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Busulfan Pharmacokinetics and Precision Dosing: Are Patients with Fanconi Anemia Different?
Biology of Blood and Marrow Transplantation ( IF 5.609 ) Pub Date : 2019-07-18 , DOI: 10.1016/j.bbmt.2019.07.014
Parinda A Mehta 1 , Chie Emoto 2 , Tsuyoshi Fukuda 2 , Brian Seyboth 3 , Ashley Teusink-Cross 1 , Stella M Davies 1 , Jamie Wilhelm 1 , Kirsten Fuller 3 , Alexander A Vinks 2 , Farid Boulad 3
Affiliation  

It is well known that pharmacokinetics (PK)-guided busulfan (BU) dosing increases engraftment rates and lowers hepatotoxicity in patients undergoing hematopoietic cell transplantation (HCT). However, there are no published PK data in patients with Fanconi anemia (FA), who are known to have baseline DNA repair defect and related inherent sensitivity to chemotherapy. In our prospective, multi-institutional study of alternative donor HCT for FA using chemotherapy-only conditioning, we replaced the single dose of total-body irradiation with BU at initial doses of 0.8 to 1.0 mg/kg and 0.6 to 0.8 mg/kg given i.v. every 12 hours for 4 doses. Patients received the first dose of i.v. busulfan on day -8, and blood levels for PK were obtained. PK samples were drawn following completion of infusion. BU PK levels were collected at 2 hours, 2 hours and 15 minutes, and 4, 5, 6, and 8 hours from the start of infusion. The remaining 3 doses of BU were given on days -7 and -6. Thirty-seven patients with available BU PK data with a median age of 9.2 years (range, 4.3 to 44 years) are included in the final analyses. The overall BU PK profile in patients with FA is similar to non-FA patients after considering their body weight. In our cohort, a strong correlation between BU clearance and weight supports current practice of per kilogram dosing. However, not surprisingly, we show that the disease (ie, host) sensitivity related to FA is the main determinant of total dose of BU that can be safely administered to patients in this high-risk population. On the basis of our results, we propose an optimal BU concentration at steady-state level of ≤350 ng/mL (equivalent to total cumulative exposure of 16.4 mg*h/L for 4 doses over 2 days) for patients with FA undergoing HCT. To our knowledge, this is the first and largest report of prospective BU PK in patients with FA undergoing HCT, providing an optimal BU target cutoff to achieve stable donor engraftment while avoiding excessive toxicity.

中文翻译:

白消安的药代动力学和精确剂量:范可尼贫血患者是否有所不同?

众所周知,在进行造血细胞移植(HCT)的患者中,药代动力学(PK)引导的白消安(BU)剂量可提高植入率,并降低肝毒性。但是,尚无公开的Fanconi贫血(FA)患者的PK数据,这些患者已知具有基线DNA修复缺陷和对化疗的相关固有敏感性。在我们仅采用化学疗法的替代供体HCT替代FA的供体HCT的前瞻性,多机构研究中,我们用BU代替了单剂量全身照射,初始剂量为0.8至1.0 mg / kg和0.6至0.8 mg / kg, iv每12小时服用4剂。患者在第-8天接受了第一剂静脉注射白消安,并获得了PK的血液水平。输注完成后抽取PK样品。2小时后收集BU PK水平,从输液开始算起2小时15分钟,以及4、5、6和8小时。在第-7天和第-6天给予其余3剂BU。在最终分析中纳入了37名具有可用BU PK数据且中位年龄为9.2岁(范围为4.3至44岁)的患者。考虑到患者的体重,FA患者的总体BU PK曲线与非FA患者相似。在我们的队列中,BU清除率与体重之间的密切相关性支持了目前的每千克剂量实践。然而,毫不奇怪,我们表明,与FA相关的疾病(即宿主)敏感性是可以安全地向该高危人群患者给药的BU总剂量的主要决定因素。根据我们的结果,我们建议接受HCT的FA患者在稳态水平下的最佳BU浓度为≤350ng / mL(相当于2天4剂的总累积暴露量16.4 mg * h / L)。据我们所知,这是接受HCT的FA患者前瞻性BU PK的第一个也是最大的报道,它提供了最佳的BU目标截止值,以实现稳定的供体植入,同时避免了过度的毒性。
更新日期:2019-07-18
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