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

November 30, 2016 updated by: Eisai Inc.

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

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.

Study Overview

Study Type

Interventional

Enrollment (Actual)

36

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 45 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Arm 1
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.
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.
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.
Experimental: Arm 2
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.
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.
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.
Experimental: Arm 3
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.
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.
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.

What is the study measuring?

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))
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).
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
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).
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
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).
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
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).
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
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).
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
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).
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
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)
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
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).
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
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).
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).

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Investigators

  • Study Director: Randi Fain, Eisai Inc.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2010

Primary Completion (Actual)

February 1, 2011

Study Completion (Actual)

March 1, 2011

Study Registration Dates

First Submitted

December 13, 2010

First Submitted That Met QC Criteria

December 13, 2010

First Posted (Estimate)

December 15, 2010

Study Record Updates

Last Update Posted (Estimate)

January 27, 2017

Last Update Submitted That Met QC Criteria

November 30, 2016

Last Verified

November 1, 2016

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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