Trial Outcomes & Findings for A Study To Assess The Anidulafungin And Voriconazole Concentration In Lung Following Intravenous Administration In Healthy Subjects (NCT NCT00940017)

NCT ID: NCT00940017

Last Updated: 2010-02-09

Results Overview

Cmax = maximum observed plasma concentration; measured in micrograms per milliliter (ug/mL). Observed directly from the data. Collected on Day 3.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 24 participants
• Primary outcome timeframe: 100 minutes (end of infusion), 2, 4, 8, 12, 24 hours after start of infusion
• Results posted on: 2010-02-09

Participant Flow

Participant milestones

Measure	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.
Overall Study STARTED	24
Overall Study Subjects Treated	21
Overall Study COMPLETED	20
Overall Study NOT COMPLETED	4

Reasons for withdrawal

Measure	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.
Overall Study did not meet entrance criteria	3
Overall Study Adverse Event	1

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Anidulafungin and Voriconazole n=24 Participants 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.
Age Continuous	27.3 years STANDARD_DEVIATION 7.8 • n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants
Sex: Female, Male Male	19 Participants n=5 Participants

PRIMARY outcome

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

Population: PK parameter analysis population

Cmax = maximum observed plasma concentration; measured in micrograms per milliliter (ug/mL). Observed directly from the data. Collected on Day 3.

Outcome measures

Measure	Anidulafungin and Voriconazole n=20 Participants 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.
Plasma Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) Anidulafungin	6.56 ug/mL Standard Deviation 1.62
Plasma Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) Voriconazole	5.32 ug/mL Standard Deviation 1.82

PRIMARY outcome

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

Population: PK parameter analysis population

Tmax = time (hours) to maximum plasma concentration (Cmax). Observed directly from data as time of first occurrence. Collected on Day 3.

Outcome measures

Measure	Anidulafungin and Voriconazole n=20 Participants 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.
Plasma PK: Time to Reach Maximum Plasma Concentration (Tmax) Voriconazole	1.74 hours Interval 1.67 to 2.05
Plasma PK: Time to Reach Maximum Plasma Concentration (Tmax) Anidulafungin	1.93 hours Interval 1.7 to 2.17

PRIMARY outcome

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

Population: PK parameter analysis population defined as all subjects randomized and treated who had at least 1 of the PK parameters of primary interest.

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.

Outcome measures

Measure	Anidulafungin and Voriconazole n=20 Participants 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.
Plasma PK: Area Under the Curve From Time Zero to Time = Tau (AUCtau) Anidulafungin	101 ug*hr/mL Standard Deviation 21.8
Plasma PK: Area Under the Curve From Time Zero to Time = Tau (AUCtau) Voriconazole	39.5 ug*hr/mL Standard Deviation 19.8

PRIMARY outcome

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

Population: PK parameter analysis population; (n) = number of subjects contributing to the mean

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.

Outcome measures

Measure	Anidulafungin and Voriconazole n=18 Participants 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.
Plasma PK: Plasma Elimination Half-life (t1/2) Anidulafungin (n=18)	20.8 hours Standard Deviation 3.06
Plasma PK: Plasma Elimination Half-life (t1/2) Voriconazole (n=15)	6.94 hours Standard Deviation 2.10

PRIMARY outcome

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

Population: PK parameter analysis population

CL total = total clearance calculated as dose divided by AUCt; measured as milliliters per minute (mL/min). Collected on Day 3.

Outcome measures

Measure	Anidulafungin and Voriconazole n=20 Participants 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.
Plasma PK: Total Clearance (CL Total) Anidulafungin	17.1 mL/min Standard Deviation 3.04
Plasma PK: Total Clearance (CL Total) Voriconazole	172 mL/min Standard Deviation 86.2

PRIMARY outcome

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

Population: PK parameter analysis population; (n) = number of subjects contributing to the mean.

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.

Outcome measures

Measure	Anidulafungin and Voriconazole n=18 Participants 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.
Plasma PK: Volume of Distribution at Steady-state (Vss) Anidulafungin (n=18)	30.8 L Standard Deviation 6.84
Plasma PK: Volume of Distribution at Steady-state (Vss) Voriconazole (n=15)	110 L Standard Deviation 34.0

PRIMARY outcome

Timeframe: 4, 8, 12, 24 hours after start of infusion

Population: PK parameter analysis population; summary parameters derived using average data for all subjects.

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).

Outcome measures

Measure	Anidulafungin and Voriconazole n=20 Participants 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.
Epithelial Lining Fluid (ELF) PK: Cmax Anidulafungin	1.13 average concentration (ug/mL)
Epithelial Lining Fluid (ELF) PK: Cmax Voriconazole	48.3 average concentration (ug/mL)

PRIMARY outcome

Timeframe: 4, 8, 12, 24 hours after start of infusion

Population: PK parameter analysis population; summary parameters derived using average data for all subjects.

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.

