The purpose of this study is to provide anidulafungin and voriconazole to healthy subjects to determine the drug concentration in the lung.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Masking
NONE
Enrollment
24
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.
Pfizer Investigational Site
Hartford, Connecticut, United States
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
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Time frame: 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).
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 4, 8, 12, 24 hours after start of infusion