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Adaptive dosing and platinum-DNA adduct formation in children receiving high-dose carboplatin for the treatment of solid tumours

Veal, GJ; Errington, J; Tilby, MJ; Pearson, ADJ; Foot, ABM; McDowell, H; Ellershaw, C; Pizer, B; Nowell, GM; Pearson, DG; Boddy, AV

Authors

GJ Veal

J Errington

MJ Tilby

ADJ Pearson

ABM Foot

H McDowell

C Ellershaw

B Pizer

DG Pearson

AV Boddy



Abstract

A pharmacokinetic–pharmacodynamic study was carried out to investigate the feasibility and potential importance of therapeutic monitoring following high-dose carboplatin treatment in children. High-dose carboplatin was administered over 3 or 5 days, with the initial dose based on renal function, to achieve target area under the plasma concentration–time curve (AUC) values of 21 or 20mgml−1.min, respectively. Dose adjustment was carried out based on observed individual daily AUC values, to obtain the defined target exposures. Platinum–DNA adduct levels were determined in peripheral blood leucocytes and toxicity data were obtained. Twenty-eight children were studied. Based on observed AUC values, carboplatin dose adjustment was performed in 75% (21 out of 28) patients. Therapeutic monitoring resulted in the achievement of carboplatin exposures within 80–126% of target AUC values, as compared to estimated exposures of 65–213% of target values without dose adjustment. The carboplatin AUC predicted with no dose modification was positively correlated with pretreatment glomerular filtration rate (GFR) values. Higher GFR values were observed in those patients who would have experienced AUC values >25% above the target AUC than those patients attaining AUC values >25% below the target AUC, following renal function-based dosing. Platinum–DNA adduct levels correlated with observed AUC values on day 1 of carboplatin and increased over a 5-day course of treatment. Real-time monitoring of carboplatin pharmacokinetics with adaptive dosing is both feasible and necessary for the attainment of consistent AUC values in children receiving high-dose carboplatin treatment. Pharmacodynamic data suggest a strong correlation between carboplatin pharmacokinetics and the drug–target interaction.

Journal Article Type Article
Publication Date Mar 1, 2007
Deposit Date May 31, 2012
Journal British Journal of Cancer
Print ISSN 0007-0920
Electronic ISSN 1532-1827
Publisher Springer Nature
Peer Reviewed Peer Reviewed
Volume 96
Issue 5
Pages 725-731
DOI https://doi.org/10.1038/sj.bjc.6603607
Keywords Carboplatin, Therapeutic monitoring, Clinical pharmacology, Paediatrics, Platinum–DNA adducts.
Public URL https://durham-repository.worktribe.com/output/1532057