50mg
100mg
结构式
10mg
Tulathromycin
25mg
4
2051579-09-8 C41H79N3O13
研发申报
A Impurity 2
50mg
100mg
10mg
Tulathromycin
25mg
5
Xtandi(enzalutamide)恩杂鲁胺 2012
Xtandi(enzalutamide恩杂鲁胺)FDA 2012年8月31日批准上市厂家：Medivation公司（美国）及合作伙伴安思泰来（Astellas）公司（日本）美国食品药品管理局(FDA)和安斯泰来制药公司宣布，Xtandi(enzalutamide)已获准用于曾接受多西他赛治疗的转移性去势耐药性前列腺癌的治疗。
Xtand是一种每日口服1次的雄激素受体抑制剂。
Xtandi的疗效和安全性已在一项随机、安慰剂对照的多中心3期临床试验中得到了评估。
这项试验招募了1,199例曾接受多西他赛治疗的转移性去势耐药性前列腺癌患者，旨在评价接受Xtandi治疗者与安慰剂组患者的总生存率。
结果显示，Xtandi组患者的中位生存期为18.4个月，而安慰剂组患者仅为13.6个月。
在临床研究中，患者最常发生的不良反应为虚弱/疲乏、背痛、腹泻、关节痛、潮热、外周水肿、肌肉骨骼痛、头痛、上呼吸道感染、肌无力、头晕、失眠、下呼吸道感染、脊髓压缩和马尾综合征、血尿、感觉异常、焦虑以及高血压。
Xtandi组患者47%发生≥3级不良反应，这一比例在安慰剂组为53%。
在这项随机临床试验中，0.9%的Xtandi组患者曾出现癫痫样发作，而安慰剂组未见这一现象。
出现癫痫样发作的患者永久停止治疗，癫痫样发作均消除。
有癫痫病史、服用可降低癫痫阈值的药物、或有其他癫痫危险因素的患者均被排除在之外。
鉴于使用Xtandi伴随癫痫风险，应告知患者可能因突然丧失意识而导致严重伤害的风险。
Xtandi的推荐剂量为160 mg(4个40 mg胶囊)，每日口服1次。
该药可与食物同服，而且不要求同时使用类固醇。
Xtandi(enzalutamide)批准日期：2012年8月31日；公司：Medivation Inc.和 Astellas Phar ma Inc.HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use XTANDI® safely and effe ctively. See full prescribing information for XTANDI.XTANDI® (enzalutamide) capsules for oral useInitial U.S. Approval: 2012INDICATIONS AND USAGEXTANDI is an androgen receptor inhibitor indicated for the treatment of patients with meta static castration-resistant prostate cancer who have previously received docetaxel. (1) DOSAGE AND ADMINISTRATIONXTANDI 160 mg (four 40 mg capsules) administered orally once daily. Swallow capsules w hole. XTANDI can be taken with or without food. (2.1)DOSAGE FORMS AND STRENGTHSCapsule 40 mg (3)CONTRAINDICATIONSPregnancy (4, 8.1)WARNINGS AND PRECAUTIONSSeizure occurred in 0.9% of patients receiving XTANDI. There is no clinical trial experience with XTANDI in patients who have had a seizure, in patients with predisposing factors for seizure, or in patients using concomitant medications that may lower the seizure threshold.(5.1)ADVERSE REACTIONS-The most common adverse reactions (≥ 5%) are asthenia/fatigue, back pain, diarrhea, art hralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory inf ection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord co mpression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension.(6.1)To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc, at 1-800-72 7-7003 or FDA at 1-800-FDA-1088 or /medwatch.DRUG INTERACTIONSAvoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co -administration is necessary, reduce the dose of XTANDI. (2.2, 7.1)Avoid strong or moderate CYP3A4 or CYP2C8 inducers as they can alter the plasma exposu re to XTANDI. (7.1, 7.2)Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTAN DI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. (7.3)See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 08/2012--------------------------------------------------------------------------------FULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGEXTANDI is indicated for the treatment of patients with metastatic castration-resistant prost ate cancer who have previously received docetaxel.2 DOSAGE AND ADMINISTRATION2.1 Dosing InformationThe recommended dose of XTANDI is 160 mg (four 40 mg capsules) administered orally on ce daily. XTANDI can be taken with or without food [see Clinical Pharmacology (12.3)]. Sw allow capsules whole. Do not chew, dissolve, or open the capsules.2.2 Dose ModificationsIf a patient experiences a ≥ Grade 3 toxicity or an intolerable side effect, withhold dosing f or one week or until symptoms improve to ≤ Grade 2, then resume at the same or a reduc ed dose (120 mg or 80 mg), if warranted.Concomitant Strong CYP2C8 InhibitorsThe concomitant use of strong CYP2C8 inhibitors should be avoided if possible. If patients must be co-administered a strong CYP2C8 inhibitor, reduce the XTANDI dose to 80 mg onc e daily. If co-administration of the strong inhibitor is discontinued, the XTANDI dose