title: Adaptive dosing and platinum-DNA adduct formation in children receiving high-dose carboplatin for the treatment of solid tumours.
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 20 mg ml(-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.
authors.affiliation: Northern Institute for Cancer Research, University of Newcastle upon Tyne, Newcastle upon Tyne, UK.
authors.forename: G J
authors.initials: GJ
authors.lastname: Veal
authors.forename: J
authors.initials: J
authors.lastname: Errington
authors.forename: M J
authors.initials: MJ
authors.lastname: Tilby
authors.forename: A D J
authors.initials: AD
authors.lastname: Pearson
authors.forename: A B M
authors.initials: AB
authors.lastname: Foot
authors.forename: H
authors.initials: H
authors.lastname: McDowell
authors.forename: C
authors.initials: C
authors.lastname: Ellershaw
authors.forename: B
authors.initials: B
authors.lastname: Pizer
authors.forename: G M
authors.initials: GM
authors.lastname: Nowell
authors.forename: D G
authors.initials: DG
authors.lastname: Pearson
authors.forename: A V
authors.initials: AV
authors.lastname: Boddy
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D016190:Carboplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D018736:DNA Adducts / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007223:Infant; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D016190:Carboplatin