Anesthesia
Conditions
Brief summary
This study is designed to characterize the pharmacokinetic and pharmacodynamic effect of fospropofol disodium in comparison to propofol. In addition, the study will compare the maximum sedative effect, safety and tolerability of fospropofol disodium and propofol.
Interventions
DRUGFospropofol disodium, propofol
Two Treatment Periods: fospropofol disodium 6.5 mg/kg single intravenous (IV) bolus followed by propofol injectable emulsion 0.65 mg/kg IV bolus, or propofol injectable emulsion 0.65 mg/kg IV bolus followed by fospropofol disodium 6.5 mg/kg IV bolus.
Sponsors
Eisai Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
Inclusion * Males or females greater than or equal to 18 or less than or equal to 45 years old * Non-smokers for at least 18 months prior to Screening * Body Mass Index (BMI) less than or equal to 30 Exclusion * Subjects having a past or current medical history of any respiratory illness including asthma * Subjects currently taking any medications (birth control will be allowed if the subject has been taking it for at least 12 weeks prior to dosing and during the entire study), including over-the-counter (OTC) medication, within 14 days of Screening * Subjects with a known or suspected history of drug or alcohol misuse within 6 months prior to Screening, or who have a positive urine drug test at Screening and pre-dose at Visit 2 and Visit 3 * Subjectw who are allergic to eggs, egg products, soybeans, or soy products * Subjects with a positive pregnancy test at Screening or breastfeeding * Subjects who are unwilling or unable to abide by the requirements of the study * Subjects who have any condition that would make him/her, in the opinion of the investigator, unsuitable for the study or who, in the opinion of the investigator, are not likely to complete the study for any reason
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Drug Plasma Concentration of Propofol | Days 1, and 7-14 (Arterial Sample: Pre-dose, and 0.5, 1, 1.5, 2, 4, 8, 16, 30, 45, 60, 120, 180, 240, 300, and 360 minutes post-dose. Venous Sample: Pre-dose, and 1, 4, and 30 minutes post-dose). | Arterial and venous blood samples were collected and analyzed for propofol concentrations as described previously. Cmax was the highest plasma drug concentration observed over the entire sampling period, and was obtained directly from the experimental plasma concentration time data without interpolation. The plasma concentrations from the venous sampling were descriptively compared head-to-head with the arterial sampling. |
| Area Under the Plasma Concentration-Time Curve From Time 0 to Time t (AUC(0-t)) of Fospropofol | Days 1, and 7-14 (Arterial Sample: Pre-dose, and 0.5, 1, 1.5, 2, 4, 8, 16, 30, 45, 60, 120, 180, 240, 300, and 360 minutes post-dose. Venous Sample: Pre-dose, and 1, 4, and 30 minutes post-dose). | Arterial and venous blood samples were collected and analyzed for fospropofol concentrations as described previously. AUC(0-t) was calculated using the log-linear trapezoidal rule (linear trapezoidal rule up to maximum observed plasma concentration (Cmax), log trapezoidal rule following Cmax) from time of dosing to the last quantifiable concentration. The plasma concentrations from the venous sampling were descriptively compared head-to-head with the arterial sampling. |
| Area Under the Plasma Concentration-Time Curve From Time 0 to Time t of Propofol | Days 1, and 7-14 (Arterial Sample: Pre-dose, and 0.5, 1, 1.5, 2, 4, 8, 16, 30, 45, 60, 120, 180, 240, 300, and 360 minutes post-dose. Venous Sample: Pre-dose, and 1, 4, and 30 minutes post-dose). | Arterial and venous blood samples were collected and analyzed for propofol concentrations as described previously. AUC(0-t) was calculated using the log-linear trapezoidal rule (linear trapezoidal rule up to Cmax, log trapezoidal rule following Cmax) from time of dosing to the last quantifiable concentration. The plasma concentrations from the venous sampling were descriptively compared head-to-head with the arterial sampling. In addition, the arterial plasma concentrations of fospropofol, propofol liberated from fospropofol, and propofol delivered from propofol injectable emulsion were used to refine the population PK model developed previously. |
| Maximum Drug Plasma Concentration (Cmax) of Fospropofol | Days 1, and 7-14 (Arterial Sample: Pre-dose, and 0.5, 1, 1.5, 2, 4, 8, 16, 30, 45, 60, 120, 180, 240, 300, and 360 minutes post-dose. Venous Sample: Pre-dose, and 1, 4, and 30 minutes post-dose). | Arterial and venous blood samples were collected and analyzed for fospropofol concentrations as described previously. Cmax was the highest plasma drug concentration observed over the entire sampling period, and was obtained directly from the experimental plasma concentration time data without interpolation. The plasma concentrations from the venous sampling were descriptively compared head-to-head with the arterial sampling. |
| Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Fospropofol (AUC(0-inf)) | Days 1, and 7-14 (Arterial Sample: Pre-dose, and 0.5, 1, 1.5, 2, 4, 8, 16, 30, 45, 60, 120, 180, 240, 300, and 360 minutes post-dose. Venous Sample: Pre-dose, and 1, 4, and 30 minutes post-dose). | AUC(0-inf) is a measure of drug concentration equal to the area under the plasma concentration-time profile from time 0 to infinity. An arterial line (A-line) and venous line (V-line) were placed prior to dosing during each treatment period and used to collect blood samples for plasma concentration measurements at specific time points. Plasma arterial and venous concentrations of fospropofol were quantified by high-performance liquid chromatography with mass spectrometric detection (LC-MS/MS). The AUC(0-inf) was calculated from the sum of AUC from time 0 to time t (AUC(0-t)) and the residual area calculated as Ct/λz, where Ct was the observed concentration at last quantifiable concentration and λz was the terminal elimination rate constant. The plasma concentrations from the venous sampling were descriptively compared head-to-head with the arterial sampling. |
| Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Propofol | Days 1, and 7-14 (Arterial Sample: Pre-dose, and 0.5, 1, 1.5, 2, 4, 8, 16, 30, 45, 60, 120, 180, 240, 300, and 360 minutes post-dose. Venous Sample: Pre-dose, and 1, 4, and 30 minutes post-dose). | An A-line and V-line were placed prior to dosing during each treatment period and used to collect blood samples for plasma concentration measurements at specific time points. Plasma arterial and venous concentrations of propofol were quantified by high-performance liquid chromatography with mass spectrometric detection (LC-MS/MS). The AUC(0-inf) was calculated from the sum of AUC(0-t) and the residual area calculated as Ct/λz, where Ct was the observed concentration at last quantifiable concentration and λz was the terminal elimination rate constant. The plasma concentrations from the venous sampling were descriptively compared head-to-head with the arterial sampling. In addition, the arterial plasma concentrations of fospropofol, propofol liberated from fospropofol, and propofol delivered from propofol injectable emulsion were used to refine the population PK model developed previously. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximal Sedative Effect Using the Modified Observer's Assessment of Alertness/Sedation Scale | Days 1, and 7-14 (2 minutes prior to study drug administration and every 2 minutes thereafter for 20 minutes or until the subject reached Fully Alert status, whichever was later). | PD effects were determined from continuous BIS score recordings and from clinical assessment of sedation using the MOAA/S scale. The MOAA/S scale was used to rate the level of alertness/sedation from a score of 0 (does not respond to painful stimulus) to 5 (alert) in the category of responsiveness, with 5 being the MOAA/S value for a fully awake adult. Time to sedation was defined as the time from the first dose of study medication to the first two consecutive MOAA/S scores less than or equal to 4. Fully awake status was reached at the first of 3 consecutive MOAA/S scores of 5 measured every 2 minutes after study drug administration. The MOAA/S scale was described by the Emax model. |
| Relative Bioavailability of Fospropofol and Propofol | Days 1, and 7-14 (Arterial Sample: Pre-dose, and 0.5, 1, 1.5, 2, 4, 8, 16, 30, 45, 60, 120, 180, 240, 300, and 360 minutes post-dose. Venous Sample: Pre-dose, and 1, 4, and 30 minutes post-dose). | The PK parameters for propofol from propofol injectable emulsion were used as the reference formulation. Because propofol is a metabolite of fospropofol, all calculations were conducted after correcting for the different molecular weights of these formulations. Molecular weights of 332.24 (288.24 for free base) and 178.27 were used for fospropofol disodium and propofol injectable emulsion, respectively. The propofol parameters were adjusted as appropriate as discussed above and natural log transformed prior to comparison. Relative bioavailability of propofol from fospropofol disodium (E2083) to propofol from propofol injectable emulsion is calculated as (AUC(FP) x Total Dose of Propofol/AUC(P) x Total Dose of E2083) x Molecular fraction, where AUC(FP) is AUC(0-t) or AUC(0-inf) of propofol from E2083, AUC(P) is AUC(0-t) or AUC(0-inf) of propofol from propofol injectable emulsion and molecular fraction is molecular weight of propofol (178.27)/E2083 (332.24). |
