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Pharmacokinetics Variability of Posaconazole (PCZ) and Its Glucuronide Metabolite During Induction and Consolidation Treatments in Patients With Acute Myeloid Leukemia (AML) (Posa-Pk)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03796533
Recruitment Status : Recruiting
First Posted : January 8, 2019
Last Update Posted : January 8, 2019
Information provided by (Responsible Party):
Hospices Civils de Lyon

Brief 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).

Condition or disease Intervention/treatment Phase
Leukemia, Myeloid, Acute Drug: Posaconazole Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Health Services Research
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
Estimated Study Start Date : February 2019
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : March 5, 2021

Arm Intervention/treatment
Posaconazole pharmacokinetics
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.
Other Name: PCZ

Primary Outcome Measures :
  1. Evolution of the blood concentration of posaconazole and its metabolite from the beginning of treatment to the end of the induction phase (pharmacokinetic). [ Time Frame: Day 21 ]

    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.

Secondary Outcome Measures :
  1. Search and identification by sequencing gene variants of UGT1A4 [ Time Frame: At diagnosis ]
    The blood sample (5 mL) for the study of polymorphisms of the UGT1A4 gene will be performed before the initiation of induction.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03796533

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Contact: Sophie Ducastelle-lepretre 04 78 86 22 36 ext +33
Contact: Mohamed EL HAMRI 04 78 86 22 20 ext +33

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Centre Hospitalier Lyon Sud, Hematology department Recruiting
Pierre-Bénite, France
Contact: Sophie DUCASTELLE-LEPRETRE, MD    04 78 86 22 36 ext +33   
Contact: Mohamed EL HAMRI, MD    04 78 86 22 20 ext +33   
Principal Investigator: Sophie Ducastelle-Lepretre, MD         
Sub-Investigator: Xavier THOMAS, MD         
Sub-Investigator: Fiorenza BARRACO, MD         
Sub-Investigator: Etienne PAUBELLE, MD         
Sub-Investigator: Hélène Labussiere-Wallet, MD         
Sub-Investigator: Eric Wattel         
Sub-Investigator: Marie Virginie Larcher, MD         
Sub-Investigator: Clement Rocher, MD         
Sub-Investigator: Gaelle Fossard, MD         
Sub-Investigator: Marie Balsat, MD         
Sponsors and Collaborators
Hospices Civils de Lyon
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Responsible Party: Hospices Civils de Lyon Identifier: NCT03796533    
Other Study ID Numbers: 69HCL18_0429
First Posted: January 8, 2019    Key Record Dates
Last Update Posted: January 8, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hospices Civils de Lyon:
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Antifungal Agents
Anti-Infective Agents
Trypanocidal Agents
Antiprotozoal Agents
Antiparasitic Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs