title: 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.
authors: Pharmacology and Toxicology Laboratory, Department of Biochemistry, Toxicology and Pharmacology, University Hospital Grenoble, France. jtonini@chu-grenoble.fr
authors: J
authors: J
authors: Tonini
authors: A
authors: A
authors: Thiébaut
authors: J F
authors: JF
authors: Jourdil
authors: A S
authors: AS
authors: Berruyer
authors: C E
authors: CE
authors: Bulabois
authors: J Y
authors: JY
authors: Cahn
authors: F
authors: F
authors: Stanke-Labesque
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents / Q000627:therapeutic use; D005260:Female; D005767:Gastrointestinal Diseases / Q000188:drug therapy* / Q000209:etiology; D006086:Graft vs Host Disease / Q000188:drug therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole