A PK/PD Study of Fospropofol Disodium Compared With Propofol Injectable Emulsion

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Open-Label, Single-Bolus, 2-Period, Multi-Dose Level, 3 Cohort Crossover Design, Pharmacokinetic/Pharmacodynamic Study of Lusedra (Fospropofol Disodium) Injection Compared With Propofol Injectable Emulsion

Conditions
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Anesthesia

Intervention / Treatment
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* Drug: Fospropofol disodium, propofol
* Drug: Fospropofol disodium, propofol
* Drug: Fospropofol disodium, propofol


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br> | Drug: Fospropofol disodium, propofol<br>* 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.<br>|
| Experimental: Arm 2<br> | Drug: Fospropofol disodium, propofol<br>* Two Treatment Periods: fospropofol disodium 10.0 mg/kg single intravenous (IV) bolus followed by propofol injectable emulsion 1.0 mg/kg IV bolus, or propofol injectable emulsion 1.0 mg/kg IV bolus followed by fospropofol disodium 10.0 mg/kg IV bolus.<br>|
| Experimental: Arm 3<br> | Drug: Fospropofol disodium, propofol<br>* Two Treatment Periods: fospropofol disodium 15.0 mg/kg single intravenous (IV) bolus followed by propofol injectable emulsion 1.5 mg/kg IV bolus, or propofol injectable emulsion 1.5 mg/kg IV bolus followed by fospropofol disodium 15.0 mg/kg IV bolus.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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). | 
| 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. | 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). | 
| 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. | 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). | 
| 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. | 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). | 
| 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. | 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). | 
| 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. | 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). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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) | 
| 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. | 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). | 
| 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). | 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). |