should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor [see Drug In teractions (7.1) and Clinical Pharmacology (12.3)].3 DOSAGE FORMS AND STRENGTHSXTANDI 40 mg capsules are white to off-white oblong soft gelatin capsules imprinted in bla ck ink with MDV.4 CONTRAINDICATIONSPregnancyXTANDI can cause fetal harm when administered to a pregnant woman based on its mecha nism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in wo men who are or may become pregnant. If this drug is used during pregnancy, or if the pati ent becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations (8.1)].5 WARNINGS AND PRECAUTIONS5.1 SeizureIn the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg onc e daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizur es occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure w ere permanently discontinued from therapy and all seizures resolved. There is no clinical tr ial experience re-administering XTANDI to patients who experienced seizures.The safety of XTANDI in patients with predisposing factors for seizure is not known becaus e these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack withi n the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous m alformation or the use of concomitant medications that may lower the seizure threshold. Because of the risk of seizure associated with XTANDI use, patients should be advised of th e risk of engaging in any activity where sudden loss of consciousness could cause serious h arm to themselves or others.6 ADVERSE REACTIONSThe following is discussed in more detail in other sections of the labeling:Seizure [see Warnings and Precautions (5.1)]6.1 Clinical Trial ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rate s observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.In the randomized clinical trial in patients with metastatic castration-resistant prostate can cer who had previously received docetaxel, patients received XTANDI 160 mg orally once d aily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months wi th XTANDI and 3.0 months with placebo. All patients continued androgen deprivation thera py. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorti coids. All adverse events and laboratory abnormalities were graded using NCI CTCAE versi on 4.The most common adverse drug reactions (≥ 5%) reported in patien ts receiving XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscula r weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and c auda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and hi gher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 s hows adverse reactions reported in the randomized clinical trial that occurred at a ≥ 2% a bsolute increase in frequency in the XTANDI arm compared to the placebo arm.Table 1. Adverse Reactions in the Randomized TrialLaboratory AbnormalitiesIn the randomized clinical trial, Grade 1-4 neutropenia occurred in 15% of patients on XTA NDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Gr ade 1-4 thrombocytopenia was similar in both arms; 0.5% of patients on XTANDI and 1% on placebo experienced Grade 3-4 thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on XTANDI (0.3% Grade 3-4) and 18% of patients on placebo (0.5% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo.InfectionsIn the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms.Falls and Fall-related InjuriesIn the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patientstreated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients tre ated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas. HallucinationsIn the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to hav e Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioid-containing medications at the time of the eve nt. Hallucinations were visual, tactile, or undefined.7 DRUG INTERACTIONS7.1 Drugs that Inhibit or Induce CYP2C8Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzal utamide in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibito r cannot be avoided, reduce the dose of XTANDI [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been ev aluated in vivo. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e. g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is rec ommended [see Clinical Pharmacology (12.3)].7.2 Drugs that Inhibit or Induce CYP3A4Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers [see Clin ical Pharmacology (12.3)].The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been ev aluated in vivo. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamaz epine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medicati on with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 indu cers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John's Wort may also reduce the plasma exposure of XTANDI and should be avoided if possible [see Clinical Ph armacology (12.3)].7.3 Effect of XTANDI on Drug Metabolizing EnzymesEnzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 su bstrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitantuse of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, siro limus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenyt oin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring [see Clinical Pharmac ology (12.3)].8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category X [see Contraindications (4)].XTANDI can cause fetal harm when administered to a pregnant woman based on its mecha nism of action. While there are no human or animal data on the use of XTANDI in pregnanc y and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI is contrain dicated in women who are or may become pregnant while receiving the drug. If this drug i s used during pregnancy, or if the patient becomes pregnant while taking this drug, appris e the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI.8.3 Nursing MothersXTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in hu man milk. Because many drugs are excreted in human milk, and because of the potential f or serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of t he drug to the mother.8.4 Pediatric UseSafety and effectiveness of XTANDI in pediatric patients have not been established.8.5 Geriatric UseOf 800 patients who received XTANDI in the randomized clinical trial, 71 percent were 65 a nd over, while 25 percent were 75 and over. No overall differences in safety or effectivene ss were observed between these patients and younger patients. Other reported clinical exp erience has not identified differences in responses between the elderly and younger patient s, but greater sensitivity of some older individuals cannot be ruled out.8.6 Patients with Renal ImpairmentA dedicated renal impairment trial for XTANDI has not been conducted. Based on the popul ation pharmacokinetic analysis using data from clinical trials in patients with metastatic cas tration-resistant prostate cancer and healthy volunteers, no significant difference in enzalu tamide clearance was observed in patients with pre-existing mild to moderate renal impair ment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and v olunteers with baseline normal renal function (CrCL ≥ 90 mL/min). No initial dosage adjust ment is necessary for patients with mild to moderate renal impairment. Severe renal impai rment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed [see Clini cal Pharmacology (12.3)].8.7 Patients with Hepatic ImpairmentA dedicated hepatic impairment trial compared the composite systemic exposure of enzalut amide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepati c impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volun teers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (C hild-Pugh Class C) has not