Pharmacokinetics of Posaconazole (Noxafil®) as Prophylaxis for Invasive Fungal Infections

Acute Graft Versus Host Disease Clinical Trial

— PIRAÑA  

Official title:

Pharmacokinetics of Posaconazole (Noxafil®) as Prophylaxis for Invasive Fungal Infections

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02805946
• Other study ID #: UMCN-AKF16.01
• Secondary ID: 2016-001182-87
• Status: Completed
• Phase: Phase 4
• Start date: April 28, 2017
• Est. completion date: September 7, 2019

Study information

• Verified date: December 2019
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study evaluates the the pharmacokinetics of posaconazole (new solid oral and IV) given as prophylaxis to patients who are at risk for developing fungal infections after receiving conditioning therapy (except strictly non-myeloablative (NMA)) for allogeneic Stem Cell Transplant (SCT), remission induction chemotherapy for acute myeloid leukemia (AML) or myelo dysplastic syndrome (MDS) or being treated for severe graft versus host disease (GvHD) and determines the impact of mucositis on the pharmacokinetics of posaconazole new solid oral.

Description:

In 2014, the new intravenous and solid oral formulation of posaconazole were marketed. This offers new treatment possibilities, specifically in patients previously unable to attain adequate exposure to posaconazole solution. To the opinion of the researchers, only limited data are available on the pharmacokinetics (PK) of the new formulations of posaconazole, however, these use strictly selected patients or healthy volunteers, but more importantly, specific aspects related to the PK remain unsolved. Despite the fact that adequate exposure is attained using the new solid oral formulation, it is hypothesized that oral bioavailability of posaconazole may be impacted during mucositis. Whether mucosal barrier injury impacts the absorption of posaconazole or alters presystemic clearance is still unknown. Therefore, it seems prudent to conduct a trial in a group of patients that will experience a severe degree of mucositis to identify changes in absorption of posaconazole and resolving the impact of various stages of mucositis on the PK of posaconazole by linking PK of posaconazole to markers of mucositis (citrulline). This research may also serve as a model for other drugs and allows for direct translations in improving patient care. For this purpose it is needed to determine the PK using both IV and PO dosing of posaconazole.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: September 7, 2019
• Est. primary completion date: July 26, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Subject is able and willing to sign the Informed Consent Form prior to screening evaluations.

2. Subject is at least 18 years of age on the day of providing informed consent.

3. Patient receives immunosuppressive therapy for acute or chronic GVHD grade II-IV, reduced intensity conditioning regimens for allogeneic stem cell transplant, or first remission induction chemotherapy for AML/MDS.

4. In case of acute GVHD grade II-IV, patient has received less than 1 week of immunosuppressive therapy.

5. If a woman, is neither pregnant nor able to become pregnant and is not nursing an infant.

6. Has an ALAT <200U/L, ALAT <225U/L, alkaline phosphatase <60 U/L and a bilirubin level <50 µmol/L.

7. Subject is capable of receiving oral tablets.

8. Subject is managed with a central venous or arterial catheter.

Exclusion Criteria:

1. Documented history of sensitivity to medicinal products or excipients similar to those found in the posaconazole preparation.

2. Relevant history or presence of cardiovascular disorders (specifically QTc-time prolongation).

3. Inability to understand the nature of the trial and the procedures required

4. Any signs or symptoms of invasive fungal disease or the use of antifungal drugs within the previous month.

5. Has previously participated in this trial.

Related Conditions & MeSH terms

• Acute Graft Versus Host Disease
• Acute Myeloid Leucaemia
• Allogeneic Stem Cell Transplant
• Graft vs Host Disease
• Invasive Fungal Infections
• Mycoses
• Myelo Dysplastic Syndrome
• Myelodysplastic Syndromes
• Preleukemia

Intervention

Drug:
• posaconazole
iv versus oral

Locations

Country	Name	City	State
Belgium	Universitaire Ziekenhuizen Leuven	Leuven
Netherlands	Radboudumc	Nijmegen

Sponsors (2)

Lead Sponsor	Collaborator
Radboud University	Universitaire Ziekenhuizen Leuven

Countries where clinical trial is conducted

Belgium,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	exposure to posaconazole (Area Under the Curve) when administered intravenously and orally (tablet formulation)	Plasma samples drawn on t=0 (pre-dose), 0.5, 1 (just prior to end of infusion), 2, 3, 4, 6, 8, 10, 12, 18 and 24 hours post infusion or post intake will be taken op day 7, day 12 and day 16 to determine posaconazole concentrations. Area Under the Curve of two routes of administration and two dosing regimens will be determined.	day 7, day 12 and day 16
Primary	impact of mucositis (determined by citrulline concentrations) on exposure (AUC) to posaconazole.	Full pharmacokinetic curve (plasma samples drawn on t=0 (pre-dose), 0.5, 1 (just prior to end of infusion), 2, 3, 4, 6, 8, 10, 12, 18 and 24 hours post infusion or post intake) will be taken op day 7, day 12 and day 16 (posaconazole). Impact of mucositis on oral absorption will be determined by comparing AUCs after intravenous administration with oral (tablet) administration in patients with mucositis.	day 7, day 12 and day 16