| Maximal Sedative Effect Using the Bispectral Index (BIS) Score | Days 1, and 7-14 (BIS measurements were to continue until the subject was fully recovered in the opinion of the investigator or until the PD effect measures returned to baseline measures) | Pharmacodynamic (PD) effects were obtained from continuous BIS score recordings obtained throughout the study and from clinical assessment of sedation using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale. The BIS measurements continued until the participant was fully recovered in the opinion of the investigator or until the PD effect measure returned to baseline. The BIS score varied between 100 (associated with being fully awake) and 0 (associated with a flat line on the electroencephalogram (EEG)). The BIS Index was described by the maximal effect (Emax) model. |
Countries
United States
Participant flow
Pre-assignment details
Each cohort had 2 treatment periods that were separated by a 7 to 14 day washout: fospropofol disodium, followed by propofol injectable emulsion; or propofol injectable emulsion, followed by fospropofol disodium.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (Sequence A) Participants were administered an intravenous (IV) bolus of 6.5 mg/kg of fospropofol disodium during Treatment Period 1, then after a 7-14 day washout began Treatment Period 2 with an IV bolus of 0.65 mg/kg propofol injectable emulsion. | 6 |
| Cohort 1 (Sequence B) Participants were administered an IV bolus of 0.65 mg/kg of propofol injectable emulsion during Treatment Period 1, then after a 7-14 day washout began Treatment Period 2 with an IV bolus of 6.5 mg/kg of fospropofol disodium. | 6 |
| Cohort 2 (Sequence C) Participants were administered an IV bolus of 10 mg/kg of fospropofol disodium during Treatment Period 1, then after a 7-14 day washout began Treatment Period 2 with an IV bolus of 1.0 mg/kg propofol injectable emulsion. | 6 |
| Cohort 2 (Sequence D) Participants were administered an IV bolus of 1.0 mg/kg of propofol injectable emulsion during Treatment Period 1, then after a 7-14 day washout began Treatment Period 2 with an IV bolus of 10 mg/kg of fospropofol disodium. | 6 |
| Cohort 3 (Sequence E) Participants were administered an IV bolus of 15 mg/kg of fospropofol disodium during Treatment Period 1, then after a 7-14 day washout began Treatment Period 2 with an IV bolus of 1.5 mg/kg propofol injectable emulsion. | 6 |
| Cohort 3 ( Sequence F) Participants were administered an IV bolus of 1.5 mg/kg of propofol injectable emulsion during Treatment Period 1, then after a 7-14 day washout began Treatment Period 2 with an IV bolus of 15 mg/kg of fospropofol disodium. | 6 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Treatment Period 1 | Study on hold | 1 | 1 | 0 | 0 | 1 | 2 |
| Treatment Period 1 | Unexplained elevated sys. BP | 0 | 0 | 0 | 0 | 1 | 0 |
| Treatment Period 1 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort 1 (Sequence A) | Cohort 1 (Sequence B) | Cohort 2 (Sequence C) | Cohort 2 (Sequence D) | Cohort 3 (Sequence E) | Cohort 3 ( Sequence F) | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 22.3 Years STANDARD_DEVIATION 1.51 | 25.5 Years STANDARD_DEVIATION 3.78 | 25.3 Years STANDARD_DEVIATION 4.46 | 22.7 Years STANDARD_DEVIATION 2.88 | 29 Years STANDARD_DEVIATION 4.34 | 23.8 Years STANDARD_DEVIATION 3.37 | 24.8 Years STANDARD_DEVIATION 3.98 |
| Gender Female | 2 Participants | 2 Participants | 3 Participants | 2 Participants | 2 Participants | 4 Participants | 15 Participants |
| Gender Male | 4 Participants | 4 Participants | 3 Participants | 4 Participants | 4 Participants | 2 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 11 | 5 / 11 | 9 / 12 | 4 / 12 | 6 / 9 | 2 / 10 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 | 0 / 12 | 0 / 12 | 0 / 9 | 0 / 10 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Fospropofol (AUC(0-inf))
AUC(0-inf) is a measure of drug concentration equal to the area under the plasma concentration-time profile from time 0 to infinity. An arterial line (A-line) and venous line (V-line) were placed prior to dosing during each treatment period and used to collect blood samples for plasma concentration measurements at specific time points. Plasma arterial and venous concentrations of fospropofol were quantified by high-performance liquid chromatography with mass spectrometric detection (LC-MS/MS). The AUC(0-inf) was calculated from the sum of AUC from time 0 to time t (AUC(0-t)) and the residual area calculated as Ct/λz, where Ct was the observed concentration at last quantifiable concentration and λz was the terminal elimination rate constant. The plasma concentrations from the venous sampling were descriptively compared head-to-head with the arterial sampling.