been assessed [see Clinical Pharmacology (12.3)].10 OVERDOSAGEIn the event of an overdose, stop treatment with XTANDI and initiate general supportive m easures taking into consideration the half-life of 5.8 days. In a dose escalation study, no se izures 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 seizures following an overdose.11 DESCRIPTIONEnzalutamide is an androgen receptor inhibitor. The chemical name is 4-{3-[4-cyano-3-(tri fluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-met hylbenzamide.The molecular weight is 464.44 and molecular formula is C21H16F4N4O2S. The structural formula is:Enzalutamide is a white crystalline non-hygroscopic solid. It is practically insoluble in wate r.XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsul e contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides. The in active ingredients are caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylat ed hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dio xide, and black iron oxide.12 CLINICAL PHARMACOLOGY12.1 Mechanism of ActionEnzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androg en binding to androgen receptors and inhibit androgen receptor nuclear translocation and i nteraction with DNA. A major metabolite, N-desmethyl enzalutamide, exhibited similar in v itro activity to enzalutamide. Enzalutamide decreased proliferation and induced cell death o f prostate cancer cells in vitro, and decreased tumor volume in a mouse prostate cancer xe nograft model.12.3 PharmacokineticsThe pharmacokinetics of enzalutamide and its major active metabolite (N-desmethyl enzal utamide) were evaluated in patients with metastatic castration-resistant prostate cancer a nd healthy male volunteers. The plasma enzalutamide pharmacokinetics are adequately de scribed by a linear two-compartment model with first-order absorption.AbsorptionFollowing oral administration (XTANDI 160 mg daily) in patients with metastatic castration -resistant prostate cancer, the median time to reach maximum plasma enzalutamide conce ntrations (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.With the daily dosing regimen, enzalutamide steady state is achieved by Day 28, and enzal utamide accumulates approximately 8.3-fold relative to a single dose. Daily fluctuations inenzalutamide 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 BindingThe mean apparent volume of distribution (V/F) of enzalutamide in patients after a single o ral dose is 110 L (29% CV).Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl en zalutamide is 95% bound to plasma proteins.MetabolismFollowing single oral administration of 14C-enzalutamide 160 mg, plasma samples were an alyzed for enzalutamide and its metabolites up to 77 days post dose. Enzalutamide, N-des methyl enzalutamide, and a major inactive carboxylic acid metabolite accounted for 88% of the 14C-radioactivity in plasma, representing 30%, 49%, and 10%, respectively, of the t otal 14C-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 theactive metabolite (N-desmethyl enzalutamide).EliminationEnzalutamide is primarily eliminated by hepatic metabolism. Following single oral administr ation of14C-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 enza lutamide), 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 he althy volunteers, the mean terminal t1/2 for N-desmethyl enzalutamide is approximately 7.8 to 8.6 days.Pharmacokinetics in Special PopulationsRenal 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 castration-r esistant prostate cancer 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 imp airment or end stage renal disease on enzalutamide pharmacokinetics cannot be determine d as clinical and pharmacokinetic data are available from only one patient [see Use in Spec ific Populations (8.6)].Hepatic Impairment:The plasma pharmacokinetics of enzalutamide and