Investigating the pharmacokinetics and dosing of anticancer drugs in infants and young children.

Abstract

10033 Background: Dosing regimens for anticancer drugs administered to infants and young children frequently differ between tumour types and protocols, with dosing based on body weight commonly implicated. We have recently highlighted a reduced exposure to 13-cis-retinoic acid in neuroblastoma patients <12kg dosed on body weight (Clin Cancer Res19:469-79,2013). Given the toxicity observed with many chemotherapeutics, it is appropriate to establish a pharmacological basis for dose adjustments implemented in younger patients. Methods: The pharmacokinetics of cyclophosphamide (CPA), actinomycin D (Act D), carboplatin and etoposide were investigated in children aged 0-6, 6-12 and 12-24 months. CPA was administered i.v. at a dose of 100-1,500 mg/m2, with infusion times up to 1.5h, Act D as a bolus i.v. infusion of 0.4-1.5mg/m2, carboplatin as an i.v. dose of 3.8-30mg/kg over 1-4h and etoposide as an i.v. dose of 3.5-14mg/kg over 1-6h. Eighty-six children were studied at 14 centres, with PK sampling carried out over 24h for CPA and Act D, 3h for carboplatin and up to 6h for etoposide. Plasma concentrations of CPA, Act D and etoposide were determined by LC-MS analysis, with carboplatin concentrations determined in plasma ultrafiltrate by AAS. PK parameters were calculated using WinNonlin or previously used PK models as appropriate. Results: Clearance values normalized to body weight ranged from 0.5-7.7 ml/min/kg for CPA, 1.7-17.4 for Act D, 1.6-10.5 for carboplatin and 0.2-1.7 for etoposide. No significant differences in normalized clearance were observed between the defined age cohorts of 0-6, 6-12 and 12-24 months and the data do not indicate clear differences in drug handling in infants and young children. However, when normalized clearance values were compared to data from older children, a greater degree of inter-patient variation was observed in patients <2 years than in children >2 years for all drugs. Conclusions: While normalized clearance values for the drugs studied do not support reduced dosing approaches, data suggest that individual drug clearance values may be more difficult to predict in younger patients. Further studies involving additional anticancer drugs may allow more rationale approaches to dosing. Clinical trial information: NCT00897871.