Dose individualization of carboplatin after a 120-hour infusion schedule: higher dose intensity but fewer toxicities

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.     

Plasminogen Paris I: congenital abnormal plasminogen and its incidence in thrombosis

An abnormal plasminogen was discovered because of a decreased level of plasminogen activity in plasma contrasting with a normal level of plasminogen antigen concentration. The same discrepancy was found in the purified plasminogen. The molecular abnormality seems to be inherited. The patient is a heterozygote. The experimental findings can be explained by assuming that half of the plasminogen is normal, while the other half is an inactive mutant protein, without catalytic activity after SK or UK addition. There was no binding of labeled DFP and a decreased binding of TLCK to the abnormal plasminogen. The role of the abnormal plasminogen in thrombotic tendency is uncertain since the patient is the only one who has suffered a thrombotic accident, while her relatives who present the same defective plasminogen have not had thrombotic problems.