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

Plasma Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax)

时间窗: 100 minutes (end of infusion), 2, 4, 8, 12, 24 hours after start of infusion

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)

时间窗: 100 minutes (end of infusion), 2, 4, 8, 12, 24 hours after start of infusion

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)

时间窗: 100 minutes (end of infusion), 2, 4, 8, 12, 24 hours after start of infusion

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)

时间窗: 100 minutes (end of infusion), 2, 4, 8, 12, 24 hours after start of infusion

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)

时间窗: 100 minutes (end of infusion), 2, 4, 8, 12, 24 hours after start of infusion

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)

时间窗: 100 minutes (end of infusion), 2, 4, 8, 12, 24 hours after start of infusion

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

时间窗: 4, 8, 12, 24 hours after start of infusion

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

时间窗: 4, 8, 12, 24 hours after start of infusion

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

时间窗: 4, 8, 12, 24 hours after start of infusion

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

时间窗: 4, 8, 12, 24 hours after start of infusion

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

时间窗: 4, 8, 12, 24 hours after start of infusion

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

时间窗: 4, 8, 12, 24 hours after start of infusion

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

时间窗: 4, 8, 12, 24 hours after start of infusion

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

时间窗: 4, 8, 12, 24 hours after start of infusion

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

时间窗: 4, 8, 12, 24 hours after start of infusion

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

时间窗: 4, 8, 12, 24 hours after start of infusion

Concentration ratio in ELF to plasma determined by a point estimate within each subject at the time-point where ELF data was available.