Intubated and Mechanically Ventilated Pediatric Subjects
Conditions
Keywords
Pharmacokinetics, Pharmacodynamics, Escalating dose, Dexmedotimidine, Intubated, Mechanically ventilated, Pediatrics
Brief summary
The objective of this study is to characterize the pharmacokinetic and pharmacodynamic profile of dexmedetomidine administered as an intravenous loading dose followed by a continuous intravenous infusion in pediatric subjects ages ≥2 through \<17 years old.
Detailed description
This is a phase II, open-label, multicenter, escalating dose study evaluating the pharmacokinetics and pharmacodynamics of dexmedetomidine in pediatric subjects. The study population consists of initially intubated and mechanically ventilated pediatric subjects, ages ≥2 through \<17 years old, that require sedation in an intensive care setting for a minimum of 6 hours. Subjects will be divided into two groups based on age: Group I will consist of subjects ages ≥2 through \<6 years old and Group II subjects age ≥6 through \<17 years old. Within each group there will be four escalating dosing levels. Both groups can enroll simultaneously; however within each group, the next dose level cannot begin to enroll until all subjects have completed the previous dose level and the Data Safety Monitoring Board (DSMB) has approved enrollment to the next level. The level of sedation will be assessed using the Ramsay Sedation Scale (RSS). Based on these scores, and clinical judgment, additional sedation with midazolam will be administered according to the label. Pain will be assessed using the Faces, Legs, Arms, Cry & Consolability (FLACC) scale. Venous blood samples for pharmacokinetic analysis will be obtained at designated times. The pharmacodynamic and safety measures that will be monitored and the pharmacodynamic impact of dexmedetomidine on tracheal extubation will also be explored if subject is extubated within 24 hours.
Interventions
DRUGDexmedetomidine, midazolam; fentanyl
Dexmedetomidine for sedation; midazolam for rescue sedation according to label; fentanyl for rescue pain according to the label
Sponsors
Hospira, now a wholly owned subsidiary of Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 16 Years
Healthy volunteers
No
Inclusion criteria
* Initially intubated and mechanically ventilated pediatric subjects in an intensive care setting anticipated to require a minimum of 6 hours of continuous intravenous sedation. * Age: subjects must fit into one of the following age ranges at screening: * ≥2 years old through \<6 years old * ≥6 years old through \<17 years old * If female, subject is non-lactating and is either: 1. Not of childbearing potential, defined as pre-menarche, or surgically sterile due to bilateral tubal ligation, bilateral oophorectomy or hysterectomy. 2. Of childbearing potential but is not pregnant at time of baseline. * Subject's parent(s) or legal guardian(s) has/have voluntarily signed and dated the informed consent document approved by the Institutional Review Board. Assent will be obtained where age-appropriate and according to state regulations.
Exclusion criteria
* Pediatric subjects with neurological conditions that prohibit an evaluation of sedation * Diminished consciousness from increased intracranial pressure. * Extensive brain surgery (surgery requiring intracranial pressure monitor). * Diminished cognitive function per PI's discretion. * Subjects with immobility from neuromuscular disease or continuous infusion of neuromuscular blocking agents. * Weight \<10 kg. * Subjects with second degree or third degree heart block unless subject has a pacemaker or pacing wires. * Hepatic impairment Serum glutamic pyruvic transaminase/Alanine aminotransferase (SGPT/ALT) \>100 U/L * Hypotension based on repeat assessments prior to starting study drug: * Age ≥2 years old through ≤12 years old: systolic blood pressure (SBP) \<80 mmHg * Age \>12 years old through \<17 years old: SBP \<90 mmHg * Pre-existing bradycardia prior to starting study drug defined as: * Age ≥2 years old through ≤6 years old: ≤70 beats per minute (bpm) * Age \>6 years old through ≤12 years old: ≤60 bpm * Age \>12 years old through ≤16 years old: ≤50 bpm * Acute thermal burns involving more than 15 percent total body surface area. * Subjects who have a known allergy to dexmedetomidine, midazolam (MDZ) or fentanyl. * Subjects with a life expectancy that is \<72 hours. * Subjects that are expected to have hemodialysis (continuous hemofiltration) or peritoneal dialysis within 48 hours. * Subjects who have been treated with α-2 agonists/antagonists within two weeks. * Subjects with a spinal cord injury above T5. * Subjects who have received another investigational drug within the past 30 days. * Subjects on nicotine replacement therapy. * Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of this clinical study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUC0-t) | ≤30 min prior to start of loading dose (LD); 5 min before finishing LD; 0.5,1,2 & 4-6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (within 24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4 & 10 hrs after end of MI. | Area under the concentration-time curve from time zero to the time of the last measurable concentration (AUC0-t) for Dexmedetomidine |
| Area Under the Concentration-time Curve From Time Zero to the Time Infinity (AUC0-∞) | ≤30 min prior to start of the loading dose (LD); 5 min before finishing the LD; 0.5,1,2&4 to 6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4&10 hrs after end of MI. | Area under the concentration-time curve from time zero to the time infinity (AUC0-∞) for Dexmedetomidine |
| Observed Peak Plasma Concentration | ≤30 min prior to start of the loading dose (LD); 5 min before finishing the LD; 0.5,1,2&4 to 6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4&10 hrs after end of MI. | Observed peak plasma concentration (Cmax) for Dexmedetomidine |
| Terminal Elimination Half-life (t1/2) | ≤30 min prior to start of loading dose (LD); 5 min before finishing LD; 0.5,1,2 & 4-6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (within 24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4 & 10 hrs after end of MI. | Terminal elimination half-life (t1/2) for Dexmedetomidine |
| Plasma Concentration at Steady State (Css) | ≤30 min prior to start of loading dose (LD); 5 min before finishing LD; 0.5,1,2 & 4-6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (within 24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4 & 10 hrs after end of MI. | Plasma concentration at steady state (Css) for Dexmedetomidine |
| Volume of Steady State Distribution (Vss) | ≤30 min prior to start of loading dose (LD); 5 min before finishing LD; 0.5,1,2 & 4-6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (within 24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4 & 10 hrs after end of MI. | Volume of steady state distribution (Vss) for Dexmedetomidine |
| Clearance (CL) | ≤30 min prior to start of loading dose (LD); 5 min before finishing LD; 0.5,1,2 & 4-6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (within 24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4 & 10 hrs after end of MI. | Clearance (CL) for Dexmedetomidine |
| Level of Sedation Based on Average Ramsay Sedation Scale (RSS) Score | Prior to loading (Baseline), 5 and 10 min during the load, at start of maintenance infusion and every 15 min for 1 hour, hourly during the maintenance period, before and within 5 min after midazolam or fentanyl dose during the dexmedetomidine infusion. | RSS Score range from 1 to 6: 1. Patient is anxious and agitated or restless, or both. 2. Patient is cooperative, orientated and tranquil. 3. Patient responds to command only. 4. Patient exhibits brisk response to light glabellar (between the eyebrows) tap or loud auditory stimulus. 5. Patient exhibits a sluggish response to light glabellar tap or loud auditory stimulus. 6. Patient exhibits no response to stimulus. |
| Number of Subjects Who Received Rescue Medication for Sedation (Midazolam) and Analgesics (Fentanyl) | During the treatment period (Approximately 24 hours) | Number of subjects who received rescue medication for Sedation (Midazolam) and analgesics (Fentanyl) while intubated during Treatment Period |
Countries
Guatemala, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 Dexmedetomidine: Loading dose (IV) 0.25 mcg/kg/hour for 10 minutes; Continuous dose (IV infusion) 0.2 mcg/kg/hour for 6-24 hours | 16 |
| Dose Level 2 Dexmedetomidine: Loading dose (IV) 0.5 mcg/kg/hour for 10 minutes; Continuous dose (IV infusion) 0.4 mcg/kg/hour for 6-24 hours | 14 |
