HealthyPhase 4VORTarget-siteNCT01539330
Assessment of Target Site Pharmacokinetics of Voriconazole in Healthy Volunteers During Sequence Therapy
A Phase 4 study testing Voriconazole and microdialysis in people with Healthy, run by Martin-Luther-Universität Halle-Wittenberg at 1 site in Austria.
Trial summary
The present study aims at measuring unbound voriconazole concentrations in plasma and at the relevant target site of systemic fungal infections, i.e. the interstitial space fluid of soft tissues, to assess the target site pharmacokinetics. Read more about this study
- Who is it for?
- Ages 18 to 50 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Healthy
- What is being tested?
- Voriconazole and microdialysis
- Type of treatment
- Injection or infusion
- How many people
- 9 participants
- Where
- 1 siteAustria
- Study dates
- Feb 2009to Aug 2013
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Healthy males aged between 18 and 50 years
- Body mass index between 20 and 28
- Known genotype of CYP2C19 and CYP2C9
- No regular concomitant (topical or systemic) medication within the last 4 weeks prior to the start of the trial
- Written informed consent given by volunteers after being provided with detailed information about the nature, risks, and scope of the clinical study as well as the expected desirable and adverse effects of the drug
- No legal incapacity and/or other circumstances rendering the subject unable to understand the nature, scope and possible consequences of the study
Who cannot join
- Known allergy or hypersensitivity against study drug or drug class
- Participation in another clinical study within the last 6 weeks prior to study
- Blood donation within the last 4 weeks prior to study
- Application of live or killed virus or bacteria vaccines within 14 days prior to study
- Alcohol or drug abuse
- Abuse of nicotine
Show all 22Show fewer
- History of severe allergic or anaphylactic reactions to any medication
- History of or ongoing optic dysfunction (all volunteers will undergo mandatory testing at screening)
- Ongoing bacterial, viral, fungal, or atypical mycobacterial infection
- Presence of malignancy within the past 5 years, including lymphoproliferative disorders
- History of or ongoing hepatic cirrhosis regardless of cause or severity
- History of or ongoing hospital admission for cardiac disease, stroke, or pulmonary disease within the last 5 years
- History of or ongoing symptoms for blood coagulation disorders
- Seropositivity for human immunodeficiency virus (HIV), all volunteers will undergo mandatory testing at screening
- Seropositivity for hepatitis B or C virus (HepB antigen, HepC antibody), all volunteers will undergo testing at screening
- Clinically significant thrombocytopenia, bleeding disorders or a platelet count < 50,000 / µL
- WBC count < 3000/L or > 14,000/L, all volunteers will undergo mandatory testing at screening
- Hepatic enzymes (aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), alkaline phosphatase (AP), gamma-glutamyltranspeptidase (Gamma-GTP), lactate dehydrogenase (LDH)) and bilirubin 3 times the upper limit of normal, all volunteers will undergo mandatory testing at screening
- Serum creatinine 2 times the upper limit of normal, all volunteers will undergo mandatory testing at screening
- Abnormalities in ECG that are considered clinically relevant, all volunteers will undergo mandatory testing at screening
- Unreliability and/or lack of cooperation
- Other objections to participate in the study in the opinion of the investigator
Trial locations and contacts
1 site in 1 country.
Austria1 site
Medical University of Vienna, Department of Clinical Pharmacology
Vienna, 1090
About this study
The present study aims at measuring unbound voriconazole concentrations in plasma and at the relevant target site of systemic fungal infections, i.e. the interstitial space fluid of soft tissues, to assess the target site pharmacokinetics. For this purpose the microdialysis technique will be employed which is capable of measuring the unbound, microbiologically active concentration of antifungals in the interstitial space fluid of virtually all tissues. This is the first human study of this drug employing the microdialysis technique determining the target site concentrations over several days (single and multiple dosing).
Read the detailed description
Voriconazole, a derivative of fluconazole, is one of the newer triazole antifungal agents launched in 2002. It has demonstrated favourable activity against primary opportunistic fungal pathogens (Aspergillus spp., Candida spp. and Cryptococcus spp.), common dermatophytes and the fungi which cause endemic mycoses. Voriconazole was approved for primary treatment of acute invasive aspergillosis, candidiasis and salvage therapy for rare but serious fungal infections.
