Krischke Miriam, Hempel Georg, Völler Swantje, André Nicolas, D'Incalci Maurizio, Bisogno Gianni, Köpcke Wolfgang, Borowski Matthias, Herold Ralf, Boddy Alan V, Boos Joachim
Pediatric Hematology and Oncology, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149, Münster, Germany.
Zentrum für Klinische Studien (ZKS), University Hospital Münster, Von-Esmarch-Straße 62, 48149, Münster, Germany.
Cancer Chemother Pharmacol. 2016 Dec;78(6):1175-1184. doi: 10.1007/s00280-016-3174-8. Epub 2016 Oct 21.
Doxorubicin is a key component in many pediatric oncology treatment regimens; still pharmacology data on which current dosing regimens are based are very limited.
We conducted a multinational pharmacokinetic study investigating age dependency of doxorubicin metabolism and elimination in children with cancer. One hundred and one patients treated with doxorubicin according to a cancer-specific national or European therapeutic trial were recruited. Doses of doxorubicin ranged from 10.4 to 57.7 mg/m. Blood samples for measurement of doxorubicin and its metabolite doxorubicinol were collected after two administrations, with five samples collected in children <3 years and eight in children ≥3 years. A population pharmacokinetic approach was used for analysis, including pharmacogenetic covariates. Natriuretic peptides and cardiac troponins were measured to evaluate their role as early indicators of cardiotoxicity.
Age dependence of doxorubicin clearance was demonstrated, with children less than 3 years having a statistically significant lower clearance (21.1 ± 5.8 l/h/m) than older children (26.6 ± 6.7 l/h/m) (p = 0.0004) after correcting for body surface area. No effect of the investigated genetic polymorphisms on the pharmacokinetics could be observed. Although natriuretic peptides were transiently elevated after each doxorubicin administration and troponin levels increased with increasing doxorubicin exposure, only limited correlation could be observed between their blood levels and doxorubicin pharmacokinetics.
In the European framework of funding and regulatory support, an add-on study to existing therapeutic trials was developed. The pediatric need concerning missing PK data could be addressed with limited burden for the patients. Empirically used dose adaptations for infants were generally found to be justified based on our PK analyses.
多柔比星是许多儿科肿瘤治疗方案中的关键成分；然而，目前给药方案所依据的药理学数据非常有限。
我们开展了一项多国药代动力学研究，调查癌症患儿多柔比星代谢和消除的年龄依赖性。招募了101例根据特定癌症的国家或欧洲治疗试验接受多柔比星治疗的患者。多柔比星剂量范围为10.4至57.7mg/m²。在两次给药后采集血样以测定多柔比星及其代谢物多柔比星醇，3岁以下儿童采集5份样本，3岁及以上儿童采集8份样本。采用群体药代动力学方法进行分析，包括药物遗传学协变量。测量利钠肽和心肌肌钙蛋白以评估它们作为心脏毒性早期指标的作用。
多柔比星清除率呈现年龄依赖性，在校正体表面积后，3岁以下儿童的清除率（21.1±5.8l/h/m²）显著低于大龄儿童（26.6±6.7l/h/m²）（p=0.0004）。未观察到所研究的基因多态性对药代动力学有影响。尽管每次多柔比星给药后利钠肽短暂升高，且肌钙蛋白水平随多柔比星暴露增加而升高，但它们的血药水平与多柔比星药代动力学之间仅观察到有限的相关性。
在欧洲的资助和监管支持框架下，开展了一项对现有治疗试验的附加研究。可以在给患者带来有限负担的情况下解决儿科对缺失药代动力学数据的需求。根据我们的药代动力学分析，通常发现经验性用于婴儿的剂量调整是合理的。
