泊沙康唑国内外临床研究介绍(1)
泊沙康唑预防恶性血液病化疗后粒细胞减少期患儿真菌感染的疗效研究
•临床研究•泊沙康E预防恶性血液病化疗后粒细胞减少期患儿真菌感染的疗效研究高海丽，刘炜（郑州大学附属儿童医院血液肿瘤科，河南郑州450000）［摘要］目的探讨恶性血液病化疗后粒细胞减少期患儿泊沙康）治疗对真菌感染的预防效果。
方法回顾性分析2015年12月至2018年12月该院收治的135例接受化疗的恶性血液病患儿的临床资料，观察化疗后粒细胞减少期预防性口服泊沙康）（泊沙康）组，70例）与口服氟康）（对照组65例）患儿侵袭性真菌感染发生率$结果泊沙康）组患儿中发生真菌感染8例，发生率为1143%，其中临床诊断3例，拟诊5例$对照组患儿中发生真菌感染21例，发生率为32.30%，其中实验室确诊2例，临床诊断10例，拟诊9例。
泊沙康）组患儿真菌感染发生率明显低于对照组，差异有统计学意义（P<005）$2组患儿不良反应发生率比较，差异无统计学意义（P>0.05）$结论恶性血液病患儿粒细胞减少期口服泊沙康）能有效降低侵袭性真菌感染发生率，不良反应轻微$［关键词］血液肿瘤；粒细胞缺乏；真菌；感染；泊沙康）%预防DOI：10.3969/j.issn.1009-5519.2020.15.040中图法分类号：R725.5；R379文章编号：10095519（2020）15243603文献标识码:B侵袭性真菌感染（IFI）是儿童血液系统恶性疾病粒细胞减少期最严重的并发症之一，也是造成患儿死亡的重要因素之一，因此，真菌感染的预防对此类患儿非常重要。
有研究表明，泊沙康哩在IFI的预防治疗中优势明显'1（;但多为成人患者，有关儿童的研究较少。
本研究对135例恶性血液病患儿化疗后粒细胞减少期口服泊沙康哩和氟康哩2种药物作为真菌感染的一级预防,探讨了恶性血液病患儿粒细胞减少期泊沙康哩治疗对真菌感染的预防效果，现报道如下。
1资料与方法1.1一般资料选取2015年12月至2018年12月本院收治的恶性血液病化疗后粒细胞减少期患儿135例，其中男70例，女65例；平均年龄（6.8士5.5）岁；急性淋巴细胞性白血病69例，急性髓细胞性白血病29例，急性混合细胞性白血病7例，淋巴瘤白血病15例，神经母细胞瘤15例；化疗期间接受泊沙康哩口服溶液抗真菌预防治疗70例（泊沙康哩组），接受氟康哩抗真菌预防治疗65例（对照组）泊沙康哩组患儿中男38例，女32例；平均年龄（5.7士4.6）岁。
泊沙康唑 美国说明书
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use NOXAFIL ORAL SUSPENSION safely and effectively. See full prescribing information for NOXAFIL ORAL SUSPENSION. NOXAFIL® (Posaconazole) ORAL SUSPENSION 40 mg/mLInitial U.S. Approval: 2006---------------------------INDICATIONS AND USAGE----------------------------- NOXAFIL is a triazole antifungal agent indicated for: •prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk ofdeveloping these infections due to being severelyimmunocompromised, such as HSCT recipients with GVHD orthose with hematologic malignancies with prolonged neutropenia from chemotherapy. (1.1)•the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole. (1.2)-------------------------DOSAGE AND ADMINISTRATION---------------------- Indication Dose and Duration of therapyProphylaxis of Invasive Fungal Infections 200 mg (5 mL) three times a day. Duration of therapy is based on recovery from neutropenia or immunosuppression. (2.1)Oropharyngeal Candidiasis (OPC) Loading dose of 100 mg (2.5 mL) twice a day on the first day, then 100 mg (2.5 mL) once a day for 13 days. (2.1)OPC Refractory(rOPC) to Itraconazole and/or Fluconazole 400 mg (10 mL) twice a day. Duration of therapy should be based on the severity of the patient’s underlying disease and clinical response. (2.1)-----------------------DOSAGE FORMS AND STRENGTHS-------------------- NOXAFIL Oral Suspension 40 mg per mL (3)-----------------------------CONTRAINDICATIONS--------------------------------- • Do not administer to persons with known hypersensitivity to posaconazole, any component of NOXAFIL, or other azoleantifungal agents (4.1)• Do not coadminister NOXAFIL with the following drugs;NOXAFIL increases concentrations of:o Sirolimus: can result in sirolimus toxicity (4.2, 7.1)o CYP3A4 substrates (pimozide, quinidine): can result inQTc interval prolongation and rare occurrences of TdP(4.3, 7.2)o Simvastatin: can result in rhabdomyolysis (4.4,7.3)o Ergot alkaloids: can result in ergotism (4.5, 7.4)-----------------------WARNINGS AND PRECAUTIONS------------------------ •Calcineurin Inhibitor Toxicity: NOXAFIL increasesconcentrations of cyclosporine or tacrolimus; reduce dose ofcyclosporine and tacrolimus and monitor concentrationsfrequently. (5.1)•Arrhythmias and QTc Prolongation: NOXAFIL has beenshown to prolong the QTc interval and cause rareoccurrences of TdP. Administer with caution to patients withpotentially proarrhythmic conditions. Do not administer withdrugs known to prolong QTc interval and metabolizedthrough CYP3A4. Correct K+, Mg++, and Ca++ before startingNOXAFIL. (5.2)•Hepatic Toxicity: elevations in LFTs (generally reversible ondiscontinuation) may occur. Discontinuation should beconsidered in patients who develop abnormal LFTs ormonitor LFTs during treatment. (5.3)● Midazolam: NOXAFIL can prolong hypnotic/sedative effects.Monitor patients and benzodiazepine receptor antagonistsshould be available. (5.4, 7.5)-------------------------------ADVERSE REACTIONS------------------------------•Common treatment-emergent adverse reactions (>30%) inprophylaxis studies are fever, diarrhea and nausea.(6.2)• Common treatment-emergent adverse reactions (>5%) incontrolled OPC pool are diarrhea, nausea, headache, andvomiting. Common adverse reactions (>20%) in the refractoryOPC pool are fever, diarrhea, nausea, and vomiting (6.2).To report SUSPECTED ADVERSE REACTIONS, contact ScheringCorporation, a subsidiary of Merck & Co., Inc., at 1-800-526-4099or FDA at 1-800-FDA-1088 or /medwatch.-------------------------------DRUG INTERACTIONS------------------------------Interaction Drug InteractionRifabutin, phenytoin, efavirenz,cimetidine, esomeprazoleAvoid co-administration unlessthe benefit outweighs the risks(7.6, 7.7, 7.8, 7.9)Other drugs metabolized byCYP3A4 (tacrolimus,cyclosporine, vinca alkaloids,calcium channel blockers)Consider dosage adjustment andmonitor for adverse effects andtoxicity (7.1,7.10, 7.11)Digoxin Monitor digoxin plasmaconcentrations (7.12)Metoclopramide Monitor for breakthrough fungalinfections (7.13)--------------------------USE IN SPECIFIC POPULATIONS---------------------• Pregnancy: Based on animal data, may cause fetal harm. (8.1)• Nursing Mothers: Discontinue drug or nursing, taking in toconsideration the importance of drug to the mother. (8.3)• Severe renal impairment: Monitor closely for breakthrough fungalInfections. (8.6)See 17 for PATIENT COUNSELING INFORMATION.Revised:10/2011FULL PRESCRIBING INFORMATION: CONTENTS*1.INDICATIONS AND USAGE1.1 Prophylaxis of Invasive Aspergillus and Candida Infections1.2 Treatment of Oropharyngeal Candidiasis IncludingOropharyngeal Candidiasis Refractory to Itraconazoleand/or