N-desmethyl enzalutamide were exami ned in volunteers with normal hepatic function (N = 16) and with pre-existing mild (N = 8, Child-Pugh Class A) or moderate (N = 8, Child-Pugh B) 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 or moderate baseline hepatic impairm ent compared to volunteers with normal hepatic function. The results are summarized in Fi gure 1. Clinical and pharmacokinetic data are not available for patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.7)].Body Weight and Age:Population pharmacokinetic analyses showed that weight (range: 46 to 163 kg) and age (r ange: 41 to 92 yr) do not have a clinically meaningful influence on the exposure to enzalut amide.Gender:The effect of gender on the pharmacokinetics of enzalutamide has not been evaluated. Race:The majority of patients in the randomized clinical trial were Caucasian (> 92%). There ar e insufficient data to evaluate potential differences in the pharmacokinetics of enzalutamid e in other races.Drug InteractionsEffect 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 inhibito r). 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 itraconazole (strong CYP3A4 inhibito r). Itraconazole increased theAUC0-inf of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold with no effect on Cm ax. The results are summarized in Figure 1 [see Dosage and Administration (2.2) and Drug Interactions (7.2)].The effects of CYP2C8 and CYP3A4 inducers on the exposure of XTANDI have not been eva luated in vivo.Figure 1. Effects of Other Drugs and Intrinsic/Extrinsic Factors on XTANDIEffect of XTANDI on Other Drugs:In an in vivo phenotypic cocktail drug-drug interaction trial in patients with castration-resis tant prostate cancer, a single oral dose of the CYP probe substrate cocktail (for CYP2C8, C YP2C9, CYP2C19, and CYP3A4) was administered before and concomitantly with XTANDI (f ollowing 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 cau se clinically meaningful changes in exposure to the CYP2C8 substrate.Figure 2. Effect of XTANDI on Other DrugsIn vitro, enzalutamide, N-desmethyl enzalutamide, and the major inactive carboxylic acid metabolite caused direct inhibition of multiple CYP enzymes including CYP2B6, CYP2C8, CY P2C9, CYP2C19, CYP2D6, and CYP3A4/5; however, subsequent clinical data showed that X TANDI is an inducer of CYP2C9, CYP2C19, and CYP3A4 and had no clinically meaningful eff ect on CYP2C8 (see Figure 2). In vitro, enzalutamide caused time-dependent inhibition of CYP1A2.In vitro studies showed that enzalutamide caused induction of CYP3A4 and that enzalutami de is not expected to 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-des methyl enzalutamide are inhibitors of human P-glycoprotein, while the major inactive carb oxylic acid metabolite is not.12.6 Cardiac ElectrophysiologyThe effect of enzalutamide 160 mg/day at steady state on the QTc interval was evaluated i n 796 patients with castration-resistant prostate cancer. No large difference (i.e., greater t han 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 corr ection method. However, small increases in the mean QTc interval (i.e., less than 10 ms) d ue to enzalutamide cannot be excluded due to limitations of the study design.13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityLong-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide.Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mut ation assay or the in vivo mouse micronucleus assay.Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymideswere observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC).14 CLINICAL STUDIESThe efficacy and safety of XTANDI in patients with metastatic castration-resistant prostate cancer who had received prior docetaxel-based therapy were assessed in a randomized, pl acebo-controlled, multicenter phase 3 clinical trial. The primary endpoint was overall surviv al. A total of 1199 patients were randomized 2:1 to receive either XTANDI orally at a dose of 160 mg once daily (N = 800) or placebo orally once daily (N = 399). All patients continu ed androgen deprivation therapy. Patients were allowed, but not required to continue or ini tiate glucocorticoids. Study treatment continued until disease progression (evidence of radi ographic progression, a skeletal-related event, or clinical progression), initiation of new sys temic antineoplastic treatment, unacceptable toxicity, or withdrawal. Patients with a histor y of seizure, taking medicines known to decrease the seizure threshold, or with other risk f actors for seizure were not eligible [see Warnings and Precautions (5.1)].The following patient demographics and baseline disease characteristics were balanced bet ween the treatment arms. The median age was 69 years (range 41-92) and the racial distr ibution was 92.7% Caucasian, 3.9% Black, 1.1% Asian, and 2.1% Other. Ninety-two perce nt of patients had an ECOG performance status score of 0-1 and 28% had a mean Brief Pai n Inventory score of ≥ 4. Ninety-one percent of patients had metastases in bone and 23% had visceral involvement in the lung and/or liver. Fifty-nine percent of patients had radiogr aphic evidence of disease progression and 41% had PSA-only progression on study entry. All patients had received prior docetaxel-based therapy and 24% had received two cytotoxi c chemotherapy regimens. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.The pre-specified interim analysis at the time of 520 events showed a statistically significa nt improvement in overall survival in patients on the XTANDI arm compared to patients on the placebo arm (Table 2 and Figure 3).Table 2. Overall Survival of Patients Treated with Either XTANDI or Placebo (Inte nt-to-Treat Analysis)Figure 3. Kaplan-Meier Overall Survival Curves (Intent-to-Treat Analysis)。
各种杂质及价格-
专业承接美国、日本、法国、德国、瑞士、意大利、英国等国家参比制剂一次性进口和代购业务，提供进口（EP、USP、LGC、BP、TLC、TRC、QCC、MC）和国产对照品，有需要的欢迎联系我咨询哈.市振强生物技术劳先生QQ3004867396各种杂质名称及英文名：依鲁替尼（Ibrutinib）杂质6个，palbociclib杂质6个，泰地唑胺杂质tedizolid phosphate 12个达格列净杂质Dapagliflozin 7个，索非布韦杂质sofosbuvir 20个，替卡格雷杂质Ticagrelor 14个，米拉贝隆杂质Mirabegron 10个，TAK 438杂质10个，沃替西汀杂质Vortioxetine 15个，LCZ696杂质6个非布司他杂质Febuxostat 14个泊沙康唑异构体Posaconazole 14个阿普斯特杂质Apremilast 6个阿奇霉素杂质Azithromycin 14个阿考替胺杂质Acotiamide 14个依托考昔杂质Etoricoxib 14个尼达尼布杂质Nintedanib 8个罗库溴铵杂质Rocuronium Bromide 8个恩杂鲁胺杂质Enzalutamide 4个卢帕他定杂质Rupatadine 6个瑞格非尼杂质Regorafenib 20个色瑞替尼杂质Ceritinib 11个依美斯汀杂质Emedastine8个依匹唑派杂质Brexpiprazole6个依帕司他杂质epalrestat 6个乌苯美司杂质Ubenimex 19个福多司坦杂质Fudosteine 6个马来酸匹杉琼杂质Maleic acid Chinese fir, Joan 6个扎鲁司特杂质Zafirlukast 6个贝利司他杂质belinostat 6个奥扎格雷的杂质ozagrel 6个酒石酸伐尼克兰片杂质Varenicline T artrate T ablets 6个莫扎伐普坦杂质Mozavaptan 5个沙芬酰胺杂质Safinamide 4个沃雷生杂质suvorexant 5个依替巴肽杂质Eptifibatide 5个乐伐替尼杂质lenvatinib 8个1.埃索美拉唑杂质esomeprazole impurity2.奥拉西坦杂质oxiracetam3.罗氟司特杂质roflumilast4.阿戈美拉汀杂质Agomelatine5.鲁拉西酮杂质Lurasidone6.莫西沙星杂质moxifloxacin7.阿齐沙坦杂质Azilsartan8.达比加群酯杂质Pradaxa9.利拉利汀杂质Linagliptin10.托法替尼杂质T ofacitinib11.依托考昔杂质12.阿西替尼杂质Axitinib13.维格列汀杂质Vildagliptin14.帕瑞昔布杂质parecoxib15.伊马替尼杂质imatinib16.阿哌沙班杂质Apixaban17.替诺福韦酯杂质T enofovir Disoproxil Fumarate18.普拉格雷杂质Prasugrel19.伊拉地平杂质isradipine20.利托那韦杂质ritonavir21.培美曲塞二钠杂质pemetrexed disodium22.依达拉奉杂质Edaravone23.吉非替尼杂质gefitinib24.替吉奥杂质BCB25.苯达莫司汀杂质Cephalon26.替加环素杂质Tigecycline27.布南色林杂质Blonanserin28.文拉法辛杂质venlafaxine29.替卡格雷杂质30.利伐沙班杂质Rivaroxaban31.伊曲茶碱杂质Istradefylline32.依度沙班杂质Edoxaban33.三氟胸苷杂质Trifluorothymidine34.盐酸阿考替胺杂质acotiamide hydrochloride35.度洛西汀杂质Duloxetine36.泊沙康唑杂质37.泰地唑胺杂质38.沃替西汀杂质39.乐伐替尼杂志40.卡博替尼杂质Cabozantinib41.依鲁替尼杂质42.恩格列净杂质EMpagliflozin43.辛伐他汀杂质simvastatin44.恩杂鲁胺杂质45. 阿苯达唑Albendazole46. 阿达帕林adapalene47. 阿夫唑嗪alfuzosin48. 阿卡地新acadesine49. 阿立哌唑aripiprazole50. 阿莫曲普坦almotriptan51. 阿莫西林amoxicillin52. 阿瑞吡坦Aprepitant53. 阿昔洛韦acyclovir54. 埃罗替尼erlotinib55. 安非他酮bupropion56. 氨苄青霉素ampicillin57. 氨基葡萄糖Glucosamine58. 氨甲环酸tranexamic59. 氨溴索Ambroxol60. 胺碘酮Amiodarone61. 奥氮平olanzapine62. 奥沙利铂Oxaliplatin63. 奥司他韦oseltamivir64. 保胆键素dihydroxydibutylether65. 保特佐米Bortezomib66. 苯达莫司汀Bendamustin67. 比卡鲁胺bicalutamide68. 吡罗昔康piroxicam69. 吡嗪酰胺Pyrazinamide70. 别嘌醇allopurinol71. 波生坦bosentan72. 布洛芬Ibuprofen73. 布美他尼Bumetanide74. 雌甾四烯estratetraenol75. 醋氯芬酸aceclofenac76. 达非那新Darifenacin77. 大黄酸Diacerein78. 地尔硫卓diltiazem79. 地拉罗司deferasirox80. 氨氯地平Amlodipine81. 硝苯地平nifedipine82. 甲氨蝶呤Methotrexate83. 氨基蝶呤Aminopterin84. 丁螺环酮buspirone85. 多奈哌齐Donepezi86. 多立酮Domperidone87. 恩丹西酮ondansetron88. 恩他卡朋entacapone89. 伐昔洛韦valacyclovir90. 泛昔洛韦famciclovir91. 非布索坦Febuxostat92. 非那雄胺inasteride-ep93. 非诺贝特fenofibrate94. 弗斯特罗定fesoterodine95. 伏立康唑Voriconazole96. 氟替卡松丙酸酯fluticasone-propionate97. 氟维司群Fulvestrant98. 格列吡嗪glipizide99. 桂利嗪cinnarizine100. 环苯扎林cyclobenzaprine101. 加巴喷丁gabapentin102. 甲状旁腺激素西那卡塞Cinacalcet 103. 甲状腺素Levothyroxine104. 卡巴拉汀利凡斯的明Rivastigmine RC's 105. 喹硫平Quetiapine106. 奥美拉唑Omeprazole107. 兰索拉唑Lansoprazol108. 雷贝拉唑Rabeprazole109. 泮托拉唑pantoprazol110. 来氟米特leflunomide111. 雷洛昔芬raloxifene112. 雷莫拉宁Ramoplanin113. 雷奈佐利Linezolid114. 利伐沙班Rivaroxaban115. 利培酮Risperidal116. 罗匹尼罗ropinirole117. 阿替洛尔Atenolol118. 比索洛尔Bisoprolol119. 醋丁洛尔Acebutolol120. 美托洛尔metoprolol121. 奈必洛尔nebivolol122. 氯吡格雷Clopidogrel123. 氯雷他定Loratadine124. 霉酚酸mycophenolate125. 美洛昔康meloxicam126. 孟鲁司特montelukast127. 米氮平mirtazapine128. 尼美舒利nimesulide129. 帕罗西汀Paroxetine130. 帕立酮Paliperidone131. 生丁Dipyridamole Dipyridamole 132. 培美曲塞二钠Pemetrexed-disodium 133. 普拉克索Pramipexole134. 喹那普利Quinapril135. 卡托普利captopril136. 赖诺普利Lisinopril137. 雷米普利Ramipril138. 培哚普利Perindopril Imp139. 群多普利Trandolapril140. 伊拉普利Enalapril141. 普瑞巴林pregabalin142. 瑞格列奈Repaglinide143. 塞来西布Celecoxib144. 噻托溴铵Tiotropium bromide 145. 沙丁胺醇salbutamol146. 沙美特罗salmeterol147. 奥美沙坦Olmesartan148. 坎地沙坦Candesartan 149. 罗沙坦Losartan150. 替米沙坦T elmisartan 151. 缬沙坦Valsartan152. 加替沙星gatifloxacin 153. 氟哌酸norfloxacin154. 菲宁达、氧氟沙星Ofloxacin 155. 恩诺沙星enrofloxacin 156. 环丙沙星Ciprofloxacin 157. 莫西沙星moxifloxacin 158. 左氧氟沙星Levofloxacin 159. 舍曲林Sertraline160. 舒马曲坦sumatriptan 161. 双醋瑞因diacerein 162. 双氯芬酸Diclofenac 163. 他达那非T adalafil 164. 阿托伐他汀atorvastatin 165. 洛伐他汀Lovastatin 166. 匹伐他汀pitavastatin 167. 普伐他汀pravastatin 168. 瑞舒伐他汀Rosuvastatin 169. 辛伐他汀Simvastatin170. 坦索罗辛T amsulosin 171. 格列美脲glimepiride172. 吡格列酮pioglitazone 173. 尼扎替丁nizatidine 174. 替卡西林Ticarcillin 175. 酮咯酸氨丁三醇Ketorolac 176. 酮基布洛芬Ketoprofen 177. 头孢氨苄cefalexin178. 头孢克洛cefaclor179. 头孢磺啶cefsulodin 180. 托特罗定tolterodine 181. 拓扑替康topotecan 182. 万古霉素vancomycin 183. 文拉伐辛Venlafaxine 184. 那非Sildenafil185. 西他列汀Sitagliptin 186. 西酞普兰Citalopram 187. 西替利嗪cetirizine 188. 伊立替康Irinotecan 189. 伊马替尼imatinib190. 伊曲康唑Itraconazole 191. 依泽替米贝ezetimibe192. 左乙拉西坦Levetiracetam193. 佐米曲普坦zolmitriptan194. 唑吡坦zolpidem195. 唑尼沙胺Zonisamide依鲁替尼（Ibrutinib）杂质6个，palbociclib杂质6个，泰地唑胺杂质tedizolid phosphate 12个达格列净杂质Dapagliflozin 7个，索非布韦杂质sofosbuvir 20个，替卡格雷杂质Ticagrelor 14个，米拉贝隆杂质Mirabegron 10个，TAK 438杂质10个，沃替西汀杂质Vortioxetine 15个，LCZ696杂质6个非布司他杂质Febuxostat 14个泊沙康唑异构体Posaconazole 14个阿普斯特杂质Apremilast 6个阿奇霉素杂质Azithromycin 14个阿考替胺杂质Acotiamide 14个依托考昔杂质Etoricoxib 14个尼达尼布杂质Nintedanib 8个罗库溴铵杂质Rocuronium Bromide 8个恩杂鲁胺杂质Enzalutamide 4个卢帕他定杂质Rupatadine 6个瑞格非尼杂质Regorafenib 20个色瑞替尼杂质Ceritinib 11个依美斯汀杂质Emedastine8个依匹唑派杂质Brexpiprazole6个依帕司他杂质epalrestat 6个乌苯美司杂质Ubenimex 19个福多司坦杂质Fudosteine 6个马来酸匹杉琼杂质Maleic acid Chinese fir, Joan 6个扎鲁司特杂质Zafirlukast 6个贝利司他杂质belinostat 6个奥扎格雷的杂质ozagrel 6个酒石酸伐尼克兰片杂质Varenicline T artrate T ablets 6个莫扎伐普坦杂质Mozavaptan 5个沙芬酰胺杂质Safinamide 4个沃雷生杂质suvorexant 5个依替巴肽杂质Eptifibatide 5个乐伐替尼杂质lenvatinib 8个。
托莫西汀杂质总结分享
托莫西汀杂质总结分享
序号
名称
CAS
分子式
规格
用途
结构式
1
Atomoxetine EP Impurity A HCl
873310-33-9
C16H19NO.
HCl
10mg 25mg 50mg 100mg
研发申报
2
Atomoxetine Impurity B
105314-53-2C17H21NO
10mg 25mg 50mg 100mg
研发申报
3
Atomoxetine EP Impurity C HCl
1643684-06-3
C17H21NO.
HCl
10mg 25mg 50mg 100mg
研发申报
4
Atomoxetine Impurity 1
42064-62-0
C18H23NO.
