Factors influencing the pharmacokinetics of prophylactic posaconazole oral suspension in patients with acute myeloid leukemia or myelodysplastic syndrome

Objectives

To estimate the pharmacokinetic (PK) properties of posaconazole in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing chemotherapy in a clinical setting.

Methods

Posaconazole concentrations in patients with AML/MDS receiving prophylactic posaconazole were determined by high-performance liquid chromatography. A population PK model with nonlinear mixed effect modeling was developed. The list of tested covariates included age, weight, height, gender, posaconazole dose, ethnicity, co-administration of antineoplastic chemotherapy, ranitidine or pantoprazole, coincident fever, diarrhea, leukocyte counts, and γ-glutamyltransterase plasma activity.

Results

A total of 643 serum concentrations of posaconazole from 84 patients were obtained. A one-compartment model with first order absorption and elimination as the basic structural model appropriately described the data, with an apparent clearance of 56.8?L/h [95% confidence interval (CI) 52.8–60.8?L/h] and an apparent volume of distribution of 2,130 L (95% CI 1,646–2,614?L). Significant effects on apparent clearance (CL/F) were found for presence of diarrhea and for co-medication with proton-pump inhibitors (1.5- and 1.6-fold increase in CL/F, respectively), weight (33.4?L larger apparent volume of distribution per kilogram), and co-administration of chemotherapy (0.6-fold lower apparent volume of distribution).

Conclusion

We developed a prediction basis for mean posaconazole concentrations in AML/MDS patients. Patient weight, presence of diarrhea, and concomitant medication (chemotherapy and pantoprazole) showed significant effects on posaconazole exposure. Corresponding adjustments of the starting dose according to the presence of diarrhea and during the co-administration of chemotherapy or proton-pump inhibitors appear justified before therapeutic drug monitoring results are available. Further investigation of the interaction between different chemotherapeutic regimens and posaconazole is warranted.     

A post-marketing evaluation of posaconazole plasma concentrations in neutropenic patients with haematological malignancy receiving posaconazole prophylaxis

This is one of the first studies to report on therapeutic drug monitoring (TDM) of posaconazole (PCZ) for antifungal prophylaxis in patients with acute myelogenous leukaemia or myelodysplastic syndrome outside of the rigours of clinical licencing trials. A number of factors have been identified or proposed as causing poor oral absorption of PCZ. Putative PCZ concentrations have been recommended for TDM (0.5 μg/mL or 0.7 μg/mL). In this study, 19 (90.5%) of 21 patients failed to reach the higher putative target of 0.7 μg/mL, and 16 patients (76.2%) failed to reach the lower target of 0.5 μg/mL. Increasing the dose did not help four of six patients reach target concentrations. Three of the patients developed 'proven' or 'possible' fungal infections, all with PCZ concentrations <0.5 μg/mL. Use of acid-suppressing agents appears to explain some of the poor absorption. TDM of PCZ is warranted in patients receiving this orally administered agent.     

泊沙康唑与伊曲康唑预防骨髓增生异常综合征/急性髓系白血病患者侵袭性真菌病的成本-效果分析

目的：开展泊沙康唑对比伊曲康唑用于预防骨髓增生异常综合征/急性髓系白血病患者发生侵袭性真菌病的成本-效果分析,为临床合理用药、药品费用不合理增长及医保药品目录的遴选提供决策依据。方法：基于医疗卫生体系角度,构建决策树模型及Markov模型,比较泊沙康唑和伊曲康唑用于预防侵袭性真菌病的短期和长期的经济性;短期健康产出为侵袭性真菌病的发生率,长期健康产出为患者所获得的生命年和质量调整生命年,成本数据来源于2019年中国真实医疗环境价格及文献研究。进行敏感性分析以验证基础分析结果的稳健性。结果：与伊曲康唑相比,泊沙康唑在短期模拟的100 d成本更高（10 992元vs. 8 038元）,但预防效果更好（侵袭性真菌病发生率4.6%vs. 11.1%）。在长期的患者全生命周期模拟中获得的生命年和质量调整生命年更多（2.949 LYs vs. 2.719 LYs,2.096 QALYs vs. 1.932 QALYs）,其增量成本-效果比为18 030元/QALY,远低于2019年中国社会意愿支付阈值（212 676元/QALY）。敏感性分析结果与基础分析结果一致。结论：在中国,泊沙康唑相比伊曲康唑用于预防骨髓增生异常综合征/急性髓系白血病患者发生侵袭性真菌病的经济性更好。     