Time frame: Days 1, and 7-14 (Arterial Sample: Pre-dose, and 0.5, 1, 1.5, 2, 4, 8, 16, 30, 45, 60, 120, 180, 240, 300, and 360 minutes post-dose. Venous Sample: Pre-dose, and 1, 4, and 30 minutes post-dose).
Population: Pharmacokinetic (PK) Analysis Set is the group of participants who have sufficient pharmacokinetic data to derive at least one PK parameter.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fospropofol 6.5 mg/kg | Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Fospropofol (AUC(0-inf)) | 16522 ug.h/L | Standard Deviation 3639.1 |
| Fospropofol 10 mg/kg | Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Fospropofol (AUC(0-inf)) | 25052 ug.h/L | Standard Deviation 5923.8 |
| Fospropofol 15 mg/kg | Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Fospropofol (AUC(0-inf)) | 36629 ug.h/L | Standard Deviation 5903.3 |
Primary
Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Propofol
An A-line and V-line were placed prior to dosing during each treatment period and used to collect blood samples for plasma concentration measurements at specific time points. Plasma arterial and venous concentrations of propofol were quantified by high-performance liquid chromatography with mass spectrometric detection (LC-MS/MS). The AUC(0-inf) was calculated from the sum of AUC(0-t) and the residual area calculated as Ct/λz, where Ct was the observed concentration at last quantifiable concentration and λz was the terminal elimination rate constant. The plasma concentrations from the venous sampling were descriptively compared head-to-head with the arterial sampling. In addition, the arterial plasma concentrations of fospropofol, propofol liberated from fospropofol, and propofol delivered from propofol injectable emulsion were used to refine the population PK model developed previously.
Time frame: Days 1, and 7-14 (Arterial Sample: Pre-dose, and 0.5, 1, 1.5, 2, 4, 8, 16, 30, 45, 60, 120, 180, 240, 300, and 360 minutes post-dose. Venous Sample: Pre-dose, and 1, 4, and 30 minutes post-dose).
Population: PK Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fospropofol 6.5 mg/kg | Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Propofol | 1541 ug.h/L | Standard Deviation 224.7 |
| Fospropofol 10 mg/kg | Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Propofol | 467 ug.h/L | Standard Deviation 88.3 |
| Fospropofol 15 mg/kg | Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Propofol | 2368 ug.h/L | Standard Deviation 435.3 |
| Propofol 1.0 mg/kg | Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Propofol | 661 ug.h/L | Standard Deviation 147.3 |
| Fospropofol 15 mg/kg | Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Propofol | 3807 ug.h/L | Standard Deviation 466.2 |
| Propofol 1.5 mg/kg | Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Propofol | 893 ug.h/L | Standard Deviation 127.7 |
Primary
Area Under the Plasma Concentration-Time Curve From Time 0 to Time t (AUC(0-t)) of Fospropofol
Arterial and venous blood samples were collected and analyzed for fospropofol concentrations as described previously. AUC(0-t) was calculated using the log-linear trapezoidal rule (linear trapezoidal rule up to maximum observed plasma concentration (Cmax), log trapezoidal rule following Cmax) from time of dosing to the last quantifiable concentration. The plasma concentrations from the venous sampling were descriptively compared head-to-head with the arterial sampling.
