Single Dose Population Pharmacokinetics of Intravenous Posaconazole in Critically Ill Patients (POSA)

• ClinicalTrials.gov Identifier: NCT02968134
• Recruitment Status: Completed
• First Posted: November 18, 2016
• Results First Posted: July 9, 2018
• Last Update Posted: September 21, 2018
• Sponsor: Royal Brisbane and Women's Hospital
• Collaborator: The University of Queensland
• Information provided by (Responsible Party): Jason Roberts, Royal Brisbane and Women's Hospital

Study Description

Brief Summary:

The purpose of this study is to try to find out how critically ill patients receiving the anti fungal medication, posaconazole, process it in their body. Investigators would like to study if the recommended doses of posaconazole achieve adequate concentrations in the patients blood to treat fungal infections.The disease process in critically ill patients can profoundly influence the concentration of anti fungal medication in the blood. The process by which a drug travels through the body in blood, how it is broken down and removed by the body is called pharmacokinetics (PK).

This information is important to know because if antifungal levels are low in the blood, the fungal infection has an opportunity to become resistant to the antifungal medication which can lead to the medication being less effective against the fungal infection potentially exposing future patients with infection to a limited range of effective antifungals.

Investigators can measure the PK by taking blood samples at specific times after the anti fungal medication is given.

This study will enroll 8 patients who are admitted to the intensive care unit and are being treated with an antifungal medication for a fungal infection. Patients will be consented and given a single dose of posaconazole and serial blood samples will be collected just prior to the dose and at 15, 45,75 minutes during the infusion and at 3, 5, 8, 12, 18, 24, 30 36 and 48 hours . Information about the patients stay in the ICU will also be collected including blood pressure, temperature, blood test results.

Condition or disease	Intervention/treatment	Phase
Systemic Fungal Infections	Drug: Posaconazole	Phase 4

Detailed Description:

Posaconazole is a new extended spectrum triazole active against a range of yeasts and molds including Aspergillus, Candida, Coccidioides, Cryptococcus neoformans, Fusarium, and Zygomycetes. It may be used for the prevention of invasive fungal infections in immunocompromised patients including febrile neutropenic patients and those receiving immunosuppressant drugs for graft-vs-host disease during stem cell transplantation. It may also be used for treatment of systemic fungal infections.The use of posaconazole in ICU patients has been limited to stable patients to ensure reliable bioavailability from the oral formulations. Oral formulations have important limitation in that they cannot be used in critically ill patients who may be unable to take oral doses or bioavailability may be compromised due to erratic absorption. Recently, an intravenous (IV) formulation has been developed to address these limitations. Initial pharmacokinetic (PK) investigations of the IV formulation were conducted in hematology patients, with further data in other patient populations still forthcoming; particularly in the critically ill where the IV formulation would probably be used most frequently.

Most of the available PK data for posaconazole is from non-critically ill patients who received the oral formulation. Although the absorption phase of the kinetics is not relevant for the IV formulation, data on the distribution, metabolism and elimination properties would still be informative of the IV kinetics. The tissue distribution of posaconazole is extensive with a very large volume of distribution owing to its high lipophilicity. It is highly bound to plasma proteins (98-99%) and therefore very likely to be affected by the variable changes in plasma protein concentration in critically ill patients. The major elimination pathway of posaconazoleis through biliary excretion (about 77%) of mainly the unchanged parent compound and the rest through renal execration of as a glucuronide conjugate.