地西他滨治疗骨髓增生异常综合征和急性髓细胞白血病临床观察

目的探讨地西他滨治疗骨髓增生异常综合征（MDS）和急性髓细胞白血病（AML）的临床疗效和安全性。方法收集2011年1月至2013年7月接受地西他滨[15mg／（m2·d）,第1—5天,静脉滴注持续1h以上1单药或联合CAGf阿糖胞苷（Ara-C）、阿克拉霉素（Acla）、粒细胞集落刺激因子（G-CSF）]方案治疗的20例MDS和AML患者的临床资料,评价其疗效和不良反应。结果20例患者中完全缓解（CR）4例,部分缓解（PR）8例,稳定（SD）及进展（PD）8例,总有效率为60．0％（12／20）。其中12例AML患者中CR2例,PR5例,总有效率为58.3％（7／12）,8例MDS患者中CR2例,PR3例,总有效率为62．5％（5／8）。1例MDS．难治性贫血伴环状铁粒幼细胞患者和2例慢性粒一单核细胞性白血病患者输血依赖情况有所改善。14例患者出现Ⅲ－Ⅳ度骨髓受抑,发生率为70．O％（14／20）。总感染率为35．0％（7,20）,其中肺部感染率为20．0％（4／20）,患者经积极抗感染、刺激造血及输血等支持治疗后感染控制。1例患者出现化疗相关死亡。20例患者均未出现严重肝功能损害及出血。结论地西他滨单药或联合CAG方案治疗MDS和AML有一定疗效,可廷缓疾病进展;患者对化疗不良反应均能耐受．且化疗相关病死率低。     

Itraconazole vs. posaconazole for antifungal prophylaxis in patients with acute myeloid leukemia undergoing intensive chemotherapy: A retrospective study

ObjectiveThe objective of this study was to compare itraconazole with posaconazole for antifungal prophylaxis in acute myeloid leukemia (AML) patients undergoing intensive chemotherapy.MethodsAdult patients with AML received either itraconazole or posaconazole for antifungal prophylaxis while undergoing intensive chemotherapy. The primary endpoint was incidence of prophylaxis failure (change in antifungal agent due to suspected invasive fungal infection [IFI], drug intolerance, drug interaction, or adverse event).ResultsFrom February 2016 to January 2018, 90 patients were included in the itraconazole group and 45 patients in the posaconazole group. Prophylaxis failure occurred in 88% of itraconazole recipients compared with 33% of posaconazole recipients (P<0.001). The primary reason for prophylaxis failure with itraconazole was suspected IFI (58%) whereas for posaconazole, failure predominantly related to drug interaction (60%). An antifungal regimen was continued upon discharge in 47% of itraconazole recipients compared with 9% of posaconazole recipients (P<0.001). The use of breakthrough IFI diagnostic tests was not significantly different in the two groups. A larger proportion of drug concentrations were collected in the posaconazole group.ConclusionsIn AML patients undergoing intensive chemotherapy, posaconazole was associated with significantly lower rates of prophylaxis failure and less need for continued antifungal therapy on discharge compared with itraconazole.     

骨髓增生异常综合征转变急性白血病的临床分析

目的：研究骨髓增生异常综合征（MDS）转变post MDS-AL临床表现及联合化疗成效。方法：运用WHO标准开展成效回顾。结果：62例患者中12例转为急性白血病（AL）,主要属于AML,中位转白期限12个月,联合化疗总体有效率为（OR）67%。结论：MDS高危向AL转化,post MDS-AL治疗难度极大,预后成效不佳。     

Pharmacokinetics of baclofen in spastic patients receiving multiple oral doses

The pharmacokinetics of racemic baclofen as determined from plasma and urine data in six spastic patients treated with individualized oral doses, 30–80 mg daily, are presented. Peak plasma concentrations were achieved 1.9 h (±0.7) after a dose. The fluctuation in the plasma concentration was great, ranging from 188 to 439%. The total body clearance averaged 175 ml·min^–1 (±44), plasma protein binding 35% (±6). Baclofen was for the greater part excreted unchanged by the kidney, 65% (±16). Its apparent renal clearance equalled the creatinine clearance. The contribution of the renal clearance to the total body clearance can explain the previously described toxicity when renal impairment is present. The results agree with earlier reports on single doses in healthy subjects.     

