Assessment of Target Site Pharmacokinetics of Voriconazole in Healthy Volunteers During Sequence Therapy
Condition: Healthy
Study type: Interventional
Phase: Phase 4

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. 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
    

Intervention name(s): Voriconazole; microdialysis
Intervention type(s): Drug; Other
Intervention description(s): 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; long-term microdialysis over study days 1-4 (visits 1-7)
Other intervention name(s): VFEND® Pfizer
Intervention MeSH terms: Voriconazole
Intervention model: Single Group Assignment
Masking: None (Open Label)
Keywords: voriconazole; microdialysis; sequence therapy; pharmacokinetics; Target Site Pharmacokinetics