Pharmacokinetics Variability of Posaconazole (PCZ) and Its Glucuronide Metabolite During Induction and Consolidation Treatments in Patients With Acute Myeloid Leukemia (AML): a Covariate Analysis With the Tablets Formulation and Evaluation of the Potential Risk of Hepatotoxicity

Overview

Among its authorized indications, posaconazole (PCZ) is prescribed for prophylaxis in onco-hematology patients at high risk of invasive fungal infections. This azole antifungal has a low bioavailability. The enteric-coated tablets form available since mid-2015 has significantly improved its pharmacokinetic profile compared to the oral suspension form initially used. According to the recommendations of The European Conference on Infections in Leukemia (ECIL-6), the minimum serum concentration desirable for prophylaxis is 0.7 mg/L. This concentration threshold was difficult to achieve in onco-hematology patients treated with oral suspension. The investigators retrospectively collected and analyzed 201 results of residual PCZ serum concentrations from 91 onco-hematology patients on Noxafil® tablets prophylaxis. The median concentration of PCZ was 1.08 mg/L. In this study, the pharmacokinetics of tablet-PCZ showed significant inter-individual variability. Thus, while 25% of the concentrations remained below the recommended threshold of 0.7 mg/L (25% percentile = 0.69 mg/L), exposure to PCZ was greater than 2.63 mg/L in 10% of cases. This level of exposure, however, did not have obvious hepatic repercussions. Nevertheless, further studies involving larger cohorts are needed to clarify a hypothetical relationship between serum PCZ concentration and the occurrence of hepatic toxicity. In addition, the investigators found significant intra-individual variability in PCZ exposure (CV = 48.8%), especially in leukemic patients. This variability is probably related to a modification during the treatment of the physio-pathological conditions of the patient likely to impact the pharmacokinetics of PCZ (absorption, distribution, metabolism, etc.) as well as the effect of possible pharmacokinetic drug interactions. The metabolism of PCZ is mediated primarily by the uridine diphosphate (UDP)-glucuronosyltransferase 1A4 (UGT1A4) pathway. Although hepatic metabolism of PCZ is low compared with other azoles (such as itraconazole or voriconazole), differences in the metabolic capacity of UGT1A4 may alter PCZ exposure. A previous study of the oral suspension form had shown that low concentrations of PCZ were associated with a high ratio of PCZ-glucuronide / PCZ concentrations. Two genetic variants of the gene encoding UGT1A4 are associated with a decrease in the metabolic clearance of glucuronide drugs via UGT1A4. A recent study suggests less exposure to PCZ in the presence of UGT1A4 polymorphism. The main objective of the investigator's project is to study prospectively in a homogeneous population of patients treated by intensive chemotherapy for acute myeloid leukemia (induction and consolidation) the pharmacokinetics of PCZ administered in its tablet formulation, and in particular: * Clinical and biological tolerance of high concentrations of PCZ * The influence of clinical and demographic covariates on PCZ and PCZ-glucuronide ratio * The influence of genetic variants of UGT1A4 on PCZ metabolism (PCZ-glucuronide / PCZ ratio).