New treatment for acute myelogenous leukemia

Introduction: Acute myelogenous leukemia (AML) is a genetically heterogeneous disease. Yet current therapy has changed little over the decades and includes the nucleoside analog cytarabine in combination with an anthracycline as primary therapy. With this approach, durable cures occur in the minority of patients. With the recent improved scientific understanding of the underlying genetic and epigenetic aberrations in AML, there is now the potential of individualized and targeted therapeutic approaches for the curative treatment of AML.

Areas covered: The focus of this article is to review the therapeutic potential of many of the novel agents currently under investigation in the treatment of acute myeloid leukemia. The results of pivotal Phase III studies, as well as ongoing Phase II and III studies and selected Phase I studies with impact on the field of AML therapy will be discussed.

Expert opinion: Advances in the scientific knowledge of the various genetic and epigenetic alterations in AML, in conjunction with more effective, rationally designed and/or novel targeted therapeutics, offers a real hope and expectation of improved AML outcomes in the future.     

地西他滨联合预激方案治疗急性髓系白血病的临床研究

目的 研究地西他滨联合预激方案治疗急性髓系白血病的临床疗效.方法 选取本院2013年1月至2016年1月38例急性髓系白血病患者为研究对象,将纳入患者抽签随机分为观察组和对照组,每组19例.观察组采用地西他滨联合预激方案,对照组采用单纯预激方案,比较两组的临床疗效与不良反应情况.结果 观察组的治疗总有效率显著高于对照组(73.7％比42.1％,P＜0.05).观察组的恶心呕吐、腹泻、脱发、肝功能损伤、肺部感染、血尿、心功能不足发生率分别为26.3％、15.8％、36.8％、15.8％、31.6％、5.3％、10.5％,与对照组(15.8％、10.5％、26.3％、10.5％、10.5％、0.0％、5.3％)比较差异无统计学意义(P＞0.05).结论 地西他滨联合预激方案治疗急性髓系白血病具有较高的缓解率,同时不会增加过多不良反应,患者耐受性较好,是一种较理想的治疗方案.     

凋亡抑制基因在急性白血病及骨髓增生异常综合征中的研究

目的探讨急性白血病及骨髓增生异常综合征患者骨髓凋亡抑制基因MCL-1、livin、aven的表达及临床意义。方法选取2012年9月~2013年12月本院收治的113例初发急性白血病患者,32例骨髓增生异常综合征患者及20例对照组患者（缺铁性贫血12例、血小板减少性紫癜8例）的新鲜骨髓液标本,采用RT-PCR方法检测MCL-1、livin、aven基因mRNA的表达水平及表达率。结果 AL组和MDS组MCL-1、livin、aven mRNA表达水平及阳性表达率分别高于对照组,差异有统计学意义（P〈0.05）。MCL-1与livin基因mRNA的表达呈正相关（r=0.586,P〈0.05）,MCL-1与aven基因的表达呈正相关（r=0.603,P〈0.05）,liven基因与aven基因表达无相关性（r=0,P〉0.05）。结论 3种凋亡抑制基因MCL-1、livin、aven基因mRNA在急性白血病及骨髓增生异常综合征中表达均增高。     

Outcomes in patients treated with gemtuzumab ozogamicin for relapsed acute myelogenous leukemia.

The outcomes of treatment with gemtuzumab ozogamicin compared with those of conventional chemotherapy for relapse of acute myelogenous leukemia (AML) were studied. The gemtuzumab ozogamicin group consisted of 104 patients treated in 15 U.S. and 25 European centers for first relapse of AML between May 1997 and December 1998. Conventional chemotherapy recipients consisted of 22 historical control patients who received treatment for their first occurrence of AML at a Boston teaching hospital between January 1991 and December 1994 and who subsequently underwent conventional inpatient reinduction chemotherapy for relapse. Patients in the gemtuzumab ozogamicin group received a two-hour i.v. infusion of 9 mg/m2 for up to three doses with at least two weeks between doses, while the historical controls received conventional chemotherapy, usually consisting of continuous-infusion cytarabine (days 1-7) plus mitoxantrone. Outcomes evaluated included differences in survival and hospitalization (occurrence and duration) for up to six weeks. Both stratified and multivariate regression methods were used in making comparisons. Adjusting for baseline differences, six-week survival rates were similar in the two groups (95% for the historical control group versus 89% for the gemtuzumab ozogamicin group). However, gemtuzumab ozogamicin recipients had significantly fewer total hospital days (adjusted mean, 19 days, versus 35 days), which was consistent with the higher prevalence of outpatient chemotherapy in this group (43% versus 0% among the historical controls). The difference in the number of hospital days was consistent across various baseline and demographic factors. Gemtuzumab ozogamicin appeared to be associated with equivalent survival and fewer total days of hospitalization than conventional chemotherapy in adults with relapsed AML.     