Outcome measures

Measure	Anidulafungin and Voriconazole n=20 Participants 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.
ELF PK: Tmax Anidulafungin	24.0 hours
ELF PK: Tmax Voriconazole	4.0 hours

PRIMARY outcome

Timeframe: 4, 8, 12, 24 hours after start of infusion

Population: PK parameter analysis population; summary parameters derived using average data for all subjects.

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).

Outcome measures

Measure	Anidulafungin and Voriconazole n=20 Participants 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.
ELF PK: AUCtau Anidulafungin	21.9 average concentration (ug*hr/mL)
ELF PK: AUCtau Voriconazole	282 average concentration (ug*hr/mL)

PRIMARY outcome

Timeframe: 4, 8, 12, 24 hours after start of infusion

Population: PK parameter analysis population; summary parameters derived using average data for all subjects. Data in ELF did not allow calculation of t1/2; not analyzed.

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.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 4, 8, 12, 24 hours after start of infusion

Population: PK parameter analysis population; summary parameters derived using average data for all subjects.

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).

Outcome measures

Measure	Anidulafungin and Voriconazole n=20 Participants 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.
Alveolar Macrophages (AM): Cmax Anidulafungin	103 average concentration (ug/mL)
Alveolar Macrophages (AM): Cmax Voriconazole	20.5 average concentration (ug/mL)

PRIMARY outcome

Timeframe: 4, 8, 12, 24 hours after start of infusion

Population: PK parameter analysis population; summary parameters derived using average data for all subjects.

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.

Outcome measures

Measure	Anidulafungin and Voriconazole n=20 Participants 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.
AM: Tmax Anidulafungin	24 hours
AM: Tmax Voriconazole	4.0 hours

PRIMARY outcome

Timeframe: 4, 8, 12, 24 hours after start of infusion

Population: PK parameter analysis population; summary parameters derived using average data for all subjects.

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).

Outcome measures

Measure	Anidulafungin and Voriconazole n=20 Participants 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.
AM: AUCtau Anidulafungin	1430 average concentration (ug*hr/mL)
AM: AUCtau Voriconazole	178 average concentration (ug*hr/mL)

PRIMARY outcome

Timeframe: 4, 8, 12, 24 hours after start of infusion

Population: PK parameter analysis population; summary parameters derived using average data for all subjects. Data in AM did not allow calculation of t1/2; not analyzed.

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.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 4, 8, 12, 24 hours after start of infusion

Population: PK parameter analysis population; summary parameters derived using average data for all subjects.

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).

Outcome measures

Measure	Anidulafungin and Voriconazole n=20 Participants 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.
Overall Drug Penetration Ratio in ELF Anidulafungin	0.22 average ELF to plasma ratio
Overall Drug Penetration Ratio in ELF Voriconazole	7.14 average ELF to plasma ratio

PRIMARY outcome

Timeframe: 4, 8, 12, 24 hours after start of infusion

Population: PK parameter analysis population; summary parameters derived using average data for all subjects. Subjects randomized to a single BAL procedure timepoint; bronchoscopy and BAL done for 5 different subjects at each timepoint.

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

Outcome measures

Measure	Anidulafungin and Voriconazole n=20 Participants 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.
Concentration Ratio in ELF to Plasma Anidulafungin 4 hours	0.15 ratio Standard Deviation 0.02
Concentration Ratio in ELF to Plasma Anidulafungin 8 hours	0.15 ratio Standard Deviation 0.07
Concentration Ratio in ELF to Plasma Anidulafungin 12 hours	0.20 ratio Standard Deviation 0.09
Concentration Ratio in ELF to Plasma Anidulafungin 24 hours	0.38 ratio Standard Deviation 0.14
Concentration Ratio in ELF to Plasma Voriconazole 4 hours	9.50 ratio Standard Deviation 2.31
Concentration Ratio in ELF to Plasma Voriconazole 8 hours	4.93 ratio Standard Deviation 2.79
Concentration Ratio in ELF to Plasma Voriconazole 12 hours	7.68 ratio Standard Deviation 3.41

Adverse Events

Anidulafungin and Voriconazole

Serious events: 0 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Anidulafungin and Voriconazole n=21 participants at risk 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.
Eye disorders Photophobia	9.5% 2/21
Eye disorders Visual impairment	14.3% 3/21
Gastrointestinal disorders Nausea	4.8% 1/21
Gastrointestinal disorders Vomiting	9.5% 2/21
General disorders Influenza like illness	19.0% 4/21
Immune system disorders Hypersensitivity	4.8% 1/21
Investigations Liver function test abnormal	4.8% 1/21
Nervous system disorders Headache	28.6% 6/21
Psychiatric disorders Hallucination, visual	4.8% 1/21
Psychiatric disorders Insomnia	4.8% 1/21
Vascular disorders Phlebitis	4.8% 1/21

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer, Inc.

Phone: 1-800-718-1021

Email: ClinicalTrials.govCallCenter@pfizer.com

Results disclosure agreements

• Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of \< 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), \< 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
• Publication restrictions are in place

Restriction type: OTHER