Carboplatin (CBDCA), an analogue of cisplatin, exhibits reduced toxicity but wide interpatient variability of its pharmacokinetic parameters. Individualization of the CBDCA dose is therefore necessary. Although various formulas have been developed for this purpose, major side effects have been reported on CBDCA administration by short-term infusion (0.5 or 1 h). We therefore propose a new schedule of CBDCA administration. Instead of a dosing method based on the estimation of renal function when a classic administration schedule is used, we propose a pharmacokinetic dosing method (Bayesian method), whereby CBDCA is given by continuous infusion for 120 h. First, CBDCA was given to 21 patients to determine the population pharmacokinetic parameters of carboplatin. Then, on the basis of total platinum plasma concentration measurements and Bayesian estimation of pharmacokinetic parameters, it was possible to individualize the CBDCA dose within the first 24 h of the infusion. This new protocol for CBDCA administration was evaluated in 36 new patients (60 courses). Three theoretical end points at the end of the infusion were considered. For a given theoretical end point, 20 courses were taken into account. The theoretical end points (i.e., 1, 1.5, and 1.8 mg/l) were compared with the concentrations measured at the end of the infusion, which were 0.99 +/- 0.10, 1.41 +/- 0.13, and 1.72 +/- 0.20 mg/l, respectively. This Bayesian dosing method can easily be used in clinical practice, and the determination of predictive performances has shown that the method is precise and unbiased. With no more toxicity or practical difficulties than those produced by other methods, and with acceptable tolerance, it was possible to reach a median dose that was 20% higher than the usual dose (484 +/- 190 mg/m2 as compared with 400 mg/m2). In conclusion, this new schedule of CBDCA administration appears to be interesting in terms of tolerance. However, new studies are required to confirm that this new scheme leads to equal or better efficacy than the classic protocol.

Carboplatin (CBDCA) is a widely used anticancer agent for which dose-effect and dose-toxicity relationships have been demonstrated, thus stressing the need for a controlled exposure to this drug. So far, carboplatin administration could only be individualized a priori following 2 classic methods, which are based on the evaluation of renal clearance: Calvert's and Chatelut's formulas. This study was designed to develop and evaluate the performance of an alternative CBDCA 120-hour schedule coupled to a Bayesian adaptive dosing with feedback strategy. Precision of the dosing method was assessed in 84 patients (256 courses performed during a 10-year period), by comparing CBDCA plasma concentrations observed at the end of the infusion with initial target values. A comprehensive monitoring of treatment-related toxicities also was performed. Finally, the authors compared doses actually delivered following the dose-tailoring method with the theoretical, standard, ones calculated retrospectively with Calvert's and Chatelut's formulas. No significant differences were found between experimental and theoretical concentrations. According to the target exposure chosen (3 levels), the mean doses administered to our patients were 517, 719, and 902 mg of CBDCA compared with 550, 509, and 538 or 657, 604, and 644 mg, which would have been given following Calvert or Chatelut formulas, respectively. These results showed that our Bayesian method led to the administration of up to 60% higher doses of carboplatin compared with those based only on the evaluation of renal clearance. Despite the markedly higher doses administered, no severe toxicities were reported in the patients treated following this new schedule. It is noteworthy that neither hematologic growth factors nor stem cells, usually associated with high-dose regimen, were used as support in this study. These data strongly suggest that it is possible to deliver higher dose- intensities of carboplatin, even in elderly, unselected patients, without increasing toxicities and with no growth factor support, provided that a therapeutic drug monitoring strategy with real-time tailored dosing is performed.

Introduction: Because of the increased use of im plantable access systems, the incidence of blood stream and catheter infections associated with these systems has concomitantly increased. Classically, he parin-lock flush solutions were used to prevent thrombosis; more recently, vancomycin was added to the solution to prevent infections caused by Gram- positive bacteria, particularly coagulase-negative Staphylococci. Disorders due to Gram-negative organ isms have now appeared in oncologic patients. We therefore tested the addition of colistin to heparin- vancomycin solutions. Colistin was chosen for its good activity against Gram-negative bacteria (98% susceptibility in our hospital), its good tolerance due to low systemic passage, and its low cost. Methods: We developed formulations contain ing heparin (100 IU/mL) and various concentrations of vancomycin (10-500 μg/mL) and colistin (10-100 μg/mL) in 0.9% NaCl. Each sterile solution was tested for physical and chemical compatibility (spectropho tometry, nuclear magnetic resonance, and pH mea surements) and its antibacterial activity (against ox acillin-resistant Staphylococcus aureus, Enterococcus faecium, Klebsiella pneumoniae exhibiting broad- spectrum betalactamase (BSBL), imipenem-resistant Pseudomonas aeruginosa) for 2 months at 4°C and at room temperature. Results: The most suitable combination of drugs is heparin (100 IU/mL), vancomycin (100 μg/mL), and colistin (100 μg/mL). This flush solution main tains activity when stored at 4°C for up to 1 month. Conclusions: We feel that the combination of heparin, vancomycin, and colistin can be used as a flush solution for indwelling catheters.

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