He Zeyuan, Wang Ying, Zhu Hua, Chen Yuqing, Ye Chen, Ou Jiebin, Junyan Wu, Yu Xiaoxia
Department of Pharmacy, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Pediatr Blood Cancer. 2025 Aug 8:e31969. doi: 10.1002/pbc.31969.
The European Society for Blood and Marrow Transplantation (EBMT) recommends a busulfan target cumulative area under the curve (cAUC) of 78-101 mg·h/L for hematopoietic stem cell transplantation (HSCT). Currently, no population pharmacokinetic (PopPK)-optimized four-times-daily (Q6H) regimen reliably achieves this range. We developed a PopPK-guided dosing protocol to address this gap.
Clinical and demographic data from pediatric HSCT recipients receiving busulfan were retrospectively analyzed to develop a PopPK model. Bayesian estimation identified the optimal busulfan dose (0.50-1.25 mg/kg/dose) for target attainment in pediatric patients (age 0.5-18 years; weight 5-80 kg). Finally, the proposed dosing strategy was validated using an independent retrospective cohort.
The PopPK model was developed using data from 65 pediatric patients. Age and bodyweight were identified as significant covariates. Optimized dosing recommendations for the Q6H × 4 days busulfan regimen were established through Bayesian estimation. For validation, two cohorts were retrospectively analyzed: (i) weight-based dosing (n = 19), and (ii) model-informed dosing (n = 15). The groups demonstrated comparable distributions in both age (p = 0.78) and weight (p = 0.63). Notably, the model-informed group achieved significantly higher cAUC values (mean difference, 18.0 mg·h/L; 95% confidence interval: 9.83-26.1 mg·h/L; p < 0.001), with 67% of these patients reaching the target exposure range.
We developed a Q6H × 4 days busulfan dosing regimen through PopPK modeling. For a representative 6-year-old patient with a bodyweight of 20 kg, the recommended dose is 1.25 mg/kg/dose. Therapeutic drug monitoring following the initial dose remains clinically essential.
欧洲血液和骨髓移植学会（EBMT）建议造血干细胞移植（HSCT）时白消安的目标曲线下累积面积（cAUC）为78 - 101mg·h/L。目前，尚无经过群体药代动力学（PopPK）优化的每日四次（Q6H）给药方案能可靠地达到该范围。我们制定了一项PopPK指导的给药方案来填补这一空白。
对接受白消安治疗的儿科HSCT受者的临床和人口统计学数据进行回顾性分析，以建立PopPK模型。贝叶斯估计确定了儿科患者（年龄0.5 - 18岁；体重5 - 80kg）达到目标时的最佳白消安剂量（0.50 - 1.25mg/kg/剂量）。最后，使用独立的回顾性队列对所提出的给药策略进行验证。
PopPK模型是利用65名儿科患者的数据建立的。年龄和体重被确定为显著的协变量。通过贝叶斯估计确定了Q6H×4天白消安给药方案的优化给药建议。为进行验证，对两个队列进行了回顾性分析：（i）基于体重给药（n = 19），以及（ii）模型指导给药（n = 15）。两组在年龄（p = 0.78）和体重（p = 0.63）方面分布相当。值得注意的是，模型指导组的cAUC值显著更高（平均差异为18.0mg·h/L；95%置信区间：9.83 - 26.1mg·h/L；p < 0.001），其中67%的患者达到了目标暴露范围。
我们通过PopPK建模制定了Q6H×4天白消安给药方案。对于一名体重20kg的代表性6岁患者，推荐剂量为1.25mg/kg/剂量。首次给药后进行治疗药物监测在临床上仍然至关重要。
