Pharmacokinetic and maximum tolerated dose study of micafungin in combination with fluconazole versus fluconazole alone for prophylaxis of fungal infections in adult patients undergoing a bone marrow or peripheral stem cell transplant
Pharmacokinetic and maximum tolerated dose study of micafungin in combination with fluconazole versus fluconazole alone for prophylaxis of fungal infections in adult patients undergoing a bone marrow or peripheral stem cell transplant
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DOI：
10.1128/aac.49.4.1331-1336.2005
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发表时间：
2005-04-01
影响因子：
4.9
通讯作者：
Buell, D
中科院分区：
文献类型：
--
作者：
Hiemenz, J;Cagnoni, P;Buell, D
在这项剂量递增研究中，74 名接受骨髓或外周血干细胞移植的成年癌症患者接受氟康唑（400 毫克/天）和生理盐水（对照）（12 名受试者）或米卡芬净（12.5 至 200 毫克/天）（62 名受试者）治疗，疗程长达 4 周。根据西南肿瘤学组制定的 3 级毒性标准，未达到米卡芬净的最大耐受剂量 (MTD)；与药物相关的毒性很少见。与米卡芬净相关的常见不良事件包括头痛（6.8%）、关节痛（6.8%）、低磷血症（4.1%）、失眠（4.1%）、斑丘疹（4.1%）和皮疹（4.1%）。第 1 天和第 7 天米卡芬净的药代动力学特征相似。平均半衰期约为 13 小时，重复或增加剂量后几乎没有变化。 0至24小时内血清中药物的平均最大浓度和浓度-时间曲线下的面积大致与剂量成正比。没有米卡芬净和氟康唑之间相互作用的临床或动力学证据。对照组 12 名患者中的 5 名 (42%) 和米卡芬净加氟康唑组 62 名患者中的 14 名 (23%) 在治疗期间疑似真菌感染，导致接受两性霉素 B 经验性治疗。发现米卡芬净和氟康唑联合用药对于这一高危患者群体是安全的。即使剂量高达 200 mg/天，持续 4 周，米卡芬净的 MTD 也未达到。接受血液或骨髓移植的成年癌症患者中米卡芬净的药代动力学特征与健康志愿者的药代动力学特征一致，并且曲线下面积与剂量成正比。
In this dose escalation study, 74 adult cancer patients undergoing bone marrow or peripheral blood stem cell transplantation received fluconazole (400 mg/day) and either normal saline (control) (12 subjects) or micafungin (12.5 to 200 mg/day) (62 subjects) for up to 4 weeks. The maximum tolerated dose (MTD) of micafungin was not reached, based on the development of Southwest Oncology Group criteria for grade 3 toxicity; drug-related toxicities were rare. Commonly occurring adverse events considered related to micafungin were headache (6.8%), arthralgia (6.8%), hypophosphatemia (4.1%), insomnia (4.1%), maculopapular rash (4.1%), and rash (4.1%). Pharmacokinetic profiles for micafungin on days I and 7 were similar. The mean half-life was approximately 13 h, with little variance after repeated or increasing doses. Mean maximum concentrations of the drug in scrum and areas under the concentration-time curve from 0 to 24 h were approximately proportional to dose. There was no clinical or kinetic evidence of interaction between micafungin and fluconazole. Five of 12 patients (42%) in the control group and 14 of 62 (23%) in the micafungin-plus-fluconazole groups had a suspected fungal infection during treatment which resulted in empirical treatment with amphotericin B. The combination of micafungin and fluconazole was found to be safe in this high-risk patient population. The MTD of micafungin was not reached even at doses up to 200 mg/day for 4 weeks. The pharmacokinetic profile of micafungin in adult cancer patients with blood or marrow transplants is consistent with the profile in healthy volunteers, and the area under the curve is proportional to dose.