Schreib Katharina M, Bräm Dominic S, Zeilhofer Ulrike Barbara, Müller Daniel, Güngör Tayfun, Krämer Stefanie D, Hauri-Hohl Mathias M
Department of Stem Cell Transplantation, University Children's Hospital Zurich-Eleonore Foundation & Children's Research Center (CRC), University of Zurich, 8032 Zurich, Switzerland.
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
Pharmaceutics. 2023 Dec 20;16(1):0. doi: 10.3390/pharmaceutics16010013.
Reaching target exposure of busulfan-based conditioning prior to hematopoietic stem cell transplantation is vital for favorable therapy outcomes. Yet, a wide inter-patient and inter-occasion variability in busulfan exposure has been reported, especially in children. We aimed to identify factors associated with the variability of busulfan pharmacokinetics in 124 consecutive patients transplanted at the University Children's Hospital Zurich between October 2010 and February 2020. Clinical data and busulfan plasma levels after twice-daily intravenous administration were analyzed retrospectively by population pharmacokinetic modeling. The volume of distribution correlated with total body water. The elimination rate constant followed an age-dependent maturation function, as previously suggested, and correlated with the levels of serum albumin. Acute lymphoblastic leukemia reduced busulfan clearance by 20%. Clearance significantly decreased by 17% on average from the start to the third day of busulfan administration, in agreement with other studies. An average reduction of 31% was found in patients with hemophagocytic lymphohistiocytosis and X-linked lymphoproliferative disease. In conclusion, we demonstrate that in addition to known factors, underlying disease and serum albumin significantly impact busulfan pharmacokinetics in pediatric patients; yet, substantial unexplained variability in some patients remained. Thus, we consider repeated pharmacokinetic assessment essential to achieve the desired target exposure in twice-daily busulfan administration.
在造血干细胞移植前达到基于白消安的预处理方案的目标暴露量对于获得良好的治疗效果至关重要。然而，据报道，白消安暴露量在患者之间和不同给药时机存在很大差异，尤其是在儿童中。我们旨在确定2010年10月至2020年2月期间在苏黎世大学儿童医院接受移植的124例连续患者中与白消安药代动力学变异性相关的因素。通过群体药代动力学建模对每日两次静脉给药后的临床数据和白消安血浆水平进行回顾性分析。分布容积与总体水相关。消除速率常数如先前所示遵循年龄依赖性成熟函数，并与血清白蛋白水平相关。急性淋巴细胞白血病使白消安清除率降低20%。与其他研究一致，从白消安给药开始到第三天，清除率平均显著降低17%。在噬血细胞性淋巴组织细胞增生症和X连锁淋巴增殖性疾病患者中发现平均降低31%。总之，我们证明，除了已知因素外，基础疾病和血清白蛋白对儿科患者的白消安药代动力学有显著影响；然而，一些患者中仍存在大量无法解释的变异性。因此，我们认为重复进行药代动力学评估对于在每日两次白消安给药中实现所需的目标暴露量至关重要。
