Assessment of Target Site Pharmacokinetics of Voriconazole in Healthy Volunteers During Sequence Therapy (VORTarget-site)
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).
|Study Design:||Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
|Official Title:||Assessment of Target Site Pharmacokinetics of Voriconazole in Healthy Volunteers During Sequence Therapy|
- 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 ] [ Designated as safety issue: No ]
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).
- AUC/MIC values [ Time Frame: up to 1 year after study visits ] [ Designated as safety issue: No ]To relate the unbound concentrations in ultrafiltered plasma and interstitial space fluid to reported MIC values in the literature.
- genotype analysis [ Time Frame: up to 10 weeks before or after study visits ] [ Designated as safety issue: No ]To exploratory evaluate the genotype of the metabolising enzymes CYP2C9, and CYP2C19 that may have an influence on the pharmacokinetics of voriconazole
- cytokine analysis [ Time Frame: up to 1 year after study visits ] [ Designated as safety issue: No ]To exploratory evaluate cytokines as local inflammatory parameters that may have an influence on the pharmacokinetics of voriconazole
|Study Start Date:||February 2009|
|Estimated Study Completion Date:||June 2013|
|Primary Completion Date:||February 2013 (Final data collection date for primary outcome measure)|
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
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
|Medical University of Vienna, Department of Clinical Pharmacology|
|Vienna, Austria, 1090|
|Principal Investigator:||Markus Müller, Prof. Dr.||Medical University of Vienna, Department of Clinical Pharmacology|