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

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

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00940017

Enrollment

Registered

2009-07-15

Start date

2008-09-30

Completion date

2008-10-31

Last updated

2010-02-09

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Aspergillosis, Candidemia

Keywords

PK, fungal infection

Brief summary

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

Interventions

DRUGanidulafungin 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.

Study design

Allocation

RANDOMIZED

Intervention model

SINGLE_GROUP

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 55 Years

Healthy volunteers

Yes

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.

Design outcomes

Primary

Measure	Time frame	Description
Plasma Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax)	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)	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)	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)	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)	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)	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	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	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.
AM: Tmax	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.
ELF PK: AUCtau	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	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	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: AUCtau	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	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	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	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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Anidulafungin and Voriconazole Anidulafungin (Eraxis™) intravenously (IV) in a loading dose of 200 milligrams (mg) on Day 1, followed by maintenance doses of 100 mg every 24 hours on Day 2 and Day 3. Simultaneously, using a separate intravenous access, subjects received voriconazole (Vfend®) in a loading dose of 6 milligrams per kilogram (mg/kg) every 12 hours on Day 1, followed by a maintenance dose of 4 mg/kg every 12 hours on Day 2, and a 4 mg/kg morning dose on Day 3.	24
Total	24

Arm

Count

Anidulafungin and Voriconazole

Anidulafungin (Eraxis™) intravenously (IV) in a loading dose of 200 milligrams (mg) on Day 1, followed by maintenance doses of 100 mg every 24 hours on Day 2 and Day 3. Simultaneously, using a separate intravenous access, subjects received voriconazole (Vfend®) in a loading dose of 6 milligrams per kilogram (mg/kg) every 12 hours on Day 1, followed by a maintenance dose of 4 mg/kg every 12 hours on Day 2, and a 4 mg/kg morning dose on Day 3.

Total

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	1
Overall Study	did not meet entrance criteria	3

Baseline characteristics

Characteristic	Anidulafungin and Voriconazole
Age Continuous	27.3 years STANDARD_DEVIATION 7.8
Sex: Female, Male Female	5 Participants
Sex: Female, Male Male	19 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	15 / 21
serious Total, serious adverse events	0 / 21

Outcome results

Primary

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).