van der Stoep M Y Eileen C, Bertaina Alice, Ten Brink Marloes H, Bredius Robbert G, Smiers Frans J, Wanders Dominique C M, Moes Dirk Jan A R, Locatelli Franco, Guchelaar Henk-Jan, Zwaveling Juliëtte, Lankester Arjan C
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, the Netherlands.
Department of Paediatric Haematology and Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Bambino Gesù Children's Hospital, Rome, University of Pavia, Pavia, Italy.
Br J Haematol. 2017 Dec;179(5):772-780. doi: 10.1111/bjh.14960. Epub 2017 Oct 19.
Treosulfan-based conditioning is increasingly employed in paediatric haematopoietic stem cell transplantation (HSCT). Data on treosulfan pharmacokinetics in children are scarce, and the relationship between treosulfan exposure, toxicity and clinical outcome is unresolved. In this multicentre prospective observational study, we studied treosulfan pharmacokinetics and the drug's relationship with regimen-related toxicity and early clinical outcome in 77 paediatric patients. Treosulfan dose was 30 g/m , administered over 3 consecutive days in infants <1 year old (n = 12) and 42 g/m in children ≥1 year old (n = 65). Mean day 1 treosulfan exposure was 1744 ± 795 mgh/l (10 g/m ) and 1561 ± 511 mg*h/l (14 g/m ), with an inter-individual variability of 56 and 33% in the respective groups. High treosulfan exposure (>1650 mgh/l) was associated with an increased risk of mucosal [Odds ratio (OR) 4·40; 95% confidence interval (CI) 1·19-16·28, P = 0·026] and skin toxicity (OR 4·51; 95% CI 1·07-18·93, P = 0·040). No correlation was found between treosulfan exposure and the early clinical outcome parameters: engraftment, acute graft-versus-host disease and donor chimerism. Our study provides the first evidence in a large cohort of paediatric patients of high variability in treosulfan pharmacokinetics and an association between treosulfan exposure and early toxicity. Ongoing studies will reveal whether treosulfan exposure is related to long-term disease-specific outcome and late treatment-related toxicity.
基于曲奥舒凡的预处理方案在儿科造血干细胞移植（HSCT）中应用越来越广泛。关于儿童曲奥舒凡药代动力学的数据稀缺，曲奥舒凡暴露量、毒性与临床结局之间的关系尚未明确。在这项多中心前瞻性观察研究中，我们研究了77例儿科患者的曲奥舒凡药代动力学及其与方案相关毒性和早期临床结局的关系。曲奥舒凡剂量在<1岁婴儿（n = 12）中为30 g/m²，连续3天给药；≥1岁儿童（n = 65）中为42 g/m²。第1天曲奥舒凡平均暴露量在各年龄组分别为1744±795 mg·h/l（10 g/m²）和1561±511 mg·h/l（14 g/m²），个体间变异性分别为56%和33%。高曲奥舒凡暴露（>1650 mg·h/l）与黏膜毒性风险增加相关[比值比（OR）4.40；95%置信区间（CI）1.19 - 16.28，P = 0.026]和皮肤毒性（OR 4.51；95% CI 1.07 - 18.93，P = 0.040）。未发现曲奥舒凡暴露与早期临床结局参数（植入、急性移植物抗宿主病和供体嵌合率）之间存在相关性。我们的研究首次在一大群儿科患者中证明了曲奥舒凡药代动力学具有高度变异性，以及曲奥舒凡暴露与早期毒性之间存在关联。正在进行的研究将揭示曲奥舒凡暴露是否与长期疾病特异性结局和晚期治疗相关毒性有关。