Antifungals such as voriconazole should display their pharmacodynamic activity in tissue, more precisely in interstitial space fluid (ISF) of tissue, because this is the site where most of the fungal pathogens are considered to reside. Microdialysis is a novel approach for determination of drug concentration in virtually all tissues and has been used in vivo in animal experiments since 1980s and for about 10 years in human studies. The advantages of this technique are that it is easy to handle and reduces the burden on the patient to a minimum because no tissue extraction is necessary. Microdialysis allows a continuous determination of tissue drug concentrations over a defined time interval. In addition this technique enables to determine only the unbound, i.e. pharmacodynamically active fraction of the extracellular drug concentration at the site of action.
Most pharmacokinetic (PK) data of voriconazole have only been obtained after single dose and only in plasma (bound and unbound concentration). Regarding the pharmacodynamic activity it is more appropriate to determine the unbound concentration at the target site. The novel microdialysis technique allows to evaluate the concentration of voriconazole in subcutaneous interstitial fluid of tissue (unbound concentration), the compartment where most of the pathogens are considered to reside. Apart from multiple i.v. administration of voriconazole, sequence therapy has been introduced, i.e. a switch from direct administration into the systemic circu¬lation to an absorption based administration process, introducing further variability on the PK. A further important reason for assessing voriconazole concentrations during sequence therapy is that the i.v. dose is normalised to body weight but the oral dose is given independently of this demographic dimension.
The study aims at determining unbound voriconazole concentrations in plasma and at the relevant target site of systemic fungal infections, i.e. the interstitial space fluid of soft tissues. Additionally, the PK of voriconazole after single and multiple i.v. and p.o. dosing will be characterised and influencing parameters on the PK will be evaluated.
The design will be a prospective, two part, open-labelled, uncontrolled, study. For this exploratory study no blinding procedure will be performed. Due to the nature of the study, there will be no placebo or comparator arm. The pharmacokinetics will be compared between
- 2 dosing schedules: after single and after multiple dosing
- 2 sampled matrices: plasma and microdialysate
- Conditions
- Healthy
- Being tested
- Voriconazole, microdialysis
- Keywords
- voriconazole, microdialysis, sequence therapy, pharmacokinetics, Target Site Pharmacokinetics
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VoriconazoleDrug
Also called VFEND® Pfizer
At beginning of study visit 1 (0-12 h): 6 mg/kg, IV (in the vein) over a period of 120 min
at beginning of study visit 2 (12-24 h): 6 mg/kg, IV (in the vein) over a period of 120 min
at beginning of study visit 3 (24-36 h): 4 mg/kg, IV (in the vein) over a period of 80 min
at beginning of study visit 4 (36-48 h): 4 mg/kg, IV (in the vein) over a period of 80 min
at beginning of study visit 5 (48-60 h), 6 (60-72 h) and 7 (72-84 h): 200 mg po
microdialysisOther
long-term microdialysis over study days 1-4 (visits 1-7)
What is being measured
The primary outcome is the main question the study is designed to answer.
Pharmacokinetics of voriconazole in plasma and interstitial space fluid of subcutaneous tissue by measuring concentrations of voriconazole in plasma and microdialysate during sequence therapy over 4 days
Rich plasma and microdialysate sampling will be done on study day 1,3 and 4. Sparse plasma and microdialysate sampling will be done on study day 2.
For characterisation of the unbound concentration-time profiles in ultrafiltered plasma and in the interstitial space fluid of subcutaneous adipose tissue (ISF) the following pharmacokinetic (PK) parameters of voriconazole will be determined by suitable PK approaches: Cmax, tmax, AUC, t1/2, CL, V after single dosing and multiple dosing (sequence therapy).
Measured: study day 1-4
Secondary outcomes (3)
AUC/MIC values
To relate the unbound concentrations in ultrafiltered plasma and interstitial space fluid to reported MIC values in the literature.