程序化预见性护理干预在急性白血病化疗后口腔感染中的临床价值

目的 探讨程序化预见性护理干预在急性白血病化疗后口腔感染中的临床价值.方法 选择我院收治的110例急性白血病患者为研究对象.随机分为对照组和观察组各55例.对照组化疗期间实施常规护理.观察组在对照组的基础上,采取程序化预见性护理干预,包括化疗前全面评估口腔黏膜状况,结合口腔pH值制定个性化漱口方案;化疗期间个体化健康指导;保持病室整洁,加强环境保护;均衡营养支持和全程心理支持.化疗后第3、5、10、15天采集患者口腔、硬颚、舌面舌下唾液分泌物进行涂片检查,并监测pH值.同时于化疗后第3周统计两组患者口腔感染的发生率及感染程度.应用自制的《患者满意度调查表》评价护理满意度.结果 观察组在化疗后第3、5、10、15天口腔、硬颚、舌面舌下唾液分泌物pH值均高于对照组(P＜0.05),观察组患者口腔内环境酸碱度更接近弱碱性,更有利于破坏真菌感染环境,预防口腔感染方面更具优势.化疗后第3周,观察组感染发生率明显低于对照组(P＜0.05).观察组护理总满意率明显高于对照组(P＜0.05).结论 在满足患者基本生理需要的基础上,科学实施程序化全方位预见性口腔护理,能有效降低急性白血病化疗后口腔感染的程度及全身感染率,改进患者生活质量,提高化疗依从性及护理满意度,促进病情的转归,临床价值较高,值得进一步推广.     

Pharmacokinetics of eribulin mesylate in patients with solid tumours receiving repeated oral rifampicin

Aim

Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that was recently approved for treatment of metastatic breast cancer. The aim of this study was to determine the effect of rifampicin, a CYP3A4 inducer, on the plasma pharmacokinetics of eribulin in patients with solid tumours.

Methods

An open-label, non-randomized phase I study was carried out. Patients received intravenous 1.4 mg m⁻² eribulin mesylate on days 1 and 15 and oral rifampicin 600 mg on days 9 to 20 of a 28 day cycle. Pharmacokinetic sampling for determination of eribulin plasma concentrations was performed up to 144 h following administration. AUC(0,∞) and C_max for eribulin exposure without or with co-administration of rifampicin were subjected to an analysis of variance (anova) and corresponding 90% confidence intervals (CI) were calculated. Subsequently, patients were allowed to continue eribulin mesylate treatment with 1.4 mg m⁻² eribulin mesylate on days 1 and 8 of a 21 day cycle. Also the adverse event profile and anti-tumour activity were assessed.

Results

Fourteen patients were included and 11 patients were evaluable for pharmacokinetic analysis. Co-administration of rifampicin had no effect on single dose exposure to eribulin (geometric least square means ratio: AUC(0,∞) = 1.10, 90% CI 0.91, 1.34 and C_max = 0.97, 90% 0.81, 1.17). The most common treatment-related grade ≥3 adverse events were grade 3 neutropenia (4/14, 29%), leucopenia and fatigue (both 3/14, 21%).

Conclusions

These results indicate that eribulin mesylate may be safely co-administered with compounds that are CYP3A4 inducers.     

地西他滨联合化疗治疗骨髓增生异常综合征转化白血病的临床研究

目的 探讨地西他滨联合化疗治疗骨髓增生异常综合征转化白血病的疗效.方法 将本院2013年1月至2014年1月间骨髓增生异常综合征转化白血病患者68例,随机将其分成研究组与对照组,每组34例.对照组采取常规化疗治疗,研究组采取地西他滨联合化疗,分析比较两组患者的疗效及对患者生存时间的影响.结果 研究组治疗总控制率、不良反应率、治疗后的6个月、1年、2年生存及满意度等指标均明显优于对照组患者,两组各项指标之间比较差异有统计学意义(P＜0.05).结论 在骨髓增生异常综合征转化白血病治疗中地西他滨联合化疗方案临床疗效较好,且毒副反应小,患者耐受性好,可提高生存率,建议临床推广应用.     

