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/m2 (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/m2 (ranging from 9.4-153 mL/min/m2), 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.