Fluconazole2.DOSAGE AND ADMINISTRATION2.1 Dosage2.2 Administration Instructions3.DOSAGE FORMS AND STRENGTHS4.CONTRAINDICATIONS4.2 Use With Sirolimus4.3 QT Prolongation With Concomitant Use With CYP3A4Substrates4.4 Use With Simvastatin4.5 Use With Ergot Alkaloids5.WARNINGS AND PRECAUTIONS5.1 Calcineurin-Inhibitor Drug Interactions5.2Arrhythmias and QT Prolongation5.3 Hepatic Toxicity5.4 Use With Midazolam6.ADVERSE REACTIONS6.1Serious and Otherwise Important Adverse Reactions6.2Clinical Trials Experience6.3 Postmarketing Experience7.DRUG INTERACTIONS7.1 Immunosuppressants Metabolized by CYP3A47.2 CYP3A4 Substrates7.3 HMG-CoA reductase Inhibitors (Statins) Metabolized ThroughCYP3A47.4 Ergot Alkaloids7.5 Benzodiazepines Metabolized by CYP3A47.6 Anti-HIV Drugs7.7 Rifabutin7.8 Phenytoin7.9 Gastric Acid Suppressors/Neutralizers7.10 Vinca Alkaloids7.11 Calcium Channel Blockers Metabolized by CYP3A47.12 Digoxin7.13 Gastrointestinal Motility Agents7.14 GlipizideE IN SPECIFIC POPULATIONS8.1Pregnancy8.3Nursing Mothers8.4Pediatric Use8.5Geriatric Use8.6Renal Insufficiency8.7Hepatic Insufficiency8.8Gender8.9Race10.OVERDOSAGE11.DESCRIPTION12.CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics12.4 Microbiology13. NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility13.2Animal Toxicology and/or Pharmacology14. CLINICAL STUDIES14.1Prophylaxis of Aspergillus and Candida Infections14.2Treatment of Oropharyngeal Candidiasis14.3Treatment of Oropharyngeal Candidiasis Refractory toTreatment With Fluconazole or Itraconazole16.HOW SUPPLIED/STORAGE AND HANDLING17.PATIENT COUNSELING INFORMATION17.1 Administration With Food17.2 Drug Interactions17.3 Serious and Potentially Serious Adverse Reactions17.4See Accompanying FDA-Approved Patient Labeling* Sections or subsections omitted from the full prescribing information are not listed.________________________________________________________FULL PRESCRIBING INFORMATION1. INDICATIONS AND USAGE1.1 Prophylaxis of Invasive Aspergillus and Candida InfectionsNOXAFIL Oral Suspension is indicated for prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy.1.2 Treatment of Oropharyngeal Candidiasis Including Oropharyngeal Candidiasis Refractory to Itraconazole and/or FluconazoleNOXAFIL is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole.2. DOSAGE AND ADMINISTRATION2.1DosageIndication Dose and Duration of TherapyProphylaxis of Invasive Fungal Infections 200 mg (5 mL) three times a day. The duration of therapy is based on recovery from neutropenia or immunosuppression.Oropharyngeal Candidiasis Loading dose of 100 mg (2.5 mL) twice a day on the first day, then100 mg (2.5 mL) once a day for 13 days.Oropharyngeal Candidiasis Refractory to itraconazole and/or fluconazole 400 mg (10 mL) twice a day. Duration of therapy should be based on the severity of the patient’s underlying disease and clinical response.2.2Administration InstructionsShake NOXAFIL Oral Suspension well before use.Figure 1: A measured dosing spoon is provided, marked for doses of 2.5 mL and 5 mL.It is recommended that the spoon is rinsed with water after each administration and before storage.Each dose of NOXAFIL should be administered with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage (e.g. ginger ale) in patients who cannot eat a full meal.To enhance the oral absorption of posaconazole and optimize plasma concentrations:•Each dose of NOXAFIL should be administered during or immediately (i.e. within 20 minutes) following a full meal. In patients who cannot eata full meal, each dose of NOXAFIL should be administered with a liquid nutritional supplement or an acidic carbonated beverage. For patientswho cannot eat a full meal or tolerate an oral nutritional supplement or an acidic carbonated beverage, alternative antifungal therapy should be considered or patients should be monitored closely for breakthrough fungal infections.•Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections.•Co-administration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections [see Drug Interactions(7.6, 7.7, 7.8, 7.9, 7.13)].3. DOSAGE FORMS AND STRENGTHSNOXAFIL Oral Suspension is available in 4-ounce (123 mL) amber glass bottles with child-resistant closures (NDC 0085-1328-01) containing105 mL of suspension (40 mg of posaconazole per mL).4. CONTRAINDICATIONS4.1HypersensitivityNOXAFIL is contraindicated in persons with known hypersensitivity to posaconazole, any component of NOXAFIL, or other azole antifungal agents.4.2 Use With SirolimusNOXAFIL is contraindicated with sirolimus. Concomitant administration of NOXAFIL with sirolimus increases the sirolimus blood concentrations by approximately 9 fold and can result in sirolimus toxicity [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].4.3 QT Prolongation With Concomitant Use With CYP3A4 SubstratesNOXAFIL is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of NOXAFIL with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and rare occurrences of torsades de pointes [see Warnings and Precautions (5.2) and Drug Interactions (7.2)].4.4 Use With SimvastatinConcomitant administration of NOXAFIL with simvastatin increases the simvastatin plasma concentrations by approximately 10 fold. Increased plasma statin concentrations can be associated with rhabdomyolysis [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].4.5 Use With Ergot AlkaloidsPosaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism [see Drug Interactions (7.4)].5. WARNINGS AND PRECAUTIONS5.1 Calcineurin-Inhibitor Drug InteractionsConcomitant administration of NOXAFIL with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. Nephrotoxicity and leukoencephalopathy (including isolated deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly.5.2 Arrhythmias and QT ProlongationSome azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, rare cases of torsades de pointes have been reported in patients taking posaconazole.Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. Multiple, time-matched ECGs collected over a 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18-85 years of age) administered posaconazole 400 mg BID with a high-fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline was –5 msec following administration of the recommended clinical dose. A decrease in the QTc (F) interval (–3 msec) was also observed in a small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc (F) interval change from baseline was <0 msec (–8 msec). No healthy subject administered posaconazole had a QTc (F) interval ≥500 msec or an increase ≥60 msec in their QTc (F) interval from baseline.Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4 [see Contraindications (4.3) and Drug Interactions (7.2)]. Rigorous attempts to correct potassium, magnesium, and calcium should be made before starting posaconazole.5.3 Hepatic ToxicityHepatic reactions (e.g.,mild to moderate elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver function tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption and rarely required drug discontinuation. Isolated cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with posaconazole. These severe hepatic reactions were seen primarily in subjects receiving the 800 mg daily (400 mg BID or 200 mg QID) in clinical trials.Liver function tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver function tests during posaconazole therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to posaconazole.5.4 Use With MidazolamConcomitant administration of NOXAFIL with midazolam increases the midazolam plasma concentrations by approximately 5 fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)].6. ADVERSE REACTIONS6.1 Serious and Otherwise Important Adverse ReactionsThe following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling: • Hypersensitivity[see Contraindications (4.1)]•Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2)][see Warnings and Precautions (5.3)]• HepaticToxicity6.2 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of NOXAFIL cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety of posaconazole therapy has been assessed in 1844 patients in clinical trials. This includes 605 patients in the active-controlled prophylaxis studies, 557 patients in the active-controlled OPC studies, 239 patients in refractory OPC studies, and 443 patients from other indications. Thisrepresents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy, neutropenia post-chemotherapy, graft vs. host disease post hematopoietic stem cell transplant, and HIV infection, as well as non-neutropenic patients. This patient population was 71% male, had a mean age of 42 years (range 8-84 years, 6% of patients were ≥65 years of age and 1% was <18 years of age), and were 64% white, 16% Hispanic, and 36% non-white (including 14% black). Posaconazole therapy was given to 171 patients for ≥6 months, with 58 patients receiving posaconazole therapy for ≥12 months. Table 1 presents treatment-emergent adverse reactions observed at an incidence of >10% in posaconazole prophylaxis studies. Table 2 presents treatment-emergent adverse reactions observed at an incidence of at least 10% in the OPC/rOPC studies.Prophylaxis of Aspergillus and Candida: In the 2 randomized, comparative prophylaxis studies, the safety of posaconazole 200 mg threetimes a day was compared to fluconazole 400 mg once daily or itraconazole 200 mg twice a day in severely immunocompromised patients.The most frequently reported adverse reactions (>30%) in the prophylaxis clinical trials were fever, diarrhea and nausea.The most common adverse reactions leading to discontinuation of posaconazole in the prophylaxis studies were associated with GI disorders,specifically, nausea (2%), vomiting (2%), and hepatic enzymes increased (2%).TABLE 1: Study 1 and Study 2. Number (%) of Randomized Subjects Reporting Treatment-Emergent Adverse Reactions: Frequency of at Least 10% in the Posaconazole or Fluconazole Treatment Groups (Pooled Prophylaxis Safety Analysis)Body SystemPreferred Term Posaconazole(n=605)Fluconazole(n=539)Itraconazole(n=58)Subjects Reporting any Adverse Reaction 595 (98) 531 (99) 58 (100) Body as a Whole - General DisordersFever 274 (45) 254 (47) 32 (55) Headache 171 (28) 141 (26) 23 (40) Rigors 122 (20) 87 (16) 17 (29) Fatigue 101 (17) 98 (18) 5 (9) Edema Legs 93 (15) 67 (12) 11 (19) Anorexia 92 (15) 94 (17) 16 (28) Dizziness 64 (11) 56 (10) 5 (9) Edema 54 (9) 68 (13) 8 (14) Weakness 51 (8) 52 (10) 2 (3) Cardiovascular Disorders, GeneralHypertension 106 (18) 88 (16) 3 (5) Hypotension 83 (14) 79 (15) 10 (17) Disorders of Blood and Lymphatic SystemAnemia 149 (25) 124 (23) 16 (28) Neutropenia 141 (23) 122 (23) 23 (40) Febrile Neutropenia 118 (20) 85 (16) 23 (40) Disorders of the Reproductive System and BreastVaginal Hemorrhage* 24 (10) 20 (9) 3 (12) Gastrointestinal System DisordersDiarrhea 256 (42) 212 (39) 35 (60) Nausea 232 (38) 198 (37) 30 (52) Vomiting 174 (29) 173 (32) 24 (41) Abdominal Pain 161 (27) 147 (27) 21 (36) Constipation 126 (21) 94 (17) 10 (17) Mucositis NOS 105 (17) 68 (13) 15 (26) Dyspepsia 61 (10) 50 (9) 6 (10) Heart Rate and Rhythm DisordersTachycardia 72 (12) 75 (14) 3 (5) Infection and InfestationsBacteremia 107 (18) 98 (18) 16 (28) Herpes Simplex 88 (15) 61 (11) 10 (17) Cytomegalovirus Infection 82 (14) 69 (13) 0Pharyngitis 71 (12) 60 (11) 12 (21)Upper Respiratory Tract Infection 44 (7) 54 (10) 5 (9)Liver and Biliary System DisordersBilirubinemia 59 (10) 51 (9) 11 (19)Metabolic and Nutritional DisordersHypokalemia 181 (30) 142 (26) 30 (52)Hypomagnesemia 110 (18) 84 (16) 11 (19)Hyperglycemia 68 (11) 76 (14) 2 (3)Hypocalcemia 56 (9) 55 (10) 5 (9)Musculoskeletal System DisordersMusculoskeletal Pain 95 (16) 82 (15) 9 (16)Arthralgia 69 (11) 67 (12) 5 (9)Back Pain 63 (10) 66 (12) 4 (7)Platelet, Bleeding and Clotting DisordersThrombocytopenia 175 (29) 146 (27) 20 (34)Petechiae 64 (11) 54 (10) 9 (16)Psychiatric DisordersInsomnia 103 (17) 92 (17) 11 (19)Anxiety 52 (9) 61 (11) 9 (16)Respiratory System DisordersCoughing 146 (24) 130 (24) 14 (24)Dyspnea 121 (20) 116 (22) 15 (26)Epistaxis 82 (14) 73 (14) 12 (21)Skin and Subcutaneous Tissue DisordersRash 113 (19) 96 (18) 25 (43)Pruritus 69 (11) 62 (12) 11 (19)* Percentages of sex-specific adverse reactions are based on the number of males/females.NOS = not otherwise specified.HIV Infected Subjects With OPC: In 2 randomized comparative studies in OPC, the safety of posaconazole at a dose of ≤400 mg QD in 557 HIV-infected patients was compared to the safety of fluconazole in 262 HIV-infected patients at a dose of 100 mg QD.An additional 239 HIV-infected patients with refractory OPC received posaconazole in 2 non-comparative trials for refractory OPC (rOPC).Of these subjects, 149 received the 800-mg/day dose and the remainder received the ≤400-mg QD dose.In the OPC/rOPC studies, the most common adverse reactions were fever, diarrhea, nausea, headache, and vomiting.The most common adverse reactions that led to treatment discontinuation of posaconazole in the Controlled OPC Pool included respiratory insufficiency (1%) and pneumonia (1%). In the refractory OPC pool, the most common adverse reactions that led to treatment discontinuation of posaconazole were AIDS (7%) and respiratory insufficiency (3%).TABLE 2: Treatment-Emergent Adverse Reactions With Frequency of at Least 10% in OPC Studies (Treated Population)Number (%) of SubjectsControlled OPC Pool Refractory OPC PoolPosaconazole Fluconazole PosaconazoleBody SystemPreferred Term n=557 n=262 n=239356 (64) 175 (67) 221 (92)Subjects Reporting any AdverseReaction*Body as a Whole – General DisordersFever 34 (6) 22 (8) 82 (34)Headache 44 (8) 23 (9) 47 (20)Anorexia 10 (2) 4 (2) 46 (19)Fatigue 18 (3) 12 (5) 31 (13)Asthenia 9 (2) 5 (2) 31 (13)Rigors 2 (<1) 4 (2) 29 (12)Pain 4 (1) 2 (1) 27 (11)Disorders of Blood and Lymphatic SystemNeutropenia 21 (4) 8 (3) 39 (16)Anemia 11 (2) 5 (2) 34 (14)Gastrointestinal System DisordersDiarrhea 58 (10) 34 (13) 70 (29)Nausea 48 (9) 30 (11) 70 (29)Vomiting 37 (7) 18 (7) 67 (28)Abdominal Pain 27 (5) 17 (6) 43 (18)Infection and InfestationsCandidiasis, Oral 3 (1) 1 (<1) 28 (12)Herpes Simplex 16 (3) 8 (3) 26 (11)Pneumonia 17 (3) 6 (2) 25 (10)Metabolic and Nutritional DisordersWeight Decrease 4 (1) 2 (1) 33 (14)Dehydration 4 (1) 7 (3) 27 (11)Psychiatric DisordersInsomnia 8 (1) 3 (1) 39 (16)Respiratory System DisordersCoughing 18 (3) 11 (4) 60 (25)Dyspnea 8 (1) 8 (3) 28 (12)Skin and Subcutaneous Tissue DisordersRash 15 (3) 10 (4) 36 (15)Sweating Increased 13 (2) 5 (2) 23 (10)OPC=oropharyngeal candidiasis; SGOT=serum glutamic oxaloacetic transaminase (same as AST);SGPT=serum glutamic pyruvic transaminase (same as ALT).* Number of subjects reporting treatment-emergent adverse reactions at least once during the study,without regard to relationship to treatment. Subjects may have reported more than 1 event.Adverse reactions were reported more frequently in the pool of patients with refractory OPC. Among these highly immunocompromised patients with advanced HIV disease, serious adverse reactions (SARs) were reported in 55% (132/239). The most commonly reported SARs were fever (13%) and neutropenia (10%).Less Common Adverse Reactions: Clinically significant adverse reactions reported during clinical trials in prophylaxis, OPC/rOPC or other trials with posaconazole which occurred in less than 5% of patients are listed below:•Blood and lymphatic system disorders: hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, neutropenia aggravated •Endocrine disorders: adrenal insufficiency•Nervous system disorders: paresthesia•Immune system disorders: allergic reaction [see Contraindications (4.1)]•Cardiac disorders: Torsades de pointes [see Warnings and Precautions (5.2)]•Vascular disorders: pulmonary embolism•Liver and Biliary System Disorders: bilirubinemia, hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice, SGOT Increased, SGPT Increased•Metabolic and Nutritional Disorders: Hypokalemia•Platelet, Bleeding, and Clotting Disorders: Thrombocytopenia•Renal & Urinary System Disorders: Renal Failure AcuteClinical Laboratory Values: In healthy volunteers and patients, elevation of liver function test values did not appear to be associated with higher plasma concentrations of posaconazole. The majority of abnormal liver function tests were minor, transient, and did not lead to discontinuation of therapy.For the prophylaxis studies, the number of patients with changes in liver function tests from Common Toxicity Criteria (CTC) Grade 0, 1, or 2 at baseline to Grade 3 or 4 during the study is presented in Table 3.TABLE 3: Study 1 and Study 2. Changes in Liver Function Test Results From CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4Number (%) of Patients With Change*Study 1Laboratory Parameter Posaconazolen=301Fluconazolen=299AST 11/266 (4) 13/266 (5)Number (%) of Patients With Change*ALT 47/271 (17) 39/272 (14) Bilirubin 24/271 (9) 20/275 (7) Alkaline Phosphatase 9/271 (3) 8/271 (3)Study 2Laboratory Parameter Posaconazole(n=304)Fluconazole/Itraconazole(n=298)AST 9/286 (3) 5/280 (2)ALT 18/289 (6) 13/284 (5)Bilirubin 20/290 (7) 25/285 (9)Alkaline Phosphatase 4/281 (1) 1/276 (<1)* Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study.These data are presented in the form X/Y, where X represents the numberof patients who met the criterion as indicated, and Y represents the numberof patients who had a baseline observation and at least one post-baselineobservation.CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase;ALT= Alanine Aminotransferase.The number of patients treated for OPC with clinically significant liver function test (LFT) abnormalities at any time during the studies is provided in Table 4. (LFT abnormalities were present in some of these patients prior to initiation of the study drug).TABLE 4: Clinically Significant Laboratory Test Abnormalities Without Regard to Baseline ValueControlled RefractoryPosaconazole Fluconazole PosaconazoleLaboratory Test n= 557(%) n=262(%) n=239(%)ALT > 3.0 x ULN 16/537 (3) 13/254 (5) 25/226 (11)AST > 3.0 x ULN 33/537 (6) 26/254(10)39/223 (17)Total Bilirubin > 1.5 x ULN 15/536 (3) 5/254 (2) 9/197 (5)Alkaline Phosphatase > 3.0 x ULN 17/535 (3) 15/253 (6) 24/190 (13)ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase.6.3 Postmarketing ExperienceNo clinically significant postmarketing adverse reactions were identified that have not previously been reported during clinical trials experience.7. DRUG INTERACTIONSPosaconazole is primarily metabolized via UDP glucuronidation and is a substrate of p-glycoprotein efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Posaconazole is also a strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole [see Clinical Pharmacology (12.3)].7.1 Immunosuppressants Metabolized by CYP3A4Sirolimus: Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9 fold and can result in sirolimus toxicity. Therefore, posaconazole is contraindicated with sirolimus [see Contraindications (4.2) and Clinical Pharmacology (12.3)].Tacrolimus: Posaconazole has been shown to significantly increase the C max and AUC of tacrolimus. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].Cyclosporine: Posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].7.2 CYP3A4 SubstratesConcomitant administration of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and rare occurrences of torsades de pointes. Therefore, posaconazole is contraindicated with these drugs. [see Contraindications (4.3), and Warnings and Precautions (5.2)].。
泊沙康唑临床应用研究进展
尽 管在 高危人 群 中开 展了 预 防性 抗 真菌 治 疗 ，
抗 宿 主 病 （ ｒｆ ｖｒｕ— ｏ ｔｄｓａｅ ＧＶＨＤ） Ｉ Ｉ ｇ ａｔ ｅｓ ｓ ｓ ｉ ｓ ， ～ ｈ ｅ 是 Ｆ
病 （ ｖ ｓ ｅａ ｐ ｒｉｏ ｉ， 的 患 病 率 （ 比 ７ ） ｉ ａｉ ｓ ｅｇｌ ｓ Ｉ ｎ ｖ ｌ ｓ Ａ） １ 明显 降 低 ， 有 效 地 预 防 了 Ｉ Ｄ 相 关 的 死 亡 （ 比 更 Ｆ ２ ５ ） 但 不 良 事 件 发 生 率 更 高 （ 比 ２ ） 以 消 化 ， ６ ， 道 反 应 最 常 见 。 外 周 血 造 血 干 细 胞 移 植 （ ｅ ｔ— ｈ ｍａｏ
ｐ ｉ ｉ ｓｅ ｃｌ ｔａ ｓ ｌ ｔｔ ｎ ＨＳ Ｔ） 移 植 物 ｏｅ ｃ ｔｍ—ｅｌ ｒｎ ｐａ ａｉ ， Ｃ 伴 ｔ ｎ ｏ
基 金 项 目 ： 家 自然科 学 基 金 一 年科 学 基金 （ １ ０ ０ ３ 。 国 青 ８ ０ ０ ０ ） 作 者 单 位 ： 二 军 医 大学 南 京 临 床 学 院 （ 京 军 区 南 京 总 医 院 ） 第 南 呼 吸 与 危 重 症 医学 科 ， 京 南 ２００ 。 １ ０ ２
疗 后 中性 粒 细 胞 减 少 的 急 性 白血 病 或 骨 髓 增 生 异 常
综合 征患 者 ， 随机 口服泊 沙 康 唑 （ ｎ＝３）） （ 和氟 康 唑 ４
（ ＝２ ０ 、 曲康 唑 （ ＝５ ） 防性 抗 真菌 治 疗 ， ４ ）伊 ｎ ８预 泊 沙康 唑 预防性 治疗后 Ｉ Ｉ２ 比 ８ ） Ｆ （ 和侵 袭 性 曲霉
（ ２ 比 ２ ） 对 侵 袭 性 肺 曲 霉 病 的 疗 效 最 好 ４ ６ ； （ ９ 比 ２ ） 对 播 散 性 曲 霉 病 更 有 效 （ ３ 比 ３ ５ ， ５ ４ ） ５ 。Ｒａｄ等 ＿ 血 液 系 统 恶 性 肿 瘤 并 侵 袭 性 ａ １在 ”
新型抗真菌药简介
新型抗真菌药简介当前真菌感染治疗面临很多挑战，侵袭性真菌感染死亡率居高不下、抗真菌药物的耐药性逐渐上升、多重耐药和高致死率的“超级真菌”的出现、抗真菌治疗疗程长、可选用的联合治疗方案有限以及抗真菌药物的安全性及药物相互作用问题等等。
再加上抗真菌药物的可及性相对较差，新型抗真菌药物具有巨大市场需求。
抗真菌药物近些年来有较好的发展，全球范围内新作用机制及新型抗真菌药物不断出现。
王明贵教授谈到，在中国，近年上市或即将上市的抗真菌药物也相对较多。
近年中国上市的抗真菌新药原研泊沙康唑在2022年之前的适应证为预防真菌感染，其混悬液、片剂和注射剂分别于2013、2018和2021年上市。
2022年3月原研泊沙康唑的片剂及注射剂被批准用于治疗侵袭性曲霉菌病。
国产泊沙康唑于2021年4月上市了片剂和注射剂，用于预防曲霉及念珠菌感染。
原研艾沙康唑胶囊于2021年12月被批准上市，用于治疗侵袭性曲霉病、毛霉病。
注射用艾沙康唑也于2022年6月获批上市。
除了艾沙康唑，毛霉病也可选择两性霉素B类进行药物治疗。
两性霉素B去氧胆酸盐不良反应较大，两性霉素B含脂制剂可使与输注相关的不良反应和肾毒性明显减少。
国产两性霉素B胆固醇硫酸酯复合物（ABCD）于2021年3月正式上市，用于治疗各类真菌病，同年该药进入医保国谈品种。
除此之外，原研脂质体两性霉素B（L-AMB）目前也处于审批当中。
正在进行或即将开展Ⅲ期临床试验的抗真菌新药目前也有一些其他药物在中国正在进行或者即将进入Ⅲ期临床试验中。
Rezafungin属于棘白菌素类药物，在国内的临床试验已经开展一段时间。
Ibrexafungerp（艾瑞芬净，IBX）作为首个全新三萜类结构的糖原合成酶抑制剂，其虽然为棘白菌素的衍生物，但IBX也可视为新作用机制的第四代抗真菌类药物。
IBX治疗念珠菌阴道炎疗效好，复发率低。
Fosmanogepix是一种新作用机制的抗真菌药物，对于曲霉病和毛霉病都可起到治疗效果，未来也将在中国开展临床试验。
泊沙康唑Noxafil(posaconazole)静脉注射剂
【剂型和规格】
每毫升Noxafil口服混悬液40毫克。
【剂量与用法】
适应症剂量和治疗时间
侵袭性真菌感染的预防200毫克（5毫升），一天三次。治疗持续时间是基于来自嗜中性白血球或免疫抑制的恢复。
口咽念珠菌病（OPC）装载的100毫克（2.5毫升）的剂量每天两次的第一天，然后100毫克（2.5毫升），每日一次，连续13天。
·心律失常及QT间期延长：Noxafil已经显示出延长QT间期和心动过速引起的罕见事件。管理慎用给患者带来潜在的致心律失常的条件。不管理与已知延长QT间期，并通过CYP3A4代谢的药物。正确的K +，镁+ +和Ca + +开始Noxafil之前。
·肝毒性：在海拔肝功（一般是可逆的停药）可能发生。应停药谁在治疗期间出现肝功异常或监测肝功能试验的患者可以考虑。
“Noxafil静脉剂型特别适用于需要静脉给药或者不能口服用药的患者。而且，部分患者可在初始治疗时选用Noxafil注射剂，之后逐渐转为口服剂型等。”Merck传染病研究室执行董事Nicholas Kartsonis表示。
Noxafil的获批，是基于一项药代动力学研究。该项研究是一项非对照、多中心临床研究，在已发生或预期将发生显著中性粒细胞减少（neutropenia）的急性髓性系白血病（AML）或骨髓增生异常综合症（MDS）患者、以及已接受造血干细胞移植（HSCT）同时正接受免疫抑制治疗以预防移植物抗宿主病（GVHD）的患者中开展中，评价了Noxafil的药代动力学、安全性和耐受性。
பைடு நூலகம்
Merck的三唑抗真菌药泊沙康唑（posaconazole，Noxafil）静脉注射剂获得美国食品和药物管理局（FDA）批准。
泊沙康唑临床应用专家共识
属于第二代三唑类抗真菌药物,其抗菌谱和药物代
代氯,同时侧链进行羟基化,一系列结构改造使其
谢过程有别于其他三唑类药物,口服混悬液、肠溶
和真菌亲和 力 更 强,稳 定 性 更 高,细 胞 毒 性 增 加,
片和注射剂分别于 2005、2013 和 2014 年经美国食
品药品监督管理局批准先后上市。在我国,泊沙康
片多中 心 PK 研 究 (n =65,AML/MDS) 显 示,
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泊沙康唑在预防和治疗肺真菌病时,虽然血药浓度
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范围广泛。本共识对泊沙康唑的 临 床 药 理 特 性、 现 有 临 床 研 究 资 料 以 及 编 写 组 专 家 的 临 床 应 用
经验进行了系统的复习和总结, 在 此 基 础 上 对 其 临 床 应 用 做 出 了 全 面 建 议, 这 些 建 议 涉 及 了 泊
沙康唑在预防和治疗侵袭性真 菌 病 中 的 临 床 应 用 原 则、 在 特 殊 人 群 中 的 使 用 原 则、 治 疗 药 物 监
泊沙康唑预防性抗真菌治疗在重型地中海贫血儿童干细胞移植中的应用
3 hepatic impairment was 7.9 % (3/38) and discontinuation rate was 5.3% (2/38). The incidence of hepatic impairment did not show
significant difference between different Pesaro risk grades. Conclusions Oral posaconazole taken as antifungal prophylaxis is effective
1 was considerd to be probable IFD, and another was considerd to be possible IFD. The incidence of fungal infection was 5.3%. No
