Pharmacokinetics of carboplatin and etoposide in infant neuroblastoma patients

Carboplatin and etoposide are commonly used chemotherapeutics for the treatment of many paediatric cancers. However, there are very limited published data concerning the pharmacokinetics of these agents in infants and very young children, for whom dose reductions are frequently implemented.

Etoposide (5 mg/kg; 2 h i.v. infusion) was co-administered with carboplatin (6.6 mg/kg; 1 h i.v. infusion) on each of 3 days of treatment and samples were taken between 0.5 and 4 h after the start of administration, from a total of 19 neuroblastoma patients aged <1 year at diagnosis and weighing <12 kg at treatment. Pharmacokinetic analysis was carried out using a non-linear mixed effects modelling approach.

Two compartment structural models were selected for both carboplatin and etoposide analysis. Body weight (BW) was strongly associated with carboplatin clearance (Cl), with a slightly weaker relationship observed with etoposide Cl. Carboplatin Cl values ranged from 12.8 to 33.6 ml/min, with total AUC values of 4.2-9.3 mg/ml.min achieved over the 3 days of treatment. Cl values normalized to BW were significantly higher in patients <12 kg than in children >12 kg, with mean +/- SD values of 2.9 +/- 0.4 and 2.5 +/- 0.4 ml/min/kg, respectively (P < 0.05). Etoposide exhibited a median half-life of 4.6 h (range 4.1-6.6), a median AUC of 7.1 mg/ml.min (range 3.4-11.0) and a median Cl of 6.6 ml/min (range 3.2-13.0).

Results suggest that prediction of absolute carboplatin Cl values may be difficult in infant patients <12 kg, with a small but significant difference in Cl values normalized to BW observed in this patient group. Etoposide pharmacokinetic data support previous findings that question the utility of modified dosing in infants. The current study demonstrates the feasibility of generating informative pharmacokinetic data in infants and young children.