Time frame: Days 1, and 7-14 (Arterial Sample: Pre-dose, and 0.5, 1, 1.5, 2, 4, 8, 16, 30, 45, 60, 120, 180, 240, 300, and 360 minutes post-dose. Venous Sample: Pre-dose, and 1, 4, and 30 minutes post-dose).
Population: PK Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fospropofol 6.5 mg/kg | Area Under the Plasma Concentration-Time Curve From Time 0 to Time t (AUC(0-t)) of Fospropofol | 16046 ug.h/L | Standard Deviation 3439.6 |
| Fospropofol 10 mg/kg | Area Under the Plasma Concentration-Time Curve From Time 0 to Time t (AUC(0-t)) of Fospropofol | 24473 ug.h/L | Standard Deviation 5729.5 |
| Fospropofol 15 mg/kg | Area Under the Plasma Concentration-Time Curve From Time 0 to Time t (AUC(0-t)) of Fospropofol | 36330 ug.h/L | Standard Deviation 5488.7 |
Primary
Area Under the Plasma Concentration-Time Curve From Time 0 to Time t of Propofol
Arterial and venous blood samples were collected and analyzed for propofol concentrations as described previously. AUC(0-t) was calculated using the log-linear trapezoidal rule (linear trapezoidal rule up to Cmax, log trapezoidal rule following Cmax) from time of dosing to the last quantifiable concentration. The plasma concentrations from the venous sampling were descriptively compared head-to-head with the arterial sampling. In addition, the arterial plasma concentrations of fospropofol, propofol liberated from fospropofol, and propofol delivered from propofol injectable emulsion were used to refine the population PK model developed previously.
Time frame: Days 1, and 7-14 (Arterial Sample: Pre-dose, and 0.5, 1, 1.5, 2, 4, 8, 16, 30, 45, 60, 120, 180, 240, 300, and 360 minutes post-dose. Venous Sample: Pre-dose, and 1, 4, and 30 minutes post-dose).
Population: PK Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fospropofol 6.5 mg/kg | Area Under the Plasma Concentration-Time Curve From Time 0 to Time t of Propofol | 1343 ug.h/L | Standard Deviation 166.9 |
| Fospropofol 10 mg/kg | Area Under the Plasma Concentration-Time Curve From Time 0 to Time t of Propofol | 385 ug.h/L | Standard Deviation 84.5 |
| Fospropofol 15 mg/kg | Area Under the Plasma Concentration-Time Curve From Time 0 to Time t of Propofol | 2009 ug.h/L | Standard Deviation 413.9 |
| Propofol 1.0 mg/kg | Area Under the Plasma Concentration-Time Curve From Time 0 to Time t of Propofol | 578 ug.h/L | Standard Deviation 107.2 |
| Fospropofol 15 mg/kg | Area Under the Plasma Concentration-Time Curve From Time 0 to Time t of Propofol | 3019 ug.h/L | Standard Deviation 468.2 |
| Propofol 1.5 mg/kg | Area Under the Plasma Concentration-Time Curve From Time 0 to Time t of Propofol | 801 ug.h/L | Standard Deviation 141.6 |
Primary
Maximum Drug Plasma Concentration (Cmax) of Fospropofol
Arterial and venous blood samples were collected and analyzed for fospropofol concentrations as described previously. Cmax was the highest plasma drug concentration observed over the entire sampling period, and was obtained directly from the experimental plasma concentration time data without interpolation. The plasma concentrations from the venous sampling were descriptively compared head-to-head with the arterial sampling.
Time frame: Days 1, and 7-14 (Arterial Sample: Pre-dose, and 0.5, 1, 1.5, 2, 4, 8, 16, 30, 45, 60, 120, 180, 240, 300, and 360 minutes post-dose. Venous Sample: Pre-dose, and 1, 4, and 30 minutes post-dose).