| Dose Level 3 Dexmedetomidine: Loading dose (IV) 1.0 mcg/kg/hour for 10 minutes; Continuous dose (IV infusion) 0.7 mcg/kg/hour for 6-24 hours | 15 |
| Dose Level 4 Dexmedetomidine: Loading dose (IV) 1.0 mcg/kg/hour for 10 minutes; Continuous dose (IV infusion) 2.0 mcg/kg/hour for 6-24 hours | 14 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 |
| Overall Study | No Longer Meets Entry Criteria | 0 | 1 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Dose Level 2 | Dose Level 3 | Dose Level 1 | Dose Level 4 | Total |
|---|---|---|---|---|---|
| Age, Continuous | 7.457 years STANDARD_DEVIATION 4.599 | 8.379 years STANDARD_DEVIATION 4.4962 | 6.358 years STANDARD_DEVIATION 3.4673 | 7.462 years STANDARD_DEVIATION 4.2259 | 7.395 years STANDARD_DEVIATION 4.1571 |
| Age, Customized ≥2 through <6 years | 6 participants | 6 participants | 8 participants | 6 participants | 26 participants |
| Age, Customized ≥6 through <17 years | 8 participants | 9 participants | 8 participants | 8 participants | 33 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 12 Participants | 13 Participants | 12 Participants | 10 Participants | 47 Participants |
| Sex: Female, Male Female | 8 Participants | 9 Participants | 10 Participants | 5 Participants | 32 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 6 Participants | 9 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 16 | 12 / 14 | 10 / 15 | 13 / 14 |
| serious Total, serious adverse events | 1 / 16 | 0 / 14 | 0 / 15 | 0 / 14 |
Outcome results
Primary
Area Under the Concentration-time Curve From Time Zero to the Time Infinity (AUC0-∞)
Area under the concentration-time curve from time zero to the time infinity (AUC0-∞) for Dexmedetomidine
Time frame: ≤30 min prior to start of the loading dose (LD); 5 min before finishing the LD; 0.5,1,2&4 to 6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4&10 hrs after end of MI.
Population: Full Evaluable Population: Participants who received study drug infusion for at least 5 hours and had available PK data were included in the full evaluable population. This was the primary population for PK and PD analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Area Under the Concentration-time Curve From Time Zero to the Time Infinity (AUC0-∞) | 3153.518 picograms*hr/mL | Standard Deviation 3343.3451 |
| Dose Level 2 | Area Under the Concentration-time Curve From Time Zero to the Time Infinity (AUC0-∞) | 6673.163 picograms*hr/mL | Standard Deviation 3781.2183 |
| Dose Level 3 | Area Under the Concentration-time Curve From Time Zero to the Time Infinity (AUC0-∞) | 17300.539 picograms*hr/mL | Standard Deviation 29935.7647 |
| Dose Level 4 | Area Under the Concentration-time Curve From Time Zero to the Time Infinity (AUC0-∞) | 28970.541 picograms*hr/mL | Standard Deviation 17936.897 |
Primary
Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUC0-t)
Area under the concentration-time curve from time zero to the time of the last measurable concentration (AUC0-t) for Dexmedetomidine
Time frame: ≤30 min prior to start of loading dose (LD); 5 min before finishing LD; 0.5,1,2 & 4-6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (within 24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4 & 10 hrs after end of MI.
Population: Full Evaluable Population: Participants who received study drug infusion for at least 5 hours and had available PK data were included in the full evaluable population. This was the primary population for pharmacokinetic (PK) and pharmacodynamic (PD) analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUC0-t) | 2681.332 picograms*hr/mL | Standard Deviation 2353.3418 |
| Dose Level 2 | Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUC0-t) | 6460.576 picograms*hr/mL | Standard Deviation 3766.4657 |
| Dose Level 3 | Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUC0-t) | 16992.540 picograms*hr/mL | Standard Deviation 29927.3911 |
| Dose Level 4 | Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUC0-t) | 28531.864 picograms*hr/mL | Standard Deviation 17496.3985 |
Primary
Clearance (CL)
Clearance (CL) for Dexmedetomidine
Time frame: ≤30 min prior to start of loading dose (LD); 5 min before finishing LD; 0.5,1,2 & 4-6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (within 24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4 & 10 hrs after end of MI.
