Michael Cole, Herbie Newell, Andrew Pearson, John Matthews, Alan Boddy
Cancer Research Unit and Departments of Statistics and Child Health, University of Newcastle upon Tyne.
Etoposide has activity against a wide range of tumours, and in the UK over 70% of children with malignant disease are treated with this drug. A high degree of interpatient variability in pharmacokinetics has been reported for etoposide in paediatric patients. This is likely to have a significant clinical impact in terms of haematological toxicity, antitumour effect and, potentially, on the possibility of secondary malignancy. The parameter found to correlate best with a pharmacodynamic endpoint (usually toxicity) is AUC, which for a given dose, is inversely related to clearance.
The analysis reported used data from 45 patients receiving etoposide as part of standard protocols. Patients ages ranged from 0.4 to 18.8 years (median 5.3), with etoposide doses from 40 – 420 mg (median 120), (88 – 258 mg/m2, median 170). Glomerular filtration rate (GFR) was determined as the clearance of 51Cr-EDTA and varied from 12 to 244 ml/min (median 58). Four patients had had prior chemotherapy with cisplatin and 16 with ifosfamide.
Data were analysed using NONMEM with a two compartment structural model and a composite intra-individual error model. Pharmacokinetic parameters were assumed to be log-normally distributed and were modelling in terms of demographic and therapeutic co-variates.
Body size (weight, surface area or age) was the covariate with the biggest impact on the objective function for each of the pharmacokinetic parameters. For the sake of consistency, weight was used for the further refinement of the population model. Addition of further co-variates identified a significant influence of serum creatinine, bilirubin and previous cisplatin and ifosfamide on clearance. Interestingly, there was a significant effect due to GFR (51CR-EDTA clearance), independently of serum creatinine. Considering the effects of these co-variates together, the influence of prior treatment on clearance did not retain significance. A final population model for clearance of etoposide in this paediatric population was:
ln(Cl)=-4.5+0.57*ln(Wt)-0.37*ln(Cr)-0.093*ln(Br)+0.21*ln(GFR)
Cl = clearance (ml/min), Wt = weight (kg), Cr = serum creatinine (uM), Br = serum bilirubin (uM), GFR (ml/min).
This model is currently being validated in a further dataset of paediatric patients.
Supported by the North of England Children’s Cancer Research Fund and the North of England Cancer Research Campaign.
Reference: PAGE 6 (1997) Abstr 593 [www.page-meeting.org/?abstract=593]
Poster: oral presentation