Population: PK Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fospropofol 6.5 mg/kg | Maximum Drug Plasma Concentration (Cmax) of Fospropofol | 95.6 ug/mL | Standard Deviation 16.45 |
| Fospropofol 10 mg/kg | Maximum Drug Plasma Concentration (Cmax) of Fospropofol | 146.3 ug/mL | Standard Deviation 25.6 |
| Fospropofol 15 mg/kg | Maximum Drug Plasma Concentration (Cmax) of Fospropofol | 207.3 ug/mL | Standard Deviation 29.17 |
Primary
Maximum Drug Plasma Concentration of Propofol
Arterial and venous blood samples were collected and analyzed for propofol concentrations as described previously. Cmax was the highest plasma drug concentration observed over the entire sampling period, and was obtained directly from the experimental plasma concentration time data without interpolation. The plasma concentrations from the venous sampling were descriptively compared head-to-head with the arterial sampling.
Time frame: Days 1, and 7-14 (Arterial Sample: Pre-dose, and 0.5, 1, 1.5, 2, 4, 8, 16, 30, 45, 60, 120, 180, 240, 300, and 360 minutes post-dose. Venous Sample: Pre-dose, and 1, 4, and 30 minutes post-dose).
Population: PK Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fospropofol 6.5 mg/kg | Maximum Drug Plasma Concentration of Propofol | 1.5 ug/mL | Standard Deviation 0.47 |
| Fospropofol 10 mg/kg | Maximum Drug Plasma Concentration of Propofol | 8 ug/mL | Standard Deviation 6 |
| Fospropofol 15 mg/kg | Maximum Drug Plasma Concentration of Propofol | 2.1 ug/mL | Standard Deviation 0.74 |
| Propofol 1.0 mg/kg | Maximum Drug Plasma Concentration of Propofol | 8.6 ug/mL | Standard Deviation 6.39 |
| Fospropofol 15 mg/kg | Maximum Drug Plasma Concentration of Propofol | 3.1 ug/mL | Standard Deviation 0.7 |
| Propofol 1.5 mg/kg | Maximum Drug Plasma Concentration of Propofol | 9.5 ug/mL | Standard Deviation 4.44 |
Secondary
Maximal Sedative Effect Using the Bispectral Index (BIS) Score
Pharmacodynamic (PD) effects were obtained from continuous BIS score recordings obtained throughout the study and from clinical assessment of sedation using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale. The BIS measurements continued until the participant was fully recovered in the opinion of the investigator or until the PD effect measure returned to baseline. The BIS score varied between 100 (associated with being fully awake) and 0 (associated with a flat line on the electroencephalogram (EEG)). The BIS Index was described by the maximal effect (Emax) model.
Time frame: Days 1, and 7-14 (BIS measurements were to continue until the subject was fully recovered in the opinion of the investigator or until the PD effect measures returned to baseline measures)
Population: PD analysis set included all participants who had sufficient PD data to derive at least one PD assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fospropofol 6.5 mg/kg | Maximal Sedative Effect Using the Bispectral Index (BIS) Score | 70.2 Scores on a scale | Standard Deviation 10.3 |
| Fospropofol 10 mg/kg | Maximal Sedative Effect Using the Bispectral Index (BIS) Score | 81.5 Scores on a scale | Standard Deviation 8.12 |
| Fospropofol 15 mg/kg | Maximal Sedative Effect Using the Bispectral Index (BIS) Score | 55.4 Scores on a scale | Standard Deviation 11.35 |
| Propofol 1.0 mg/kg | Maximal Sedative Effect Using the Bispectral Index (BIS) Score | 65.8 Scores on a scale | Standard Deviation 15.17 |
| Fospropofol 15 mg/kg | Maximal Sedative Effect Using the Bispectral Index (BIS) Score | 38.6 Scores on a scale | Standard Deviation 7.78 |
| Propofol 1.5 mg/kg | Maximal Sedative Effect Using the Bispectral Index (BIS) Score | 49 Scores on a scale | Standard Deviation 10.1 |
Secondary
Maximal Sedative Effect Using the Modified Observer's Assessment of Alertness/Sedation Scale
PD effects were determined from continuous BIS score recordings and from clinical assessment of sedation using the MOAA/S scale. The MOAA/S scale was used to rate the level of alertness/sedation from a score of 0 (does not respond to painful stimulus) to 5 (alert) in the category of responsiveness, with 5 being the MOAA/S value for a fully awake adult. Time to sedation was defined as the time from the first dose of study medication to the first two consecutive MOAA/S scores less than or equal to 4. Fully awake status was reached at the first of 3 consecutive MOAA/S scores of 5 measured every 2 minutes after study drug administration. The MOAA/S scale was described by the Emax model.