Pharmacokinetics of liposomal amphotericin B in neutropenic cancer patients

This study was conducted to characterise the pharmacokinetics of a liposomal pharmaceutical product of amphotericin B (LAB) in three neutropenic cancer patients complicated by suspected fungal infections. LAB was administered at a constant dose of 50 mg/day over 1--6 h by intravenous infusion, and blood samples were obtained between two infusion intervals without complicating the systemic therapy of the patients. Quantitative analysis of amphotericin B (AB) in plasma was established by a validated reversed-phase high-performance liquid chromatographic (HPLC) assay. Model independent pharmacokinetic parameters were estimated using area and moment analysis. Administration of LAB to the first patient (day 1) diagnosed as malignant melanoma resulted in a mean maximum concentration (C(max)) of 679+/-6 ng/ml and a mean minimum concentration (C(min)) of 139+/-9 ng/ml of AB. Pre-dose, C(max) and C(min) values of AB, after multiple LAB dosing to the other two patients both having acute myeloblastic leukemia were found to be 440+/-6, 1140+/-10, 409+/-11 ng/ml (day 19) and 408+/-3, 1180+/-10, and 283+/-1 ng/ml (day 9), respectively. The area under the plasma concentration-time curve (AUC) and the mean residence time (MRT) calculated between the two infusion intervals were 6180 ngh/ml, 7.79 h (day 1) for the first patient; 13,700 ng.h/ml, 10.5 h (day 19) and 14,000 ng.h/ml, 9.93 h (day 9) for the other two patients, respectively. The pharmacokinetic profiles and non-compartmental parameters calculated were comparable for both patients diagnosed with acute myeloblastic leukemia after multiple dosing at steady state, which also demonstrated a twofold increase in their AUC values compared with the AUC of the first patient. Although C(min) values supported the assumption that there was AB accumulation in plasma and this accumulation could be increased at high doses, LAB was administered safely to these patients and well tolerated at the doses given.     

Amifostine: an update on its clinical status as a cytoprotectant in patients with cancer receiving chemotherapy or radiotherapy and its potential therapeutic application in myelodysplastic syndrome

Amifostine (WR-2721) is a cytoprotective agent that protects a broad range of normal tissues from the toxic effects of chemotherapy and radiotherapy without attenuating tumour response. This selective protection is due to the greater conversion and uptake of the active metabolite, WR- 1065, in normal versus neoplastic tissues. In a pivotal phase III trial, 242 patients with advanced ovarian cancer were randomised to receive treatment with cisplatin 100 mg/m2 and cyclophosphamide 1000 mg/m2 every 3 weeks with or without pretreatment with intravenous amifostine 910 mg/m2. Over 6 cycles of therapy, amifostine significantly reduced haematological, renal and neurological toxicities: treatment delays, treatment discontinuation and days in hospital related to these adverse events were also significantly reduced in patients receiving amifostine versus patients receiving chemotherapy alone. In another randomised phase III trial in 303 patients with head and neck cancer undergoing irradiation therapy (total dose 50 to 70Gy), pretreatment with intravenous amifostine 200 mg/m2 significantly reduced the incidence of acute and late grade > or =2 xerostomia. However, mucositis was not significantly reduced in amifostine recipients compared with patients receiving radiotherapy alone, although this has been shown in smaller randomised trials. Amifostine (340 mg/m2) also provided significant protection against pneumonitis and oesophagitis in patients with lung cancer receiving thoracic irradiation in a preliminary report from a phase III trial (n = 144). Other studies have demonstrated protective effects of amifostine in other tumour types and other chemotherapy, radiation and radiochemotherapy regimens; however, evidence is still limited in these indications. No evidence of tumour protection by amifostine has been demonstrated in any clinical trials. Amifostine has also been shown to stimulate haematopoietic stem cells and has been investigated as a therapy for patients with myelodysplastic syndrome in number of small preliminary studies. At the recommended dose and schedule, amifostine is generally well tolerated. Adverse effects are usually reversible and manageable and those most frequently experienced include nausea and vomiting, transient hypotension and somnolence and sneezing. CONCLUSION: The results of phase III trials have confirmed the safety and efficacy of amifostine as a cytoprotectant to ameliorate cisplatin-induced cumulative renal toxicity, for which it is the only agent proven to be effective, and neutropenia in patients with advanced ovarian cancer, and to reduce xerostomia in patients with head and neck cancer receiving irradiation therapy. Depending on the outcome of numerous ongoing clinical trials, amifostine may eventually find broader clinical applications, both as a cytoprotectant and as a potential therapy in myelodysplastic syndrome.