gastrointestinal reactions (nausea, vomiting or diarrhea), rash, or elevated creatinine above grade 3 occurred. The incidence of grade
Oral posaconazole as antifungal prophylaxis in the pediatric patients with major thalassemia following allogeneic stem cell transplantation
LU Jingyuan, HONG Xiuli, CHEN Yamei, ZHUANG Yanhong, HU Jiasheng, YAN Xiuzhen, LU Quanyi （Department of Hematology, Zhongshan Hospital, Xiamen University, Xiamen Fujian 361004, China）
泊沙康唑预防或挽救性治疗血液病患者侵袭性真菌病的临床研究
泊沙康唑预防或挽救性治疗血液病患者侵袭性真菌病的临床研究泊沙康唑属于新型广谱三唑类抗真菌药物，主要用于免疫缺陷患者侵袭性真菌病（IFD）的预防性治疗，被批准的适应证包括急性髓系白血病（AML）和骨髓增生异常综合征（MDS）化疗引起的中性粒细胞减少症患者及造血干细胞移植（HSCT）后发生移植物抗宿主病（GVHD）患者IFD的预防。
泊沙康唑具有广泛的抗菌活性，对念珠菌属、曲霉菌属，甚至既往唑类药物不敏感的接合菌属（如毛霉菌等）等均具有良好的作用，在国外已经得到广泛应用。
由于泊沙康唑在我国被批准应用于临床的时间较短（2013年6月批准注册），国内文献尚鲜见其用于IFD预防或治疗的临床报道。
我们回顾性分析25例接受泊沙康唑预防或挽救性治疗IFD的血液病患者的临床资料，对其疗效及安全性进行探讨。
1 资料与方法1.1 一般资料2014年2月至2015年2月共有25例血液病患者接受了泊沙康唑预防性或挽救性治疗，平均年龄32.6岁（16~ 64岁）。
其中18例接受了泊沙康唑预防性治疗，包括急性白血病患者8例[6例为AML, 2例为急性淋巴细胞白血病（ALL）]，均为化疗后严重骨髓抑制期（中性粒细胞计数<0.5×109/L）；HSCT患者10例，其中非血缘脐血移植7例，自体外周血干细胞移植（PBSCT）、人类白细胞抗原（HLA）相合同胞PBSCT及非血缘PBSCT各1例。
10例HSCT患者接受泊沙康唑预防性治疗主要是由于移植前3个月曾发生过侵袭性肺部真菌病（IPFD），经过伏立康唑治愈（7例）（即泊沙康唑二级预防）或出现Ⅲ～Ⅳ度急性GVHD(aGVHD）（3例）。
7例患者接受了泊沙康唑挽救性治疗，其中4例为HSCT患者，1例为极重型再生障碍性贫血患者，接受抗胸腺细胞球蛋白（ATG）、环孢素（CsA）免疫抑制治疗联合脐血输注，1例为ALL患者（化疗后骨髓抑制期间），1例为多发性骨髓瘤（MM）患者。
所有接受泊沙康唑挽救性治疗的患者均是在伏立康唑预防期间出现肺部真菌感染的突破或IPFD治疗无效（6例）或不耐受（1例）者。
泊沙康唑药动学及其治疗药物监测方法研究进展
• 222•第 44 卷第 1期2021 年 1月名袷卞河元Drug Evaluation Research Vol. 44 No. 1January 2021泊沙康唑药动学及其治疗药物监测方法研究进展叶珍洁，吴灵洁，张晓颖，郑玲‘福建医科大学盂超肝胆医院，福建福州350025摘要：泊沙康唑作为第二代三唑类抗真菌药物，其抗菌谱广、抗菌作用强、耐受性好，因而受到临床广泛关注。
泊沙康 唑口服制剂达峰时间为3〜5 h,血浆蛋白结合率高达98%,其体内药物代谢受食物、用药方案、药物相互作用等因素影响，导致个体间血浆药物浓度变异性大，而泊沙康唑血浆药物浓度与其临床疗效密切相关，故推荐临床开展泊沙康唑治疗药物 监测，以保证其稳态谷浓度大于有效浓度。
目前常用于泊沙康唑浓度检测的方法有微生物检定法、化学荧光法及色谱法，其中液相色谱串联质谱法灵敏、准确、简单，为药物浓度检测“金标准”。
关键词：泊沙康唑；药动学；治疗药物监测：侵袭性真菌感染病；检测方法中图分类号：R978.5文献标志码：A文章编号：1674-6376(2021)01-0222-07D O I：10.7501/j.issn.1674-6376.2021.01.031Advances research on pharm acokinetics and therapeutic d ru g m onitoring of posaconazoleYE Zhenjie,WU Lingjie,ZHANG Xiaoying,ZHENG LingM e n g c h a o hepatobiliary hospital o f F u jian m e d i c a l university, F u z h o u 350025, C h i n aAbstract: A s a s e c o n d g e n e ration o f triazole antifungal drug, p o s a c o n a z o l e h a s b e e n w i d e l y u s e d in clinic b e c a u s e o f its w i d e antibacterial s p e c t r u m, strong antimicrobial activity a n d g o o d tolerance. T h e /maxo f p o s a c o n a z o l e is 3 — 5 h, a n d the b i n d i n g rate o fp l a s m a protein w a s u p to 98%.H o w e v e r,the p h a r m a c o k i n e t i c s o f p o s a c o n a z o l e are easily affected b y food, d r u g r e g i m e n,d r u g interaction a n d other factors, resulting in great variability o f d r u g c o n centration in p l a s m a a m o n g individuals, a n d d r u g concentration o f p o s a c o n a z o l e is closely related to its clinical efficacy. Therefore, i t is r e c o m m e n d e d to carry out therapeutic d r u g m o n i t o r i n g o fp o s a c o n a z o l e.A t present, the c o m m o n l y u s e d m e t h o d s for the detection o f p o s a c o n a z o l e c o n centration include m i c r o b i a l assay, c h e m i c a l f l u o r escence a n d c h r o m a t o g r a p h y. A m o n g t h e m,liquid c h r o m a t o g r a p h y t a n d e m m a s s s p e c t r o m e t r y is sensitive, accurate a n d simple, a n d is the "g o l d standard" for the detection o f d r u g concentration.Key words: p o s a c o n a z o l e; p h a r m a c o k i n e t i c s; therapeutic d r u g m o n i t o r i n g; invasive fungal disease; detection m e t h o d近年来，随着广谱抗生素、抗肿瘤药物、免疫抑 制剂的大量应用，放射治疗和侵袭性操作的广泛开 展以及获得性免疫缺陷患者的急速增加，侵袭性真 菌感染病（invasive fungal disease，IFD)发病率逐年 上升，侵袭性真菌感染己成为艾滋病及肿瘤等疾病 重要致死因素之一[1]。
泊沙康唑的合成工艺改进研究
泊沙康唑的合成工艺改进研究泊沙康唑是一种广谱抗真菌药物，常用于治疗真菌感染病。
目前泊沙康唑的合成工艺已经相对成熟，但仍然存在一些需要改进的地方，本文将就泊沙康唑的合成工艺进行改进研究。
首先，目前泊沙康唑的合成工艺主要是从7-氯基-3，4-二氢羧基喹唑啉起始合成，经过多步反应得到最终产物泊沙康唑。
其中最主要的环节就是从7-氯基-3，4-二氢羧基喹唑啉合成中间体4-羟基-1，2,4-三唑-3-酮。
在这个反应中，需要使用强碱溶液作为催化剂，并经历一系列加热和冷却过程，整个反应时间较长且操作较为繁琐。
为了改进这个工艺，可以考虑使用更加温和的反应条件，以提高反应效率和产物纯度。
可以尝试使用催化剂替代强碱条件，例如过渡金属催化剂，如铜、钯等，或者使用中性基质作为催化剂，如各类有机碱。
通过反应条件的改变，可以进一步优化反应过程，提高泊沙康唑的产率和产物纯度。
另外，原有工艺中泊沙康唑的合成需要经历多步反应，中间产物的分离和纯化过程较为繁琐。
可以考虑引入连续流动合成的方法，通过控制反应条件和反应物的流动速率，在连续流动反应器中进行合成反应，提高反应效率和产物纯度。
此外，合成过程中的催化剂的选择也有待优化。
传统的合成方法中，往往需要大量的催化剂，且催化剂的产生会增加废弃物的排放和废弃物处理的成本。
可以考虑绿色催化技术的应用，如过渡金属有机框架催化剂、固体酸碱催化剂等，以减少催化剂用量、提高催化剂的重复使用性，从而减少对环境的负面影响。
此外，还可以考虑引入新的催化反应，如微生物催化、酶催化等。
这些催化方法具有底物选择性高、产物纯度高、反应温和等特点，能够为泊沙康唑的生产提供更加高效、环保的方法。
综上所述，通过改进合成工艺，可以提高泊沙康唑的合成效率、产物纯度，减少废弃物的排放和催化剂的用量，从而提高工艺的经济性和环保性。
需要进一步开展实验和优化设计，以实现这些改进的目标。
泊沙康唑在预防恶性血液病患者侵袭性真菌病中的应用研究
• 108•现物医学 Progress in Modern Biomedicine VoL21 NO.l JAN*2021doi: 10.13241 /ki.p m b.2021.01.023泊沙康唑在预防恶性血液病患者侵袭性真菌病中的应用研究*郎涛徐艳芳王增胜王一淳李蒙蒙李燕△(新疆维吾尔自治区人民医院血液病科新疆乌鲁木齐830001)摘要目的：研究泊沙康唑在预防恶性血液病患者侵袭性真菌病中的应用效果方法：选取我院2018年1月~2019年9月收治的 50例恶性血液病患者，按照随机数余数分组法分为采取泊沙康唑预防的泊沙康唑组以及采取伊曲康唑预防的伊曲康唑组各25 例，对两组预防效果进行对比。
结果：泊沙康唑组预防治疗成功率为84.00%(21/25)，显著高于伊曲康唑组的68.00%( 17/25),侵 袭性真菌病发生率为4.00 %(1/25),显著低于伊曲康唑组的16.00 %(4/25)(P<0.05);给药前两组炎性细胞因子差异无统计学意 义(/>>0.05),给药结束后均较本组给药前降低(P<0.05),组间比较泊沙康唑组均低于伊曲康唑组(P C0.05);泊沙康唑组治疗期 间不良反应发生率为8.00 %(2/25),伊曲康唑组治疗期间不良反应发生率为20.00 %(5/25),两组不良反应发生率对比无统计学 意义(P>0.05)。
结论:在预防恶性血液病患者侵袭性真菌病中泊沙康唑效果更佳且安全性高，可作为优选用药方案推广使用。