Measured: up to 1 year after study visits
genotype analysis
To exploratory evaluate the genotype of the metabolising enzymes CYP2C9, and CYP2C19 that may have an influence on the pharmacokinetics of voriconazole
Measured: up to 10 weeks before or after study visits
cytokine analysis
To exploratory evaluate cytokines as local inflammatory parameters that may have an influence on the pharmacokinetics of voriconazole
Measured: up to 1 year after study visits
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Feb 2012 (estimated)
- Study startFeb 2009
- Primary completionFeb 2013
- Study completionAug 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for HealthyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- Martin-Luther-Universität Halle-Wittenberg
- Sponsor type
- University, hospital or other
- Collaborators
- Medical University of Vienna
- Responsible party
- Principal investigator, Prof. Dr. Charlotte Kloft, Martin-Luther-Universität Halle-Wittenberg
- Investigators
- Markus Müller, Prof. Dr., Principal investigator, Medical University of Vienna, Department of Clinical Pharmacology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01539330
- Sponsor's protocol ID
- KP-VOR03
- Other IDs
- 2008-008524-32, 2008
- Acronym
- VORTarget-site
- Status last verified
- Oct 2013
- First submitted
- 9 Feb 2012
- Last updated
- 1 Nov 2013
- Results posted
- No
- Data monitoring committee
- No
Publications
Simmel F, Kloft C. Microdialysis feasibility investigations with the non-hydrophilic antifungal voriconazole for potential applications in nonclinical and clinical settings. Int J Clin Pharmacol Ther. 2010 Nov;48(11):695-704. doi: 10.5414/cpp48695.
PubMed 20979927Simmel F, Kirbs C, Erdogan Z, Lackner E, Zeitlinger M, Kloft C. Pilot investigation on long-term subcutaneous microdialysis: proof of principle in humans. AAPS J. 2013 Jan;15(1):95-103. doi: 10.1208/s12248-012-9412-z. Epub 2012 Oct 13.
PubMed 23065438
Study at a glance
From the registry record, last updated by the sponsor on 1 Nov 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Assessment of Target Site Pharmacokinetics of Voriconazole in Healthy Volunteers During Sequence Therapy
- ClinicalTrials.gov ID
- NCT01539330
- Acronym / sponsor ID
- VORTarget-site / KP-VOR03
- Conditions
- Healthy
- Keywords
- voriconazole, microdialysis, sequence therapy, pharmacokinetics, Target Site Pharmacokinetics
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 9 participants (actual)
- Lead sponsor
- Martin-Luther-Universität Halle-WittenbergUniversity, hospital or other
- Collaborators
- Medical University of Vienna
- Study start
- Feb 2009
- Primary completion
- Feb 2013 (actual)
- Study completion
- Aug 2013 (actual)
- First posted
- 27 Feb 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The present study aims at measuring unbound voriconazole concentrations in plasma and at the relevant target site of systemic fungal infections, i.e. the interstitial space fluid of soft tissues, to assess the target site pharmacokinetics. For this purpose the microdialysis technique will be employed which is capable of measuring the unbound, microbiologically active concentration of antifungals in the interstitial space fluid of virtually all tissues. This is the first human study of this drug employing the microdialysis technique determining the target site concentrations over several days (single and multiple dosing).
Detailed description
Voriconazole, a derivative of fluconazole, is one of the newer triazole antifungal agents launched in 2002. It has demonstrated favourable activity against primary opportunistic fungal pathogens (Aspergillus spp., Candida spp. and Cryptococcus spp.), common dermatophytes and the fungi which cause endemic mycoses. Voriconazole was approved for primary treatment of acute invasive aspergillosis, candidiasis and salvage therapy for rare but serious fungal infections.
Antifungals such as voriconazole should display their pharmacodynamic activity in tissue, more precisely in interstitial space fluid (ISF) of tissue, because this is the site where most of the fungal pathogens are considered to reside. Microdialysis is a novel approach for determination of drug concentration in virtually all tissues and has been used in vivo in animal experiments since 1980s and for about 10 years in human studies. The advantages of this technique are that it is easy to handle and reduces the burden on the patient to a minimum because no tissue extraction is necessary. Microdialysis allows a continuous determination of tissue drug concentrations over a defined time interval. In addition this technique enables to determine only the unbound, i.e. pharmacodynamically active fraction of the extracellular drug concentration at the site of action.
Most pharmacokinetic (PK) data of voriconazole have only been obtained after single dose and only in plasma (bound and unbound concentration). Regarding the pharmacodynamic activity it is more appropriate to determine the unbound concentration at the target site. The novel microdialysis technique allows to evaluate the concentration of voriconazole in subcutaneous interstitial fluid of tissue (unbound concentration), the compartment where most of the pathogens are considered to reside. Apart from multiple i.v. administration of voriconazole, sequence therapy has been introduced, i.e. a switch from direct administration into the systemic circu¬lation to an absorption based administration process, introducing further variability on the PK. A further important reason for assessing voriconazole concentrations during sequence therapy is that the i.v. dose is normalised to body weight but the oral dose is given independently of this demographic dimension.