HCl
10mg 25mg 50mg 100mg
研发申报
5
Atomoxetine Impurity 2
115290-81-8C10H15NO
10mg 25mg 50mg 100mg
研发申报
湖北瑞诺医药---专注杂质对照品、标准品：①雷尼替丁杂质②利伐沙班杂质③甲泼尼龙杂质④依折麦布杂质⑤恩杂鲁胺杂质q：300-
⑥文拉法辛杂质⑦坦索罗辛杂质⑧雷贝拉唑杂质⑨奥美拉唑杂质⑩诺氟沙星杂质-8058-⑪孟鲁司特杂质⑫美托洛尔杂质
⑬氯雷他定杂质
⑭兰索拉唑杂质
⑮伊曲康唑杂质
-303
⑯头孢孟多酯杂质......等更多项目品种
并代理：CP/EP/USP/TRC/TLC/MC/LGC/RHINO 等品牌。
恩杂鲁胺PPT课件
8
常见不良反应与处理
整体感觉：虚弱、外周水肿。 肌肉与骨骼：腰痛、关节痛、肌肉骨骼痛、肌无力、肌肉骨骼僵硬。 消化系统：腹泻。 血管：热潮红、高血压。 神经系统：头痛、头晕、脊髓受压、马尾综合征、感觉异常、感觉迟钝、精神障碍、焦虑、 失眠。 泌尿系统：血尿、尿频。 皮肤：瘙痒、皮肤干燥。 实 验 室 检 査 ： 中 性 粒 细 胞 减 少 、 血 小 板 减 少 、 A LT 升 高 、 胆 红 素 升 高 。
图注：阿比特龙与恩杂鲁胺作用原理图 3
哪些患者适合用恩杂鲁胺治疗?
恩杂鲁胺是一种雄激素受体抑制剂适，用于治疗有转移去势耐受前列腺癌和转移 去势敏感性前列腺癌（mCSPC）。
对于又转移的去势抵抗性前列腺癌，阿比特龙+强的松（即波尼松，是一种糖皮质激素）和 恩杂鲁胺都作为一类推荐。
4
恩杂鲁胺怎么吃?
5
剂量调整
1. 如果一个病人经历≥3级毒性或无法忍受副作用,停止加药一周或直到症状改善≤2级,然后恢复在 同一剂量或减少剂量(120毫克或80毫克)。
2. 如果可能，应尽量避免使用CYP2C8抑制剂。如果患者必须联合使用CYP2C8抑制剂，将恩杂 鲁胺剂量减少到每天80毫克。如果强效抑制剂的联合管理停止，则应将恩杂鲁胺剂量返回到 CYP2C8抑制剂开始前使用的剂量。
基因毒性杂质控制
② 降解杂质
实际检出杂质：长期稳定性及制剂过程中检出的报告限度以上杂质（ICH Q3A/B ）；
潜在杂质：加速试验及光照试验检出的鉴定限以上杂质，长期未确认。
三、基因毒性杂质的鉴别--警示结构
A为烷烃基、芳香基或H；EWG为吸电子取代基，如氰基、羰基或酯基等。 基因毒性的警示结构不只限于以上所列，进一步了解可参见: 马磊,马玉楠等.遗传毒性杂质的警示结构 .中国新药杂志 ,2014，23(18) :2106~11
理化性质如反应活性，溶解性、挥发性，电离度等分析。
三、基因毒性杂质的控制
方法3：案例1（M7 第24页 case1）
a、中间体X距原料药尚有2步反应，标准定入杂质A，杂质A化学性质稳定； b、将杂质A以不同浓度加入中间体X进行加标试验，达1%水平能持续从原
料药中去除至限度的30%以下； c、中试规模多批次成品杂质A结果低于基于TTC限度的30%以下；
杂质的检测水平及拟定限度不超过参比制剂的测得水平；
(2) The impurity is a significant metabolite of the drug substance. 杂质为原料药的重要代谢物；
(3) The observed level and the proposed acceptance criterion for the impurity are adequately justified by the scientific literature.
三、基因毒性杂质的分类
3、举例如下：
例1：瑞戈非尼(Regorafenib)
加拿大审评报告中，一个中间体Ames结果阳性，大鼠肝慧星致突变试验确立NOEL（无反应剂量 水平），提示每日最大摄入该杂质为0.0027mg/kg，如果体重按50kg计，则摄入量为 0.0027×50=0.135mg；瑞戈非尼日最大用量为160mg，故可推测其标准中该杂质限度为 0.0027×50kg/160=0.084%，即840ppm。（显著大于基于TTC水平的约9ppm限度）