关键词：恶性血液病;侵袭性真菌病；泊沙康吐;伊曲康唆中图分类号:R519;R55文献标识码:A文章编号：1673-6273(2021)01-108-04Study on the Application of Posaconazole in the Prevention of Invasive Mycosis in Patients with Malignant Hematological Diseases*LANG Tao, X U Yan-fang, WANG Zeng-sheng, WANG Yi-chun, LI Meng-meng, LI Yarf^ (Department o f H ematology, People's Hospital o f X injiang Uygur Autonomous Region, Urumqi, Xinjiang, 830001, China)A B S T R A C T Objective: To study the effect of posaconazole i n the prevention of invasive mycosis i n patients with malignant hematological diseases. Methods: Fifty patients with malignant hematological diseases treated in our hospital from January 2018 to September 2019 were randomly divided into Poisson conazole group (n=25) and itraconazole group (n=25). The preventive effects of the two groups were compared.Results:The success r ate of preventive treatment i n the posaconazole group was 84.00 %(21/25), which was significantly higher than the 68.00 %(17/25) of the itraconazole group,and the incidence of invasive fungal disease was 4.00 %(1/25), significantly lower than that 16.00 %(4/25) of the itraconazole group (P<0.05). There was no significant difference in inflammatory cytokines between the two groups before administration.(/)>0.05), after the administration was lower than that before the administration of t h i s group (P<0.05), compared between the groups,the posaconazole group was lower than the itraconazole group (P<0.05). The incidence of adverse reactions during the treatment of posaconazole group was 8.00 %(2/25), and the incidence of adverse reactions during treatment of itraconazole group was 20.00 %(5/25). The incidence of adverse reactions between the two groups was not s t a t i s t i c a l l y significant (P>0.05). Conclusion: Posaconazole has better effect and high safety in the prevention of invasive mycosis in patients with malignant hematology.Key words:Malignant hematological disease;Invasive mycosis;Posaconazole;ItraconazoleChinese Library Classification(C L C):R519; R55 Document code: AArticle ID: 1673-6273(2021)01-108-04i/. —^刖目恶性血液病已经成为临床中较为常见的一类病症类型，除 了常见的白血病外，再生障碍性贫血、骨髓异常增生综合征、浆 细胞肿瘤如多发性骨髓瘤、淋巴瘤、恶性组织细胞增生症等亦 属于此类疾病范畴m。
诺科飞泊沙康唑的介绍课件
常见副作用
01
消化系统反应
02
皮肤反应
03
肝功能异常
04
神经系统反应
不良反应处理
01
02
轻度副作用
中度副作用
03 重度副作用
使用注意事 项
肝功能不全者慎用 由于泊沙康唑主要经肝脏代谢，肝功 能不全者应谨慎使用。
定物使用安全。
避免与其他药物同时使用
与其他药物的相互作用
利福平 苯妥英
CATALOGUE
诺科飞泊沙康唑的研发历程与未来展望
研发历程
早期研究
。
临床前研究
临床试验 上市申请
未来研究方向
扩大适应症
联合治疗
改进剂型 耐药机制研究
市场前景
广阔的应用前景 政策影响
竞争格局 技术创新
THANKS
感谢观看
诺科飞泊沙康唑的 介绍课件
目 录
• 诺科飞泊沙康唑简介 • 诺科飞泊沙康唑的药理作用 • 诺科飞泊沙康唑的临床应用 • 诺科飞泊沙康唑的副作用及注意事项 • 诺科飞泊沙康唑与其他药物的相互作用 • 诺科飞泊沙康唑的研发历程与未来展望
contents
CATALOGUE
诺科飞泊沙康唑简介
产品背景
泊沙康唑是一种由Novartis（诺 华）公司研制的抗真菌药物，用
诺科飞泊沙康唑的药理作用
抗菌 谱
诺科飞泊沙康唑是一种广谱抗真菌药物，对念珠菌、曲霉菌、肺孢子菌等多种真 菌具有抗菌活性。
该药物对其他抗真菌药物耐药的真菌也有一定作用，如对氟康唑耐药的念珠菌和 曲霉菌。
抗真菌活性
耐药性
CATALOGUE
诺科飞泊沙康唑的临床应用
适应症
01
泊沙康唑的临床药7.28效——【血液内科】
菌种
数量 AMB FCZ
ICZ
新生隐球菌 罗伦隐球菌
5 0.25-2 1-4 0.25-1 2 0.5-1 2-4 0.5-1
VCZ
0.030.125 0.125
POS
CAS
MCF
0.125-1 16->16 16->16 0.25-1 16->16 >16
阿萨希毛孢子菌 3
Trichosporon loubieri
白念珠菌热带念珠菌近平滑念珠菌克柔念珠菌光滑念珠菌新生隐球菌烟曲霉土曲霉毛霉镰刀霉荚膜组织胞浆菌皮炎芽生菌球孢子菌对耐flc念珠菌的mic值范围gml菌种数量ambfcziczvczposcasmcffczr白念珠菌05116640062003050030125006025003fczs白念珠菌051012520125050030250030060125025003025光滑念珠菌05116640540062003050125025003近平滑念珠菌012505025100300301250125286414003025003012512052140510030030060250500305克柔念珠菌32050250501250125葡萄牙念珠菌0510500602500300302501250500305希木龙念珠菌26401250500610250500605012505解脂念珠菌02500301250250125对其他酵母菌的mic值范围gml菌种数量ambfcziczvczposcasmcf新生隐球菌025214025100301250125116161616罗伦隐球菌051240510125025116161612240125050030060125051616trichosporonloubieri050125051616马尔尼菲篮状菌0250512003006003003012505白地霉02505对耐唑类的曲霉的micmec值gml菌种数量ambfcziczvczposcasmcficzr烟曲霉641605202516003006003vczr烟曲霉640516025003003其他烟曲霉1012640125100620060250030125003iczr黄曲霉0505003其他黄曲霉051003012500311264120252006025003003黑曲霉01251640060250030030250030125003土曲霉2464006025003003025012505003对其他丝状真菌的micmec值gml菌种数量ambfcziczvczposcasmcf16641616161864241205105茄病镰刀菌161616161612641605116161616不规则毛霉025056424160511616卷枝毛霉641616161616冻土毛霉05641602516161605
2024年泊沙康唑市场调研报告
2024年泊沙康唑市场调研报告一、引言泊沙康唑是一种抗真菌药物，属于抗真菌酮类药物，可用于治疗各类真菌感染疾病。
该药物在临床上广泛应用，并且具有良好的疗效和安全性。
为了了解泊沙康唑在市场上的现状和前景，本报告对泊沙康唑进行了市场调研分析。
二、市场概况根据市场调研数据，泊沙康唑是一种非处方药，可在医院和药店内销售。
泊沙康唑属于中高价位药物，一般需由医生开具处方才能购买。
由于其良好的治疗效果以及较少的副作用，泊沙康唑在市场上具有一定的竞争优势。
三、市场竞争分析目前，市场上存在着多种抗真菌药物，其中包括泊沙康唑在内。
针对不同的真菌感染病种，医生会根据患者的具体情况来选择合适的药物。
在泊沙康唑所涵盖的真菌感染病种中，该药物的竞争对手主要有克霉唑、伊曲康唑等。
通过与竞争对手的比较，泊沙康唑在治疗效果、药物安全性以及价格等方面均具有一定的优势。
此外，泊沙康唑也一直在不断进行研发和创新，以满足市场和患者的需求。
四、市场前景分析根据市场调研资料显示，泊沙康唑的市场需求正在逐渐增加。
随着人们健康意识的提高，真菌感染疾病的发生率也在不断上升。
泊沙康唑作为一种常见的抗真菌药物，具有较广泛的应用领域，对市场需求有着较强的驱动力。
同时，不同病原体对抗真菌药物的耐药性也是市场发展的一个重要因素。
针对此问题，泊沙康唑的研发团队一直在努力提高药物的抗菌效果，以应对潜在的耐药性风险。
综上所述，泊沙康唑在市场上具有一定的竞争优势和市场潜力。
未来，随着真菌感染疾病的增加以及泊沙康唑的不断创新，相信泊沙康唑在市场上的地位将进一步巩固和提升。
五、结论通过对泊沙康唑的市场调研分析，可以得出以下结论：1.泊沙康唑具有较好的治疗效果和安全性；2.泊沙康唑在市场上具有一定的竞争优势；3.泊沙康唑的市场需求正在逐渐增加；4.泊沙康唑在未来具有较大的市场前景。
在市场竞争激烈的情况下，泊沙康唑需要进一步进行市场营销和创新，以保持其竞争优势并提高市场份额。
泊沙康唑临床应用研究进展
泊沙康唑临床应用研究进展
孙禾;苏欣;徐小勇;孙文逵;施毅
【期刊名称】《中国感染与化疗杂志》
【年(卷),期】2012(012)003
【总页数】4页(P230-233)
【作者】孙禾;苏欣;徐小勇;孙文逵;施毅
【作者单位】第二军医大学南京临床学院(南京军区南京总医院)呼吸与危重症医学科,南京210002;第二军医大学南京临床学院(南京军区南京总医院)呼吸与危重症医学科,南京210002;第二军医大学南京临床学院(南京军区南京总医院)呼吸与危重症医学科,南京210002;第二军医大学南京临床学院(南京军区南京总医院)呼吸与危重症医学科,南京210002;第二军医大学南京临床学院(南京军区南京总医院)呼吸与危重症医学科,南京210002
【正文语种】中文
【中图分类】R978.5
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《泊沙康唑临床应用专家共识》(2020)要点
《泊沙康唑临床应用专家共识》（2020）要点近年来,随着各类免疫缺陷人群及危重疾患的增多,侵袭性真菌病(IFD)的整体发病率逐年上升,且非白念珠菌、曲霉及毛霉等真菌感染的比例在血液科、呼吸科、器官移植科等科室普遍呈升高趋势。
泊沙康唑属于第二代三唑类抗真菌药物,其抗菌谱和药物代谢过程有别于其他三唑类药物,口服混悬液、肠溶片和注射剂分别于2005、2013和2014年经美国食品药品监督管理局批准先后上市。
在我国,泊沙康唑口服混悬液于2013年上市,肠溶片也于2018年12月上市,在IFD的预防和治疗领域适用范围广泛。
1 临床药理学特性1 1 作用机制及分子结构特征1 2 药代动力学(PK)泊沙康唑的吸收会因剂型不同而有差异,主要在胃部溶解,在十二指肠部位吸收。
肠溶缓释片剂使用独特的热熔挤压工艺将药物分散在pH敏感的高分子聚合体中,有效避免药物在低pH的胃部释放,利于在中性pH的小肠溶解,从而使泊沙康唑吸收达到最大化。
注射针剂几乎在注射完毕时即可达血药峰浓度,且除首日双倍剂量外每日仅需给药1次,适用于不能耐受口服剂型的患者。
1 3 治疗药物监测(TDM)在深部真菌病的预防治疗中,基础疾病、合并用药、饮食情况、诊疗措施等多种因素都会对抗真菌药物的吸收、分布、代谢和清除产生影响,TDM 既是保证治疗充分的重要手段,又是避免过度药物暴露、减少药物相关不良反应的重要措施。
专家建议：有条件的医疗机构应积极开展泊沙康唑的TDM,监测指标为泊沙康唑血药谷浓度。
首次泊沙康唑血药谷浓度监测的采血时间建议为用药后第5天。
用于预防IFD时,泊沙康唑的血药谷浓度应维持在0.7mg/L以上；用于治疗IFD时,泊沙康唑的血药谷浓度应维持在1.0～1.25mg/L以上。
1 4 药物间相互作用泊沙康唑的主要药物相互作用结果及应对措施见表2。
1 5 安全性及耐受性泊沙康唑口服混悬液常见不良反应为恶心、头痛、呕吐、腹痛、皮疹等,症状较轻微,大多数情况下不需要停药,长期治疗(≥6个月)时QT间期延长、肝酶升高等不良反应的发生率仍然保持在较低水平。
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Cornely OA et al. N Engl J Med. 2007;356:348-359.
