A Study To Assess The Anidulafungin And Voriconazole Concentration In Lung Following Intravenous Administration In Healthy Subjects

Study Overview
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Brief Summary
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The purpose of this study is to provide anidulafungin and voriconazole to healthy subjects to determine the drug concentration in the lung.

Official Title
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A Phase 4, Open Label Study To Assess The Bronchopulmonary Pharmacokinetics Of Anidulafungin And Voriconazole Following Intravenous Administration In Healthy Subjects

Conditions
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Aspergillosis, Candidemia

Intervention / Treatment
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* Drug: anidulafungin and voriconazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adult subjects willing to comply with the study requirement. Exclusion Criteria: Clinical significant disease. Sensitive to study medication. Not willing to comply with the study requirement.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: anidulafungin and voriconazole<br>* Subjects will be admitted to the clinical research unit on Day 0. Subjects will receive anidulafungin intravenously in a loading dose of 200 mg on Day 1, followed by maintenance doses of 100 mg Q24h on Day 2 and Day 3. Simultaneously, using a separate intravenous access, subjects will receive voriconazole in a loading dose of 6 mg/kg Q12h on Day 1, followed by a maintenance dose of 4 mg/kg Q12h on Day 2, and a 4 mg/kg morning dose on Day 3.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) | Cmax = maximum observed plasma concentration; measured in micrograms per milliliter (ug/mL). Observed directly from the data. Collected on Day 3. | 100 minutes (end of infusion), 2, 4, 8, 12, 24 hours after start of infusion | 
| Plasma PK: Time to Reach Maximum Plasma Concentration (Tmax) | Tmax = time (hours) to maximum plasma concentration (Cmax). Observed directly from data as time of first occurrence. Collected on Day 3. | 100 minutes (end of infusion), 2, 4, 8, 12, 24 hours after start of infusion | 
| Plasma PK: Area Under the Curve From Time Zero to Time = Tau (AUCtau) | AUCtau = area under the plasma concentration-time profile from time zero (0) to time = t (AUCt), the dosing interval, where t is 24 hours for anidulafungin and 12 hours for voriconazole; measured as micrograms times hours per milliliter (ug*hr/mL). Collected on Day 3. | 100 minutes (end of infusion), 2, 4, 8, 12, 24 hours after start of infusion | 
| Plasma PK: Plasma Elimination Half-life (t1/2) | t1/2 = terminal elimination half-life in hours; Loge(2)/Kel, where Kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Collected on Day 3. | 100 minutes (end of infusion), 2, 4, 8, 12, 24 hours after start of infusion | 
| Plasma PK: Total Clearance (CL Total) | CL total = total clearance calculated as dose divided by AUCt; measured as milliliters per minute (mL/min). Collected on Day 3. | 100 minutes (end of infusion), 2, 4, 8, 12, 24 hours after start of infusion | 
| Plasma PK: Volume of Distribution at Steady-state (Vss) | Vss = volume of distribution at steady-state; measured as liters (L). Calculated as (CL multiplied by mean residence time extrapolated to infinity [MRTinf]). MRTinf = [(AUMCt plus t (AUCinf minus AUCt)) divided by AUCt] minus (infusion time divided by 2); AUMCt = area under the first moment curve from time zero to time t; AUCinf = area under the plasma concentration-time curve extrapolated to infinity. | 100 minutes (end of infusion), 2, 4, 8, 12, 24 hours after start of infusion | 
| Epithelial Lining Fluid (ELF) PK: Cmax | Cmax=maximum observed plasma concentration. ELF collected by bronchoscopy and bronchoalveolar lavage (BAL) Day 3; determined from BAL sample using urea dilution method: [Drug ELF]=[Drug BAL] multiplied by [Urea SERUM] divided by [Urea BAL]. Drug ELF=anidulafungin or voriconazole (drug) concentration in ELF corrected for dilution; Drug BAL=assayed drug concentration in BAL; Urea SERUM and Urea BAL simultaneously collected. Summary parameters derived using average data for all subjects; associated to a single subject for reporting purposes (mean with standard deviation not calculated). | 4, 8, 12, 24 hours after start of infusion | 
| ELF PK: Tmax | Tmax = time (hours) to maximum plasma concentration (Cmax). Observed directly from data as time of first occurrence. ELF collected by bronchoscopy and BAL on Day 3. | 4, 8, 12, 24 hours after start of infusion | 
| ELF PK: AUCtau | AUCtau = area under the plasma concentration-time profile from time zero (0) to time = t (AUCt), the dosing interval, where t is 24 hours for anidulafungin and 12 hours for voriconazole. ELF collected by bronchoscopy and BAL on Day 3. Summary parameters were derived using average data for all subjects and associated to a single subject for reporting purposes (mean with standard deviation was not calculated). | 4, 8, 12, 24 hours after start of infusion | 
| ELF PK: t1/2 | t1/2 = terminal elimination half-life in hours; Loge(2)/Kel, where Kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. ELF collected by bronchoscopy and BAL on Day 3. | 4, 8, 12, 24 hours after start of infusion | 
| Alveolar Macrophages (AM): Cmax | Cmax = maximum observed plasma concentration; observed directly from the data. AM collected by bronchoscopy and BAL on Day 3. Summary parameters were derived using average data for all subjects and associated to a single subject for reporting purposes (mean with standard deviation was not calculated). | 4, 8, 12, 24 hours after start of infusion | 
| AM: Tmax | Tmax = time (hours) to maximum plasma concentration (Cmax). Observed directly from data as time of first occurrence. AM collected by bronchoscopy and BAL on Day 3. | 4, 8, 12, 24 hours after start of infusion | 
| AM: AUCtau | AUCtau = area under the plasma concentration-time profile from time zero (0) to time = t (AUCt), the dosing interval, where t is 24 hours for anidulafungin and 12 hours for voriconazole. AM collected by bronchoscopy and BAL on Day 3. Summary parameters were derived using average data for all subjects and associated to a single subject for reporting purposes (mean with standard deviation was not calculated). | 4, 8, 12, 24 hours after start of infusion | 
| AM: t1/2 | t1/2 = terminal elimination half-life in hours; Loge(2)Kel, where Kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. AM collected by bronchoscopy and BAL on Day 3. | 4, 8, 12, 24 hours after start of infusion | 
| Overall Drug Penetration Ratio in ELF | ELF collected by bronchoscopy and BAL on Day 3. ELF to plasma penetration ratio calculated by dividing area under the plasma concentration-time profile (AUC) in ELF by AUC in plasma from 20 subjects where t is 24 hours for anidulafungin and 12 hours for voriconazole. Summary parameters were derived using average data for all subjects and associated to a single subject for reporting purposes (mean with standard deviation was not calculated). | 4, 8, 12, 24 hours after start of infusion | 
| Concentration Ratio in ELF to Plasma | Concentration ratio in ELF to plasma determined by a point estimate within each subject at the time-point where ELF data was available. | 4, 8, 12, 24 hours after start of infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PK, fungal infection