Therapeutic drug monitoring of posaconazole in allogeneic hematopoietic stem cell transplantation patients who develop gastrointestinal graft-versus-host disease

Abstract

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.

Figures

Fig 1

Mean PCZ Cmin value for each patient (n = 29), independent of clinical status. The histogram bars represent individual means, and histogram lower and upper limits represent minimal and maximal Cmins, respectively. Black histogram bars represent patients with breakthrough infection (invasive aspergillosis). Dashed line, FDA-recommended efficacy threshold (Cmin, 0.7 mg/liter).

Fig 2

PCZ Cmin by clinical status of diarrhea in patients who did not declare invasive aspergillosis, stratified by location of GVHD. *, P < 0.05.

Fig 3

PCZ Cmin by clinical status of diarrhea and invasive aspergillosis. *, P < 0.05.

Fig 4

Individual illustrative evolution of the PCZ Cmin, depending on clinical status of diarrhea and invasive aspergillosis in 2 patients: one without IA (patient A) and the second who declared IA (patient B).