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结论
对于因急性髓性白血病/骨髓异常增生综合症而接受化疗的 患者，泊沙康唑较伊曲康唑或氟康唑能更好的预防侵袭性 真菌感染的发生，并且泊沙康唑的使用可以改善上述患者 总体的生存率。
Cornely OA et al. N Engl J Med. 2007;356:348-359.
设计 开放性、前瞻、对照、多中心 13 岁；预计出现粒缺 (绝对中性粒细胞数 ≤500 cells/mm3) 7 天；因新诊断或复发的AML/MDS使用了密集化疗方案 N=602 泊沙康唑口服混悬液 200 mg TID 氟康唑口服混悬液 400 mg QD 伊曲康唑 口服混悬液 200 mg BID
严重不良事件泊沙康唑与标准唑类相当
*不良事件的统计是从患者随机化至最后一次用药后30天。由于部分患者出现上述不良反 应不止一次，因此不良反应的统计仅按照病例数而非不良事件发生的次数. †该表中包括了本次研究中所有的严重不良反应.
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Cornely OA et al. N Engl J Med. 2007;356:348-359.
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治疗失败率泊沙康唑低于氟康唑
因接受系统性抗真菌治疗/临床诊断及确诊IFI导致的治疗失败，泊沙康唑组 显著低于氟康唑组。
Yang Shen et al.International Journal of Clinical Pharmacology and Therapeutics. 2013,51(9):738-745
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治疗期泊沙康唑组临床诊断/确诊IFI 发生率低于氟康唑
9.4%
3.42%
11/117
4/117
主要疗效评价终点： 治疗期间（随机至末次给药日＋7 天）确诊或临床诊断的IFI的发生率。
泊沙康唑非劣效于氟康唑成立。
Yang Shen et al.International Journal of Clinical Pharmacology and Therapeutics. 2013,51(9):738-745
泊沙康唑国内外临床研究介绍
泊沙康唑用于侵袭 性真菌病的预防
泊沙康唑用于侵袭 性真菌病的治疗
国外研究
国外研究
国内研究
2
国内研究
泊沙康唑 vs 氟康唑或伊曲康唑在中性粒缺乏的患者预防中的应用
泊沙康唑或氟康唑在严重的移植物抗宿主病（GVHD）预防性治疗应用
3
因AML/MDS接受化疗导致粒缺的患者 Oliver A, NEJM 2007
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Cornely OA et al. N Engl J Med. 2007;356:348-359.
实验设计
Posaconazole (n = 301)
N = 600
首剂
(n = 299)
Fluconazole
末剂
末剂 +7天
第112天
第112天 +2月
次要终点时间
主要终点时间
随访
固定治疗期 （固定时期）：112天（主要终点时间）。 暴露期 （治疗期）： 首剂至末剂后7天（次要终点时间）。
N = 602
化疗 & 预防
氟康唑 或伊曲康唑
化疗 & 预防 (如需要)
(n = 298)
随机化疗后100天
主要终点时段 次要终点时段
主要终点时段：随机从每个化疗期开始直至粒缺恢复或发生突破性真菌感染。如随机至84天 则可停止给药。 次要终点时段：随机化后的100天和疗程结束后的30天
Cornely OA et al. N Engl J Med. 2007;356:348-359. 5 Additional information available in Study Report P01899, p 3,4. SPRI, Kenilworth, NJ, USA; November 2005.
Ullmann AJ et al. N Engl J Med. 2007;356:335-347. 15 June 2005. Study report C/I98-316, p 3, 4, 47. SPRI, Kenilworth, NJ, USA;
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固定治疗期/暴露期泊沙康唑IFI/IA的发生率 比例低于氟康唑
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Yang Shen et al.International Journal of Clinical Pharmacology and Therapeutics. 2013,51(9):738-745
实验设计
入组条件：高危粒缺患者，预防侵袭性真菌病
N=245
多中心、随机、开放、平行组对照研究
1:1
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Ullmann AJ et al. N Engl J Med. 2007;356:335-347
泊沙康唑用于侵袭 性真菌病的预防
泊沙康唑用于侵袭 性真菌病的治疗
国外研究
国外研究
国内研究
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国内研究
参研单位（2008.9-2010.5）
上海瑞金医院 北大人民医院 北京协和医院 301 医院 四川大学华西医院 西安西京医院 中南大学湘雅医院
30
泊沙康唑用于侵袭 性真菌病的预防
*预防用药期间.
†随机化后100天.
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Cornely OA et al. N Engl J Med. 2007;356:348-359.
泊沙康唑在粒缺患者IFI的预防价值
• 有效性 泊沙康唑在预防侵袭性真菌感染方面优于标准唑类预防用药 泊沙康唑在预防侵袭性曲霉感染方面优于标准唑类预防用药 泊沙康唑的使用能够带来明显的生存获益 • 安全性 泊沙康唑与标准唑类预防用药有着相似的安全性
泊沙康唑组发生IFI的时间晚于氟康唑
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Ullmann AJ et al. N Engl J Med. 2007;356:335-347
泊沙康唑与氟康唑不良事件的发生率相当
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Ullmann AJ et al. N Engl J Med. 2007;356:335-347
结论
• 对于Allo-HCT的患者，泊沙康唑在预防侵袭性真菌感染 上非劣效于氟康唑，在预防侵袭性曲霉感染的疗效上优于 氟康唑。
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预防Allo-HCT伴GVHD患者IFI发生 Andrew J., NEJM 2007
设计 纳入患者 样本量 剂量 对照组 主要功效 终点指标 次要功效 终点指标 双盲双模拟、随机、对照、跨国多中心 13 岁；Allo-HCT伴GVHD N=600 泊沙康唑口服混悬液 200 mg TID 氟康唑胶囊 400 mg QD 固定治疗期（随机化开始至第112d）突破性感染（确诊/临床诊断） 发生率 在暴露期（首剂至末剂后7d），确诊或临床诊断突破侵袭性真菌感 染的发病率；在固定治疗期和暴露期，由曲霉菌引起的侵袭性真菌 感染的发病率；全因死亡率；从首剂至侵袭性真菌感染的时间
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治疗期泊沙康唑组拟诊/临床诊断/确诊 IFI发生率低于氟康唑
22.2% 26/117 9.4%
11/117
主要疗效评价终点： 泊沙康唑组拟诊+临床诊断 +确诊IFI发生率显著低于氟康唑组。 治疗期间（随机至末次给药日＋ 7 天）确诊或临床诊断的 IFI的发生率。
（P=0.011)
Yang Shen et al.International Journal of Clinical Pharmacology and Therapeutics. 2013,51(9):738-745
福建协和医院
温州医学院附一医院 浙江大学附一医院 苏州大学附属第一医院
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天津血研所
中国医科大学附属第一医院 西安唐都医院
持续粒缺的患者 Yang Shen, et al. International Journal of Clinical Pharmacology and Therapeutics，2013 设计 纳入患者 样本量 剂量 对照组 主要功效 终点指标 开放性、前瞻、随机、对照、多中心 18-70 岁之间的男性或女性;有持续性中性粒细胞减少症（ANC < 500/mm3 ），或预计很可能在3~5 天内发生中性粒细胞减少症， 中性粒细胞减少的时间≥7 天 N=245 泊沙康唑口服混悬液 200 mg TID 氟康唑片剂 400 mg QD 治疗期间（随机至末次给药日＋7 天）确诊或临床诊断的IFI的 发生率
纳入患者
样本量 剂量 对照组
主要功效 终点指标 次要功效 终点指标
治疗期突破性感染（确诊/临床诊断）发生率
随机化100d内侵袭性曲霉菌病、侵袭性真菌病的发生率及治疗期 间的成功率
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Cornely OA et al. N Engl J Med. 2007;356:348-359.
实验设计
泊沙康唑 (n = 304)
治疗期失败率泊沙康唑低于标准唑类
*治疗期被定义为随机化开始至最后一个化疗疗程结束用药的第7d. 病人被确定为预防失败可能是基于不止一个原因。临床失败包括那些被随机分入各组，但是没有进行 治疗的患者 (泊沙康唑组, 7 [2%]; 标准唑类组, 6 [2%]).
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Cornely OA et al. N Engl J Med. 2007;356:348-359.
5
治疗期突破性感染的发生率泊沙康唑低于标准唑类
6
Cornely OA et al. N Engl J Med. 2007;356:348-359.
随机化后100d突破性感染/死亡的发生率泊沙康唑 优于标准唑类
7
Cornely OA et al. N Engl J Med. 2007;356:348-359.
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