Barnett Shelby, Errington Julie, Sludden Julieann, Jamieson David, Poinsignon Vianney, Paci Angelo, Veal Gareth J
Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Department of Pharmacology and Drug Analysis, Gustave Roussy Cancer Campus Grand Paris, Université Paris-Sud, 94805 Villejuif, France.
Pharmaceuticals (Basel). 2021 Mar 16;14(3):272. doi: 10.3390/ph14030272.
Infants and young children represent an important but much understudied childhood cancer patient population. The pharmacokinetics and pharmacogenetics of the widely used anticancer prodrug cyclophosphamide were investigated in children <2 years of age. Concentrations of cyclophosphamide and selected metabolites were determined in patients administered cyclophosphamide at doses ranging from 100-1500 mg/m (5-75 mg/kg), with various infusion times as determined by the standard treatment regimen that each patient was receiving. Polymorphisms in genes including CYP2B6 and CYP2C19 were investigated. Data generated for cyclophosphamide were analysed using a previously published population pharmacokinetic model. Cyclophosphamide pharmacokinetics was assessed in 111 samples obtained from 25 patients ranging from 4-23 months of age. The average cyclophosphamide clearance for the patients was 46.6 mL/min/m (ranging from 9.4-153 mL/min/m), with marked inter-patient variability observed (CV 41%). No significant differences in cyclophosphamide clearance or exposure (AUC) were observed between patient groups as separated by age or body weight. However, marked differences in drug clearance and metabolism were noted between the current data in children <2 years of age and recently published results from a comparable study conducted by our group in older children, which reported significantly lower cyclophosphamide clearance values and metabolite exposures using the same population pharmacokinetic model for analysis. Whilst this study demonstrates no significant differences in cyclophosphamide clearance in patients <2 years, it highlights large differences in dosing protocols across tumour types. Furthermore, the study suggests marked differences in cyclophosphamide clearance in children less than two years of age as compared to older patients.
婴幼儿是儿童癌症患者群体中的一个重要部分，但对其研究却非常不足。我们对2岁以下儿童广泛使用的抗癌前体药物环磷酰胺的药代动力学和药物遗传学进行了研究。在接受环磷酰胺治疗的患者中，测定了环磷酰胺及其选定代谢物的浓度，剂量范围为100 - 1500 mg/m²（5 - 75 mg/kg），输注时间根据每位患者接受的标准治疗方案而定。研究了包括CYP2B6和CYP2C19在内的基因多态性。使用先前发表的群体药代动力学模型对环磷酰胺生成的数据进行了分析。在25名年龄在4 - 23个月的患者中采集了111份样本，评估了环磷酰胺的药代动力学。患者的环磷酰胺平均清除率为46.6 mL/min/m²（范围为9.4 - 153 mL/min/m²），观察到患者间存在显著差异（变异系数41%）。按年龄或体重分组的患者组之间，环磷酰胺清除率或暴露量（AUC）未观察到显著差异。然而，在2岁以下儿童的当前数据与我们小组最近在年龄较大儿童中进行的一项类似研究的结果之间，注意到药物清除和代谢存在显著差异，后者使用相同的群体药代动力学模型进行分析，报告的环磷酰胺清除率值和代谢物暴露量明显较低。虽然这项研究表明2岁以下患者的环磷酰胺清除率没有显著差异，但它突出了不同肿瘤类型给药方案的巨大差异。此外，该研究表明，与年龄较大的患者相比，2岁以下儿童的环磷酰胺清除率存在显著差异。
