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

Leukemia, Myeloid, Acute Clinical Trial

— Posa-Pk  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03796533
• Other study ID #: 69HCL18_0429
• Secondary ID: 2018-003488-67
• Status: Recruiting
• Phase: N/A
• Start date: December 10, 2018
• Est. completion date: April 10, 2023

Study information

• Verified date: February 2022
• Source: Hospices Civils de Lyon
• Contact: Sophie Ducastelle-lepretre
• Phone: 04 78 86 22 36
• Email: Sophie.ducastelle-lepretre[@]chu-lyon.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: April 10, 2023
• Est. primary completion date: April 10, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Exclusion Criteria:

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

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

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.

Locations

Country	Name	City	State
France	Centre Hospitalier Lyon Sud, Hematology department	Pierre-Bénite

Sponsors (1)

Lead Sponsor	Collaborator
Hospices Civils de Lyon

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Day 21
Secondary	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.	At diagnosis