Treosulfan is given off‐label in pediatric allogeneic hematopoietic stem cell transplant. This study investigated treosulfan's pharmacokinetics (PKs), efficacy, and safety in a prospective trial. Pediatric patients (n  = 87) receiving treosulfan‐fludarabine conditioning were followed for at least 1 year posttransplant. PKs were described with a two‐compartment model. During follow‐up, 11 of 87 patients died and 12 of 87 patients had low engraftment (≤ 20% myeloid chimerism). For each increase in treosulfan area under the curve from zero to infinity (AUC_(0‐∞)) of 1,000 mg hour/L the hazard ratio (95% confidence interval) for mortality increase was 1.46 (1.23–1.74), and the hazard ratio for low engraftment was 0.61 (0.36–1.04). A cumulative AUC_(0‐∞) of 4,800 mg hour/L maximized the probability of success (> 20% engraftment and no mortality) at 82%. Probability of success with AUC_(0‐∞) between 80% and 125% of this target were 78% and 79%. Measuring PK at the first dose and individualizing the third dose may be required in nonmalignant disease.

中文翻译：

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拟议中降低毒性小儿同种异体造血干细胞移植治疗中硫丹的治疗范围：一项前瞻性试验的结果。

小儿同种异体造血干细胞移植中不推荐使用硫丹。这项研究在一项前瞻性试验中研究了硫代硫丹的药代动力学（PKs），疗效和安全性。小儿患者（n  = 87）接受了硫丹-氟达拉滨的调理，在移植后至少随访了1年。PK用两室模型描述。在随访期间，87例患者中有11例死亡，87例患者中有12例植入率低（≤20％髓样嵌合）。在从零到无穷大（AUC _（0-∞））曲线下，每增加1000 mg·h / L的硫磺面积，死亡率增加的危险比（95％置信区间）为1.46（1.23-1.74），低植入的比例为0.61（0.36-1.04）。累积AUC _{（0‐∞）}4,800 mg hour / L的最大剂量成功率（> 20％植入，无死亡率）达到82％。在该目标的80％至125％之间进行AUC _（0-∞）成功的可能性分别为78％和79％。在非恶性疾病中可能需要以第一剂量测量PK并个体化第三剂量。