A Phase 1 Trial and Pharmacokinetic Study of Dexmedetomidine
in Neonates Following Open Heart Surgery
Felice Su MD, Susan C. Nicolson MD, Jeffrey S. Barrett PhD, Peter C. Adamson MD, David S. Kang,
Mary Ann Diliberto, Athena F Zuppa MD MSCE
Division of Clinical Pharmacology and Therapeutics & Divisions of Cardiac Anesthesia and Critical Care Medicine, The Children’s Hospital of Philadelphia
Funded
by NIH, GCRC #M01-RR-00240 & NICHD, PPRU #HD037255-09
C.
C.
Background and Significance
Preliminary Results
Analysis
Dexmedetomidine is a highly selective α2agonist with hypnotic, analgesic and anxiolytic
properties.
In intubated adults, it provides
sedation while preserving respiratory function
facilitating extubation. There is no neonatal
pharmacokinetic (PK) or pharmacodynamic (PD)
data reported to guide therapy.
Validated liquid chromatography & tandem mass spectrometry assay
XIC of +MRM (2 pairs): 201.0/95.0 amu from Sample 12 (STD_9_1500 pg/ml) of Pt 3 & 4_111105.wiff (T...
Population Predicted vs. Observed
Dexmedetomidine Concentrations
Max. 4.0e5 cps.
3.79
4.0e5
3.8e5
3.6e5
3.4e5
Standard
pg/mL
1
5
2
10
3
25
4
50
5
100
6
250
7
500
8
1000
9
1500
1500 pg/mL 
I n t e n s it y , c p s
2.8e5
2.6e5
2.4e5
2.2e5
2.0e5
1.8e5
1.4e5
1.2e5
Aims
1.0e5
8.0e4
6.0e4
4.0e4
2.0e4
XIC of
0.0+MRM (2 pairs): 201.0/95.0 amu from Sample 4 (STD_1_5 pg/ml) of Pt 3 & 4_111105.wiff (Turb...
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Time, min
2100
Primary
•To define the pharmacokinetics and safety of dexmedetomidine in neonates
following open heart surgery
4.0
4.5
Max. 2100.0 cps.
5.0
5.5
3.83
2000
1900
5 pg/mL 
1800
1700
1600
1500
3.94
Patient population
• 36 evaluable neonates post-operative from open heart surgery
-
-
Exclusicon Criteria
Investigational drug since birth
Postoperative neuromuscular blockade
Ongoing bloodstream infection
Symptoms of elevated intracranial
pressure
Pre-existing hypotension based on age
Pre-existing bradycardia based on age
Heart block
Weight < 2 kg
2.14
1200
1.21
1100
4.01
1000
Dose Level
Infusion
mcg/kg/hr
1 (n=9)*
0.25
0.2
2 (n=9)*
0.50
0.4
3 (n=9)
0.75
0.6
4 (n=9)
1.00
0.8
* Preliminary
2.43
1.91
900
2.84 2.91 3.24
1.80
800
5.37
4.13
3.43
5.11
4.36
700
1.70
600
1.30
500
400
300
200
100
0
0.5
1.0
1.5
2.0
2.5
3.0
Time, min
3.5
4.0
4.5
5.0
Preliminary Results
Pharmacodynamics
• Tracheal extubation
- 6 subjects extubated successfully
while receiving infusion
- 3 subjects extubated shortly after
discontinuation of infusion
- 5 subjects not medically suitable
for extubation within 24 hours of
initiation of infusion
Demographics
Dosing Level 1
Dosing Level 2
Overall
Age (days), median (range)
3 (2-18)
4 (2-7)
3.5
Weight (kg), median (range)
3.5 (2.3-4.3)
3.4 (3.4-3.6)
3.5
Gender
Female
Male
Surgical procedure
Two ventricle physiology
Aortic arch reconstruction
Aortic arch reconstruction & VSD1 closure
Arterial switch operation
Tetralogy of Fallot repair
Truncus arteriosus repair
Single ventricle physiology
Stage I BTS2
Stage I BTS2 & PA3 reconstruction
6
3
2
3
8
6
10
1
1
4
1
1
1
1
4
1
1
1
1
Observed Plasma Concentrations (pg/mL)
Representative Patient UMSS-Plasma
Concentration vs. Time (Dose Level 1)
400
4
350
300
3
250
200
2
150
100
1
50
0
0
0
5
10
15
20
25
30
3
5
40
Time (hours)
Plasma Concentration
Safety Monitoring
• Cardiovascular events
- 2 subjects with increased cardiac ischemia
possibly related to study drug not clinically
significant (Dose 2, n = 2)
- 1 subject developed intermittent accelerated
junctional rhythm possibly related to study
drug not clinically significant (Dose 1)
• No evidence of elevated transaminases, ocular
