Posaconazole (PCZ) is the latest triazole antifungal agent that has been approved for prophylaxis of invasive aspergillosis in high-risk immunocompromised patients, such as allogeneic hematopoietic stem cell transplantation patients, who develop graft-versus-host disease (GVHD). PCZ has high interindividual variability with regard to its plasma drug trough concentrations (C min ). Moreover, the concentration-efficiency relationship remains to be better characterized in prophylaxis. To determine the variability factors in plasma drug concentrations, the PCZ C min and clinical parameters (localization of GVHD, presence of diarrhea, and diagnosis of invasive aspergillosis) were collected retrospectively in 29 consecutive allogeneic hematopoietic stem cell transplantation patients who developed GVHD and were receiving prophylactic PCZ (200 mg, 3 times/day, for >7 days). Blood samples were analyzed at steady state to determine the PCZ C min by liquid chromatography-tandem mass spectrometry. The average PCZ C min was 1.28 ؎ 0.82 mg/liter (mean ؎ standard deviation; n ؍ 292 dosages), with an intraindividual variability of 49% and an interindividual variability of 64%. Twenty percent of C min s were below 0.7 mg/liter, which is considered the threshold of efficacy by the Food and Drug Administration. The patients who had gastrointestinal (GI) GVHD experienced a 24% reduction in the posaconazole C min , compared with those with other localizations of GVHD. This decrease reached 33% when patients presented with diarrhea due to GI GVHD or an infectious etiology. PCZ C min s were 26% lower when invasive aspergillosis was declared. These data demonstrate that GI disturbances affect drug concentrations. Thus, therapeutic monitoring of PCZ can be used to detect low drug concentrations, possibly resulting in a lack of efficacy of invasive aspergillosis prophylaxis.
Despite the availability of new antifungal agents, invasive aspergillosis (IA) remains a leading cause of morbidity in immunocompromised patients. Posaconazole (PCZ) is the most recent broad-spectrum triazole antifungal agent to be approved for use to prevent IA in high-risk immunocompromised patients. In graft-versus-host disease (GVHD), a frequent complication after allogeneic stem cell transplantation, patients who receive PCZ prophylaxis have a lower cumulative incidence of proven or probable IA than those who are given fluconazole (19).Until now, the only way of administering PCZ was a 40-mg/ml oral suspension, which led to wide variations in bioavailability (17). Based on its lipophilicity, high-fat-content meals improve its absorption rate, leading to the recommendation of taking PCZ with at least a regular meal (4, 12). Because the gastric pH value also influences drug absorption, the concomitant intake of a PCZ oral suspension with an acidic beverage increases its absorption (12,14).Furthermore, due to its saturable absorption, bioavailability rises when the daily dose is split, i.e., for prophylactic treatment with 200 mg three times a day (t.i.d.) (6). B...
