Serial Plasma Voriconazole Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation |
| |
| Authors: | Steven M. Trifilio Paul R. Yarnold Marc H. Scheetz Judy Pi Gennethel Pennick Jayesh Mehta |
| |
| Affiliation: | Hematopoietic Stem Cell Transplant Program, Northwestern Memorial Hospital, Chicago, Illinois,1. Department of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois,2. The Feinberg School of Medicine, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois,3. Department of Pharmacy Practice, Midwestern University Chicago College of Pharmacy, Chicago, Illinois,4. Fungus Testing Laboratory, University of Texas Health Science Center-SA, San Antonio, Texas5. |
| |
| Abstract: | Plasma voriconazole concentrations vary considerably between patients receiving standard dosing, and trough voriconazole concentrations are known to affect efficacy and toxicity. Temporal variations in serial plasma voriconazole concentrations through the course of therapy in hematopoietic stem cell transplantation patients has not been carefully described. Paired voriconazole concentrations in 64 patients were studied to determine the predictability of the second concentration based on the first. The difference between the two values was ≤5% in six patients. In 25 patients, the second concentration was higher by a median of 40%. In 33 patients, the subsequent concentration was lower by a median of 59%. For patients with an initial concentration of <2 μg/ml, the correlation between the two values was poor (r = 0.24; P < 0.17). For those with an initial concentration of ≥2 μg/ml, the correlation was good (r = 0.72; P < 0.0001). There was no relationship between the magnitude of the change and the time elapsing between the two measurements. Among the 43 patients who had an initial concentration of ≥1 μg/ml, the two voriconazole measurements were strongly correlated (r = 0.66, P < 0.0001), but only 67% had a voriconazole serum concentration of ≥1 μg/ml on the second measurement. No studied variables were reliable predictors in identifying concentrations above or below 1 or 2 μg/ml. Our data suggest that variations in voriconazole concentrations are unpredictable despite standard dosing, and the acceptability of a concentration on one occasion cannot be extrapolated to future concentrations in the same patient. This suggests that ongoing therapeutic drug monitoring and dose adjustment may be beneficial in patients requiring prolonged voriconazole therapy.Invasive fungal infections are a significant source of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Voriconazole, a triazole antifungal agent, is frequently used in the treatment of many yeast and mold infections following HSCT (2, 7). Use of voriconazole for prevention of opportunistic fungal infections has also shown merit (16). Voriconazole is metabolized by the cytochrome P450 isoenzyme system, primarily CYP 3A4, CYP 2C9, and CYP 2C19 (3). Genetic polymorphism of the CYP 2C19 isoenzyme, interactions with several drugs used during the posttransplantation period, self-induced voriconazole metabolism, and direct hepatotoxicity from the conditioning regimen can alter the metabolism and disposition of voriconazole significantly (1, 8). This may increase or decrease voriconazole exposure in an unpredictable fashion, and large inter- and intrapatient variations in voriconazole plasma concentrations have been observed in several reports (11, 12, 14). Recent studies have suggested that there is an association between voriconazole plasma concentrations and successful treatment outcomes, indicating a possible need for therapeutic drug monitoring (TDM) (5, 9, 13).Although the optimum duration of voriconazole prophylaxis and therapy for most fungal infections has not been defined clearly, most allogeneic HSCT recipients require prolonged antifungal therapy—often for several months. Since physiologic (e.g., absorption, metabolism, and protein binding) and pharmacologic (e.g., drug interactions and nonlinear kinetics) conditions change over time following HSCT, plasma voriconazole concentrations would be expected to vary.The temporal variation of plasma voriconazole concentrations through the course of therapy in HSCT patients when measured serially has not been carefully described. We report the results of paired plasma voriconazole measurements in 64 patients following allogeneic HSCT. |
| |
| Keywords: | |
|
|
