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

Eksperimentel: 1

Medicin: anidulafungin and voriconazole

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.

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.

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.

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.

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.

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.

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.

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).

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.

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).

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.

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).

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.

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).

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.

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).

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.