dryness or clinically significant adrenal
suppression possibly, probably or definitely
related to study drug
UMSS
• Significant adverse events
- 1 subject experienced atrial ectopy with
hypotension (Dose 1)
- 3 subjects underwent mediastinal
exploration with clot removal (Dose 2)
- 3 subjects received CPR (Dose 2)
 2 subjects experienced profound
bradycardia and hypotension during
endotracheal suctioning
 1 subject experienced intermittent atrial
ectopy
– Ventricular septal defect
2BTS – Blalock-Taussig shunt
3PA – Pulmonary artery
1VSD
Conclusion
results reflect dose level 1 and 2
Pharmacodynamics
• Standardized intra-operative anesthetic
• Extubation while receiving dexmedetomidine infusion
• Collected for 48 hours following initiation of dexmedetomidine infusion:
University of Michigan Sedation Scale
- Vital signs
0 – Awake and alert
- Cardiac rhythm
1 – Minimally sedated: tired/sleepy
- FiO2
- University of Michigan Sedation Scale 2 – Moderately sedated: sleeping,
easily arousable with light tactile
(UMSS) score
stimulation or verbal command
- Supplemental analgesia/sedation use
3 – Deeply sedated: deep sleep,
- Evaluation of tracheal extubation
arousable only with significant
readiness
physical stimulation
4 – Unarousable
Iselin-Chaves IA, et al. Anesth Analg 1998. 87: 949-55
Safety monitoring
Observed Plasma Concentrations (pg/mL)
5.5
Base Model
• NONMEM ADVAN 3, TRANS 4, first order conditional estimation (FOCE) with interaction
• Two-compartment disposition model
Clearance (CL, mL/min), inter-compartmental clearance (Q, mL/min) volume of central
compartment (V1, L), volume of peripheral compartment (V2, L)
• Exponential error model for inter-individual variability
• Additive and proportional error model for random residual variability
Pharmacokinetics
• Dose escalation study
B.
A. immediately followed by a continuous intravenous
B.
• Loading dose
infusion (CIVI)
• Dexmedetomidine infusion ≤ 24 hours
Bolus
mcg/kg
2.23
UMSS
Study Design
1300
Dexmedetomidine Plasma
Concentration (pg/mL)
Secondary
•Pharmacodynamics
- Tracheal extubation readiness
- Relationship between level of sedation and plasma concentration
- Supplemental sedation requirements
- Impact on heart rate and blood pressure
I n t e n s it y , c p s
1400
Individual Predicted
Plasma Concentration (pg/mL)
3.0e5
Population Predicted
Plasma Concentration (pg/mL)
3.2e5
1.6e5
Inclusion Criteria
Age: ≤1 month
Postconceptual age ≥ 37 weeks
Isolated heart surgery
Anticipated tracheal intubation
< 24 hours
Normal renal function
Normal hepatic function
Informed consent
Individual Predicted vs. Observed
Dexmedetomidine Concentrations
Pharmacokinetics
Parameter
Cl (mL/kg/min)
Q (mL/kg/min)
V1 (L/kg)
V2(L/kg)
Estimate (SE%)
11.4 (8.2%)
2.2 (102%)
1.9 (25.3%)
0.4 (51.2%)
Clearance
(mL/kg/min)
Volume of
Distribution
(L/kg)
9.0
1.6
13 – 16.8
1.8 – 2.3
Infants3
31.2
2.6
Study
Population
11.4
2.2
Patient
Population
Adults1
Children2
•
•
•
•
Clearance appears to be reduced in neonates when compared to infants
An infusion of 0.4 mcg/kg/hour is associated with a number of significant adverse events
Dexmedetomidine at 0.2 mcg/kg/hour is well-tolerated in study population
Dexmedetomidine may facilitate tracheal extubation
Future Directions
• Analysis of pharmacokinetic covariates
• Pharmacodynamic analysis
Acknowledgements
1Hospira,
Precedex Product Label 2004
2Petroz GC, et al. Anesthesiology 2006. 105:1098–1110
3Su F, et al. The Children’s Hospital of Philadelphia. Data not yet published.
• CTRC Nursing
• Cardiac ICU Staff
• Division of Clinical Pharmacology and Therapeutics
Laboratory