Informations générales (source: ClinicalTrials.gov)
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 (Posa-Pk)
Interventional
N/A
Hospices Civils de Lyon (Voir sur ClinicalTrials)
décembre 2018
avril 2023
29 juin 2024
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).
Etablissements
| Les établissements hors Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| Centre Hospitalier Lyon Sud, Hematology department - Pierre-Bénite - France | Sophie DUCASTELLE-LEPRETRE, MD | Contact (sur clinicalTrials) | |||
Critères
Tous
Inclusion Criteria:
1. Patient aged 18 or over
2. Patients with AML de novo or secondary to myelodysplastic syndrome or
therapy-related AML except acute myeloid leukemia (AML3)
3. Patient hospitalized for the treatment of leukemia (induction chemotherapy or
consolidation)
4. General state retained (ECOG performance scale ≤ 3)
5. alanine aminotransferase aspartate transaminase (ASAT) and alanine aminotransferase
(ALAT) ≤ 2.5 times the upper limit of normal (ULN), total bilirubin ≤ 2 times the
ULN, creatinine <150 μmol / L unless these biological abnormalities are related to
leukemia
6. Patients affiliated or beneficiaries of a social security scheme (Social Security or
Universal Medical Coverage)
7. Having read and understood the information sheet and signed the informed consent
1. Patient aged 18 or over
2. Patients with AML de novo or secondary to myelodysplastic syndrome or
therapy-related AML except acute myeloid leukemia (AML3)
3. Patient hospitalized for the treatment of leukemia (induction chemotherapy or
consolidation)
4. General state retained (ECOG performance scale ≤ 3)
5. alanine aminotransferase aspartate transaminase (ASAT) and alanine aminotransferase
(ALAT) ≤ 2.5 times the upper limit of normal (ULN), total bilirubin ≤ 2 times the
ULN, creatinine <150 μmol / L unless these biological abnormalities are related to
leukemia
6. Patients affiliated or beneficiaries of a social security scheme (Social Security or
Universal Medical Coverage)
7. Having read and understood the information sheet and signed the informed consent
1. Patients with acute promyelocytic leukemia (AML3)
2. History of uncontrolled cancer for at least two years
3. Patient included in another clinical study that may interfere with the objectives of
this study
4. Treatment with antifungal other than posaconazole
5. Severe uncontrolled infection at the time of inclusion
6. Positive serology for HIV 1 or 2 or human T-cell lymphoma virus (HTLV 1) or 2, or
active viral infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
7. Pregnant woman (beta positive HCG) or breastfeeding
8. A woman of childbearing potential who can not justify the use of effective
contraception during treatment with Noxafil®
9. Patient incapacitated, under guardianship, curators or safeguard of justice