A number of studies have described PK variability of posaconazole due to altered absorption/bioavailability which can frequently result in sub-therapeutic plasma concentrations, forming strong case for therapeutic drug monitoring. Nonetheless, it is unclear whether the observed low concentrations can also be explained, at least in part, by other factors such as disease-related PK changes or if the obvious plausibility of altered absorption has masked such investigations. Most population PK models described so far are based on one compartment models, which do not reveal if the observed variability in concentrations is due to changes in PK parameters such as volume of distribution or clearances. The influence of disease state on these PK parameters has been extensively described for several antimicrobials in the critically ill patient populations. Although data on the new IV formulation of posaconazole in this patient population is lacking, there is evidence from previous PK studies on the oral formulation that PK variability not observed in healthy study participants was observed in patients with invasive fungal infections, although it was explained primarily in relation to altered bioavailability from the oral formulation. In surgical ICU patients low plasma concentration of posaconazole were observed, after administration via nasogastric tube. Similar findings were reported in general ICU patients. Although the explanation in these reports was again the irregular absorption, the influence of other pathologic changes remains to be investigated. A PK evaluation of IV posaconazole in critically ill patients, not confounded by the absorption factor, would reveal if there is any pathophysiology-induced PK alteration. Such a study will also give insight into the dose-exposure relationships and optimal treatment regimen.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 8 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Single Dose Population Pharmacokinetics of Intravenous Posaconazole in Critically Ill Patients
• Actual Study Start Date: January 16, 2017
• Actual Primary Completion Date: May 21, 2017
• Actual Study Completion Date: May 21, 2017

Arms and Interventions

Arm	Intervention/treatment
Posaconazole; The study will enrol eight patients with presumed or confirmed systemic fungal infections, who are admitted to ICU	Drug: Posaconazole; A single dose of 300mg intravenous posaconazole will be administered and blood samples will be taken prior to start of infusion, at 15,45,75minutes, 3,5,8,12,18,24,30,36 and 48 hours.; Other Name: Noxafil

Outcome Measures

Primary Outcome Measures :

1. Posaconazole Exposure Described as Area Under the Total Plasma Concentration-time Curve From Time Zero to Infinity After a Single Dose [ Time Frame: 48 hours ]
   The primary outcome is plasma posaconazole exposure expressed as the area under the total plasma concentration-time curve from time zero to infinity resulting from a single dose of 300 mg of posaconazole administered intravenously.
2. Posaconazole Exposure Expressed as Area Under the Unbound Concentrations-time Curve From Time Zero to Infinity [ Time Frame: 48 hours ]
   This is a measure of free posaconazole ( not bound to plasma proteins) exposure in the plasma. This is an important measure of exposure because its the free concentration that distributes into targets sites of infection to produce clinical effect.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Age greater than 18 years
• Admission for ICU care
• The presence of suspected or confirmed fungal infection requiring systemic antifungal therapy
• Presence of central venous access for drug administration

Exclusion Criteria:

• Age < 18 years
• Pregnancy
• Prescription of drugs that are known to interact with posaconazole
• Oral posaconazole use within the last two week prior to enrolment
• Documented history of drug reaction to the triazole antifungal medications

Contacts and Locations

Sponsors and Collaborators

Royal Brisbane and Women's Hospital

The University of Queensland

Investigators

• Principal Investigator: Jason A Roberts, BPharm; Royal Brisbane and Womens Hospital

  Study Documents (Full-Text)

Documents provided by Jason Roberts, Royal Brisbane and Women's Hospital:

Study Protocol and Statistical Analysis Plan  [PDF] July 20, 2016

More Information

Publications of Results:

Sime FB, Stuart J, Butler J, Starr T, Wallis SC, Pandey S, Lipman J, Roberts JA. Pharmacokinetics of Intravenous Posaconazole in Critically Ill Patients. Antimicrob Agents Chemother. 2018 May 25;62(6). pii: e00242-18. doi: 10.1128/AAC.00242-18. Print 2018 Jun.

• Responsible Party: Jason Roberts, Professor, Royal Brisbane and Women's Hospital
• ClinicalTrials.gov Identifier: NCT02968134
• Other Study ID Numbers: HREC/16/QRBW/377
• First Posted: November 18, 2016
• Results First Posted: July 9, 2018
• Last Update Posted: September 21, 2018
• Last Verified: August 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: De-identified data for all primary and secondary endpoints will be reported as a collective data set. Individual results will not be reported.

Additional relevant MeSH terms:

Mycoses; Bacterial Infections and Mycoses; Infections; Posaconazole; 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