Time frame: Days 1, and 7-14 (2 minutes prior to study drug administration and every 2 minutes thereafter for 20 minutes or until the subject reached Fully Alert status, whichever was later).
Population: PD Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fospropofol 6.5 mg/kg | Maximal Sedative Effect Using the Modified Observer's Assessment of Alertness/Sedation Scale | 4.1 Scores on a scale | Standard Deviation 1.58 |
| Fospropofol 10 mg/kg | Maximal Sedative Effect Using the Modified Observer's Assessment of Alertness/Sedation Scale | 4.7 Scores on a scale | Standard Deviation 0.65 |
| Fospropofol 15 mg/kg | Maximal Sedative Effect Using the Modified Observer's Assessment of Alertness/Sedation Scale | 2.8 Scores on a scale | Standard Deviation 1.64 |
| Propofol 1.0 mg/kg | Maximal Sedative Effect Using the Modified Observer's Assessment of Alertness/Sedation Scale | 3.9 Scores on a scale | Standard Deviation 1.44 |
| Fospropofol 15 mg/kg | Maximal Sedative Effect Using the Modified Observer's Assessment of Alertness/Sedation Scale | 0.3 Scores on a scale | Standard Deviation 0.71 |
| Propofol 1.5 mg/kg | Maximal Sedative Effect Using the Modified Observer's Assessment of Alertness/Sedation Scale | 1.7 Scores on a scale | Standard Deviation 1.57 |
Secondary
Relative Bioavailability of Fospropofol and Propofol
The PK parameters for propofol from propofol injectable emulsion were used as the reference formulation. Because propofol is a metabolite of fospropofol, all calculations were conducted after correcting for the different molecular weights of these formulations. Molecular weights of 332.24 (288.24 for free base) and 178.27 were used for fospropofol disodium and propofol injectable emulsion, respectively. The propofol parameters were adjusted as appropriate as discussed above and natural log transformed prior to comparison. Relative bioavailability of propofol from fospropofol disodium (E2083) to propofol from propofol injectable emulsion is calculated as (AUC(FP) x Total Dose of Propofol/AUC(P) x Total Dose of E2083) x Molecular fraction, where AUC(FP) is AUC(0-t) or AUC(0-inf) of propofol from E2083, AUC(P) is AUC(0-t) or AUC(0-inf) of propofol from propofol injectable emulsion and molecular fraction is molecular weight of propofol (178.27)/E2083 (332.24).
Time frame: Days 1, and 7-14 (Arterial Sample: Pre-dose, and 0.5, 1, 1.5, 2, 4, 8, 16, 30, 45, 60, 120, 180, 240, 300, and 360 minutes post-dose. Venous Sample: Pre-dose, and 1, 4, and 30 minutes post-dose).
Population: PK Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fospropofol 6.5 mg/kg | Relative Bioavailability of Fospropofol and Propofol | AUC(0-t) | 0.684 ng x hr/mL | Standard Deviation 0.1505 |
| Fospropofol 6.5 mg/kg | Relative Bioavailability of Fospropofol and Propofol | AUC(0-inf) | 0.694 ng x hr/mL | Standard Deviation 0.0882 |
| Fospropofol 10 mg/kg | Relative Bioavailability of Fospropofol and Propofol | AUC(0-t) | 0.661 ng x hr/mL | Standard Deviation 0.0987 |
| Fospropofol 10 mg/kg | Relative Bioavailability of Fospropofol and Propofol | AUC(0-inf) | 0.68 ng x hr/mL | Standard Deviation 0.0495 |
| Fospropofol 15 mg/kg | Relative Bioavailability of Fospropofol and Propofol | AUC(0-t) | 0.713 ng x hr/mL | Standard Deviation 0.0671 |
| Fospropofol 15 mg/kg | Relative Bioavailability of Fospropofol and Propofol | AUC(0-inf) | 0.836 ng x hr/mL | Standard Deviation 0.0198 |