Population: Full Evaluable Population: Participants who received study drug infusion for at least 5 hours and had available PK data were included in the full evaluable population. This was the primary population for PK and PD analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Clearance (CL) | 32.208 Litre/hour | Standard Deviation 40.3982 |
| Dose Level 2 | Clearance (CL) | 20.268 Litre/hour | Standard Deviation 10.3508 |
| Dose Level 3 | Clearance (CL) | 18.565 Litre/hour | Standard Deviation 8.6995 |
| Dose Level 4 | Clearance (CL) | 22.199 Litre/hour | Standard Deviation 14.1623 |
Primary
Level of Sedation Based on Average Ramsay Sedation Scale (RSS) Score
RSS Score range from 1 to 6: 1. Patient is anxious and agitated or restless, or both. 2. Patient is cooperative, orientated and tranquil. 3. Patient responds to command only. 4. Patient exhibits brisk response to light glabellar (between the eyebrows) tap or loud auditory stimulus. 5. Patient exhibits a sluggish response to light glabellar tap or loud auditory stimulus. 6. Patient exhibits no response to stimulus.
Time frame: Prior to loading (Baseline), 5 and 10 min during the load, at start of maintenance infusion and every 15 min for 1 hour, hourly during the maintenance period, before and within 5 min after midazolam or fentanyl dose during the dexmedetomidine infusion.
Population: Full Evaluable Population: Participants who received study drug infusion for at least 5 hours and had available PK data were included in the full evaluable population. This was the primary population for PK and PD analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Level of Sedation Based on Average Ramsay Sedation Scale (RSS) Score | 2.4 units on a scale | Standard Deviation 0.96 |
| Dose Level 2 | Level of Sedation Based on Average Ramsay Sedation Scale (RSS) Score | 2.8 units on a scale | Standard Deviation 0.74 |
| Dose Level 3 | Level of Sedation Based on Average Ramsay Sedation Scale (RSS) Score | 2.4 units on a scale | Standard Deviation 0.5 |
| Dose Level 4 | Level of Sedation Based on Average Ramsay Sedation Scale (RSS) Score | 4.0 units on a scale | Standard Deviation 1.04 |
Primary
Number of Subjects Who Received Rescue Medication for Sedation (Midazolam) and Analgesics (Fentanyl)
Number of subjects who received rescue medication for Sedation (Midazolam) and analgesics (Fentanyl) while intubated during Treatment Period
Time frame: During the treatment period (Approximately 24 hours)
Population: Full Evaluable Population: Participants who received study drug infusion for at least 5 hours and had available PK data were included in the full evaluable population. This was the primary population for PK and PD analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Level 1 | Number of Subjects Who Received Rescue Medication for Sedation (Midazolam) and Analgesics (Fentanyl) | Midazolam | 7 participants |
| Dose Level 1 | Number of Subjects Who Received Rescue Medication for Sedation (Midazolam) and Analgesics (Fentanyl) | Fentanyl | 12 participants |
| Dose Level 2 | Number of Subjects Who Received Rescue Medication for Sedation (Midazolam) and Analgesics (Fentanyl) | Fentanyl | 10 participants |
| Dose Level 2 | Number of Subjects Who Received Rescue Medication for Sedation (Midazolam) and Analgesics (Fentanyl) | Midazolam | 7 participants |
| Dose Level 3 | Number of Subjects Who Received Rescue Medication for Sedation (Midazolam) and Analgesics (Fentanyl) | Midazolam | 5 participants |
| Dose Level 3 | Number of Subjects Who Received Rescue Medication for Sedation (Midazolam) and Analgesics (Fentanyl) | Fentanyl | 13 participants |
| Dose Level 4 | Number of Subjects Who Received Rescue Medication for Sedation (Midazolam) and Analgesics (Fentanyl) | Midazolam | 3 participants |
| Dose Level 4 | Number of Subjects Who Received Rescue Medication for Sedation (Midazolam) and Analgesics (Fentanyl) | Fentanyl | 8 participants |
Primary
Observed Peak Plasma Concentration
Observed peak plasma concentration (Cmax) for Dexmedetomidine
Time frame: ≤30 min prior to start of the loading dose (LD); 5 min before finishing the LD; 0.5,1,2&4 to 6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4&10 hrs after end of MI.