The study aims at determining unbound voriconazole concentrations in plasma and at the relevant target site of systemic fungal infections, i.e. the interstitial space fluid of soft tissues. Additionally, the PK of voriconazole after single and multiple i.v. and p.o. dosing will be characterised and influencing parameters on the PK will be evaluated.
The design will be a prospective, two part, open-labelled, uncontrolled, study. For this exploratory study no blinding procedure will be performed. Due to the nature of the study, there will be no placebo or comparator arm. The pharmacokinetics will be compared between
- 2 dosing schedules: after single and after multiple dosing
- 2 sampled matrices: plasma and microdialysate
Study design
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
Who may qualify
- Ages
- 18 to 50 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- Healthy males aged between 18 and 50 years
- Body mass index between 20 and 28
- Known genotype of CYP2C19 and CYP2C9
- No regular concomitant (topical or systemic) medication within the last 4 weeks prior to the start of the trial
- Written informed consent given by volunteers after being provided with detailed information about the nature, risks, and scope of the clinical study as well as the expected desirable and adverse effects of the drug
Key exclusion criteria (22 listed)
- Known allergy or hypersensitivity against study drug or drug class
- Participation in another clinical study within the last 6 weeks prior to study
- Blood donation within the last 4 weeks prior to study
- Application of live or killed virus or bacteria vaccines within 14 days prior to study
- Alcohol or drug abuse
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| VoriconazoleAlso: VFEND® PfizerAt beginning of study visit 1 (0-12 h): 6 mg/kg, IV (in the vein) over a period of 120 min at beginning of study visit 2 (12-24 h): 6 mg/kg, IV (in the vein) over a period of 120 min at beginning of study visit 3 (24-36 h): 4 mg/kg, IV (in the vein) over a period of 80 min at beginning of study visit 4 (36-48 h): 4 mg/kg, IV (in the vein) over a period of 80 min at beginning of study visit 5 (48-60 h), 6 (60-72 h) and 7 (72-84 h): 200 mg po | Drug | – |
| microdialysislong-term microdialysis over study days 1-4 (visits 1-7) | Other | – |
Primary outcome
Pharmacokinetics of voriconazole in plasma and interstitial space fluid of subcutaneous tissue by measuring concentrations of voriconazole in plasma and microdialysate during sequence therapy over 4 days
Time frame: study day 1-4
Rich plasma and microdialysate sampling will be done on study day 1,3 and 4. Sparse plasma and microdialysate sampling will be done on study day 2. For characterisation of the unbound concentration-time profiles in ultrafiltered plasma and in the interstitial space fluid of subcutaneous adipose tissue (ISF) the following pharmacokinetic (PK) parameters of voriconazole will be determined by suitable PK approaches: Cmax, tmax, AUC, t1/2, CL, V after single dosing and multiple dosing (sequence therapy).
3 secondary outcomes
AUC/MIC values
Time frame: up to 1 year after study visits
genotype analysis
Time frame: up to 10 weeks before or after study visits
cytokine analysis
Time frame: up to 1 year after study visits
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Nov 2013.
- Background: PubMed 20979927Simmel F, Kloft C. Microdialysis feasibility investigations with the non-hydrophilic antifungal voriconazole for potential applications in nonclinical and clinical settings. Int J Clin Pharmacol Ther. 2010 Nov;48(11):695-704. doi: 10.5414/cpp48695.
- Results publication: PubMed 23065438Simmel F, Kirbs C, Erdogan Z, Lackner E, Zeitlinger M, Kloft C. Pilot investigation on long-term subcutaneous microdialysis: proof of principle in humans. AAPS J. 2013 Jan;15(1):95-103. doi: 10.1208/s12248-012-9412-z. Epub 2012 Oct 13.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Markus Müller, Prof. Dr. principal investigator
Medical University of Vienna, Department of Clinical Pharmacology
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Voriconazole and microdialysis in people with Healthy, run by Martin-Luther-Universität Halle-Wittenberg at 1 site in Austria.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Nov 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Austria. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Pharmacokinetics of voriconazole in plasma and interstitial space fluid of subcutaneous tissue by measuring concentrations of voriconazole in plasma and microdialysate during sequence therapy over 4 days (time frame: study day 1-4). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01539330, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Nov 2013.