An interventional study of Posaconazole in Leukemia, Myeloid, Acute, sponsored by Hospices Civils de Lyon. Status unknown at 1 site in France. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-02-24.
Sponsored by Hospices Civils de Lyon · Not applicable, Interventional, and Health services research
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:
3,035 studies on the registry are indexed under Leukemia, Myeloid, Acute; 746 are open to participants now.
This study's planned enrollment of 120 is above the median of 40 across 2,561 interventional studies indexed under Leukemia, Myeloid, Acute.
Browse Leukemia, Myeloid, Acute studies →Hospices Civils de Lyon is the lead sponsor of 1,854 studies on the registry; 441 are open to participants now.
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Exclusion Criteria:
Patients with AML over the age of 18 years treated with intensive chemotherapy in induction and consolidation whose was under antifungal prophylaxis by PCZ formulation tablets.
Drug: Posaconazole
* PCZ will be used as recommended in tablet formulation at an initial dosage of 300 mg twice a day on the first day and then once a day at a dose of 300 mg the following days. * PCZ prophylaxis will be started on the same day as the start of chemotherapy and will be continued until the end of aplasia. * The dosage of the PCZ can be adjusted according to the results of the PCZ assay. It may be interrupted if the transaminase level is greater than 3 times higher than normal (3N) or on medical decision.
Also known as: PCZ
Evolution of the blood concentration of posaconazole and its metabolite from the beginning of treatment to the end of the induction phase (pharmacokinetic).
Posaconazole (PCZ) treatment will start at Day 1 at the beginning of induction/ consolidation therapy. * For the pharmacokinetics study of PCZ during induction, blood samples (5 mL) will be taken on days 3, 7, 14 and 21. Predoses (just prior to a daily dose) or trough concentrations (C0) will be collected on days 3, 7, 14 and 21. A peak concentration (at 3 hours post dose) will also be collected on day 14. * After achieving complete remission, patients receive a consolidation cure. During the consolidation cures, trough concentrations will be collected on days 3, 7, 14 and 21. A peak concentration (at 3 hours post dose) will also be collected on day 14.
Time frame: Day 21
Search and identification by sequencing gene variants of UGT1A4
The blood sample (5 mL) for the study of polymorphisms of the UGT1A4 gene will be performed before the initiation of induction.
Time frame: At diagnosis
Started Dec 2018 (actual). Primary completion is estimated for Apr 2023, 52 months after the start.
Of 121 non-industry interventional studies with no phase under Leukemia, Myeloid, Acute, half reached primary completion within 47 months of starting (the median), counting those still running; a quarter within 26 and three quarters within 106. This study's planned 52 months is above that.
Counting every sponsor, half of 125 studies reached it within 47 months; a quarter within 25 and three quarters within 106.
How these figures are worked out, and which studies are left out of them.
This study is status unknown, as verified in Feb 2022. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: Posaconazole