Population: Full Evaluable Population: Participants who received study drug infusion for at least 5 hours and had available PK data were included in the full evaluable population. This was the primary population for PK and PD analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Observed Peak Plasma Concentration | 480.437 picograms per milliliter | Standard Deviation 625.9946 |
| Dose Level 2 | Observed Peak Plasma Concentration | 847.691 picograms per milliliter | Standard Deviation 633.7352 |
| Dose Level 3 | Observed Peak Plasma Concentration | 3385.569 picograms per milliliter | Standard Deviation 7384.0699 |
| Dose Level 4 | Observed Peak Plasma Concentration | 3090.939 picograms per milliliter | Standard Deviation 1625.5241 |
Primary
Plasma Concentration at Steady State (Css)
Plasma concentration at steady state (Css) for Dexmedetomidine
Time frame: ≤30 min prior to start of loading dose (LD); 5 min before finishing LD; 0.5,1,2 & 4-6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (within 24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4 & 10 hrs after end of MI.
Population: Full Evaluable Population: Participants who received study drug infusion for at least 5 hours and had available PK data were included in the full evaluable population. This was the primary population for PK and PD analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Plasma Concentration at Steady State (Css) | 402.026 picograms per milliliter | Standard Deviation 535.1718 |
| Dose Level 2 | Plasma Concentration at Steady State (Css) | 539.848 picograms per milliliter | Standard Deviation 166.7423 |
| Dose Level 3 | Plasma Concentration at Steady State (Css) | 1347.284 picograms per milliliter | Standard Deviation 1308.0988 |
| Dose Level 4 | Plasma Concentration at Steady State (Css) | 2827.144 picograms per milliliter | Standard Deviation 1169.4226 |
Primary
Terminal Elimination Half-life (t1/2)
Terminal elimination half-life (t1/2) for Dexmedetomidine
Time frame: ≤30 min prior to start of loading dose (LD); 5 min before finishing LD; 0.5,1,2 & 4-6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (within 24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4 & 10 hrs after end of MI.
Population: Full Evaluable Population: Participants who received study drug infusion for at least 5 hours and had available PK data were included in the full evaluable population. This was the primary population for PK and PD analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Terminal Elimination Half-life (t1/2) | 1.546 hour | Standard Deviation 0.3401 |
| Dose Level 2 | Terminal Elimination Half-life (t1/2) | 1.743 hour | Standard Deviation 0.3018 |
| Dose Level 3 | Terminal Elimination Half-life (t1/2) | 2.045 hour | Standard Deviation 0.6582 |
| Dose Level 4 | Terminal Elimination Half-life (t1/2) | 2.145 hour | Standard Deviation 0.6763 |
Primary
Volume of Steady State Distribution (Vss)
Volume of steady state distribution (Vss) for Dexmedetomidine
Time frame: ≤30 min prior to start of loading dose (LD); 5 min before finishing LD; 0.5,1,2 & 4-6 hrs after start of maintenance infusion (MI); 30 min prior to end of MI (within 24 hrs of start of MI); 10 min after end of MI and 0.5,1,2,4 & 10 hrs after end of MI.
Population: Full Evaluable Population: Participants who received study drug infusion for at least 5 hours and had available PK data were included in the full evaluable population. This was the primary population for PK and PD analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Level 1 | Volume of Steady State Distribution (Vss) | 56.808 Litre | Standard Deviation 44.5127 |
| Dose Level 2 | Volume of Steady State Distribution (Vss) | 35.246 Litre | Standard Deviation 25.0233 |
| Dose Level 3 | Volume of Steady State Distribution (Vss) | 32.789 Litre | Standard Deviation 22.5478 |
| Dose Level 4 | Volume of Steady State Distribution (Vss) | 43.652 Litre | Standard Deviation 30.6577 |