Temple/Artesian Poster

1
A Phase 1 Trial and Pharmacokinetic Study of
Dexmedetomidine in Neonates Following Open Heart
SurgeryFelice 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 Childrens
Hospital of Philadelphia Funded by NIH, GCRC
M01-RR-00240 NICHD, PPRU HD037255-09

C.
C.
Preliminary Results
Background and Significance
Analysis
Dexmedetomidine is a highly selective a2-agonist
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
Population Predicted vs. Observed Dexmedetomidine
Concentrations
Individual Predicted vs. Observed Dexmedetomidine
Concentrations
Standard pg/mL
1 5
2 10
3 25
4 50
5 100
6 250
7 500
8 1000
9 1500
1500 pg/mL ?
Aims
Population Predicted Plasma Concentration (pg/mL)

• Primary
• To define the pharmacokinetics and safety of
  dexmedetomidine in neonates following open heart
  surgery
• Secondary
• Pharmacodynamics
• Tracheal extubation readiness
• Relationship between level of sedation and
  plasma concentration
• Supplemental sedation requirements
• Impact on heart rate and blood pressure

Individual Predicted Plasma Concentration (pg/mL)
5 pg/mL ?
Observed Plasma Concentrations (pg/mL)
Observed Plasma Concentrations (pg/mL)

• 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

• 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

Study Design
Representative Patient UMSS-Plasma Concentration
vs. Time (Dose Level 1)

• Patient population
• 36 evaluable neonates post-operative from open
  heart surgery

Inclusion Criteria Age 1 month Postconceptual age 37 weeks Isolated heart surgery Anticipated tracheal intubation lt 24 hours Normal renal function Normal hepatic function Informed consent 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 lt 2 kg
Dexmedetomidine Plasma Concentration (pg/mL)
UMSS
Preliminary Results
Demographics
Dosing Level 1 Dosing Level 2 Overall Overall
Age (days), median (range) 3 (2-18) 4 (2-7) 3.5 3.5
Weight (kg), median (range) 3.5 (2.3-4.3) 3.4 (3.4-3.6) 3.5 3.5
Gender Female Male 6 3 2 3 8 6 8 6
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 1 1 4 1 1 1 1 1 1 1 1 10 4 10 4
1VSD Ventricular septal defect 2BTS Blalock-Taussig shunt 3PA Pulmonary artery
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 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

• Pharmacokinetics
• Dose escalation study
• Loading dose immediately followed by a
  continuous intravenous infusion (CIVI)
• Dexmedetomidine infusion 24 hours

B.
B.
A.
Dose Level Bolus mcg/kg Infusion mcg/kg/hr
1 (n9) 0.25 0.2
2 (n9) 0.50 0.4
3 (n9) 0.75 0.6
4 (n9) 1.00 0.8
Conclusion
Preliminary 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

Pharmacokinetics

• 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

Patient Population Clearance (mL/kg/min) Volume of Distribution (L/kg)
Adults1 9.0 1.6
Children2 13 16.8 1.8 2.3
Infants3 31.2 2.6
Study Population 11.4 2.2
Parameter Estimate (SE)
Cl (mL/kg/min) 11.4 (8.2)
Q (mL/kg/min) 2.2 (102)
V1 (L/kg) 1.9 (25.3)
V2(L/kg) 0.4 (51.2)
University of Michigan Sedation Scale 0 Awake and alert 1 Minimally sedated tired/sleepy 2 Moderately sedated sleeping, easily arousable with light tactile stimulation or verbal command 3 Deeply sedated deep sleep, arousable only with significant physical stimulation 4 Unarousable
Vital signs Cardiac rhythm FiO2 University of Michigan Sedation Scale (UMSS) score Supplemental analgesia/sedation use Evaluation of tracheal extubation readiness
Future Directions
Analysis of pharmacokinetic covariates Pharmacodynamic analysis
Acknowledgements
1Hospira, Precedex Product Label 2004 2Petroz GC,
et al. Anesthesiology 2006. 10510981110 3Su F,
et al. The Childrens Hospital of Philadelphia.
Data not yet published.
CTRC Nursing Cardiac ICU Staff Division of Clinical Pharmacology and Therapeutics Laboratory
Iselin-Chaves IA, et al. Anesth Analg 1998. 87
949-55
Safety monitoring