Therapeutic drug monitoring
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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. ⋯ 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.
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Comparative Study Controlled Clinical Trial
Ketoconazole renders poor CYP3A phenotype status with midazolam as probe drug.
Drugs metabolized by cytochrome CYP3A isoenzymes have wide interindividual variability and normally distributed plasma clearance distributions. This makes precise dosing difficult to achieve clinically, which may compromise safe therapy. We hypothesized that with potent inhibition of CYP3A, we could clinically render patients "poor metabolizer" phenotype status, and thus reduce interindividual pharmacokinetic variability of midazolam, a well-known CYP3A substrate. ⋯ A limited sampling model consisting of time points at 15 and 300 minutes was validated as a phenotype for CYP3A activity to facilitate the use of midazolam as a probe drug for CYP3A activity. Potent inhibition of CYP3A by ketoconazole reduced midazolam CL and area-under-the-curve variability, allowing for more precise achievement of therapeutic target drug exposure. Prospective evaluation of this approach, together with dose adjustment based on limited sampling, seems warranted.