Individualised dosing strategy for high-dose carboplatin in patients with germ cell cancer.
In contrast to conventional chemotherapy, carboplatin is still dosed per unit of body surface area (BSA) in high-dose chemotherapy protocols in clinical practice. To individualise dosing, a population pharmacokinetic model for poor-risk germ cell tumour patients receiving 1500 mg m(-2) carboplatin was developed. The typical central volume of distribution (19.9 l) and typical clearance (110 ml min(-1)) corresponded approximately to the extracellular fluid space or glomerular filtration rate, respectively. The covariate analysis identified several patient-specific factors. Carboplatin clearance was significantly related to creatinine clearance and body height, explaining 73% of the interindividual variability. Thus, an equation to predict individual clearance prior to treatment was developed (CL=0.41 x creatinine clearance+1.05 x body height-124.4). The relative frequency of developing toxicity increased significantly with higher AUC values for different types of toxicity. In addition, overall nonhaematological toxicity correlated significantly with exposure of carboplatin, leading to the assessment of a target AUC. Based on the prediction of individual clearance and the definition of a target AUC associated with moderate toxicity, an individualised dosing equation is proposed. Retrospectively, the individualised dosing strategy would have led to a higher dose on average and a broader range to be administered, compared to empirical dosing per unit BSA in the high-dose setting.
Kloft
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C
Department of Clinical Pharmacy, Insitute of Pharmacy, Freie Universitaet Berlin, Kelchstr. 31, 12169 Berlin, Germany. ckloft@zedat.fu-berlin.de
Siegert
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W
Jaehde
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U
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D019540:Area Under Curve; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008657:Metabolic Clearance Rate; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy*
D016190:Carboplatin