EFFECT OF METABOLIC-INHIBITORS ON CYCLOSPORINE PHARMACOKINETICS USINGA POPULATION APPROACH

Drugs known to inhibit the metabolism of cyclosporine are administered concomitantly to those who undergo cardiothoracic transplantation. Th e aim of this study was to examine in quantitative terms the relations hip between cyclosporine oral dose rate and the trough concentration ( Css(trough)) at steady state in patients who undergo cardiothoracic tr ansplantation and are administered cyclosporine alone or in combinatio n with drugs known to inhibit its metabolism. Dose and whole blood cyc losporine Css(tough) observations measured using the enzyme-multiplied immunoassay technique (EMIT) (396 observations) or the TDx assay (435 observations) were collected as part of routine blood concentration m onitoring from 182 patients who underwent cardiothoracic transplantati on. Data were analyzed using a linear mixed-effects modeling approach to examine the effect of metabolic inhibitors on dose-rate-Css(trough) ratio. The mean (and 95% confidence interval) dose-rate-Css(trough) r atio for cyclosporine generated from concentrations measured using EMI T was 94 (82.5-105.5) Lh(-1) for patients administered cyclosporine al one, 66.7 (58.1-75.3) Lh(-1) for patients administered concomitant dil tiazem, 47.9 (15.4 -80.4) Lh(-1) for patients administered concomitant itraconazole, 21.7 (14.8-28.5) Lh(-1) for patients administered conco mitant ketoconazole, and 14.9 (11.8-18.1) Lh(-1) for patients concomit antly administered diltiazem and ketoconazole. For patients administer ed concomitant cyclosporine, ketoconazole, and diltiazem, the dosage o f cyclosporine, if it is administered alone, should be 20% to achieve the same blood concentrations. This will allow safer drug concentratio n targeting of cyclosporine after cardiothoracic transplantation.