Transcript Temple/Artesian Poster

Population Pharmacokinetics of Dexmedetomidine in Infants Following Open Heart Surgery
Felice Su MD, Susan C. Nicolson MD, Jeffrey S. Barrett PhD, Peter C. Adamson MD,
David S. Kang BS, Rodolfo Godinez MD PhD, 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 #MO1-RR-00240 & NICHD, PPRU #HD037255-09
•To define the PK and safety of DEX in infants following open heart surgery
•To develop a population PK model exploring sources of variability in DEX PK
Study Design
Patient population
• 36 evaluable infants post-operative from open heart surgery
-
Age: ≥1 month and < 24 months
Isolated heart surgery
Post-operative tracheal intubation
Normal renal function
Normal hepatic function
Informed consent
Weight ≥ 5 kg
Exclusion Criteria
-
Investigational drug within the past 30 days
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
Design and Conduct
• Dose escalation study
• Loading dose immediately followed by a continuous intravenous infusion (CIVI)
• Dexmedetomidine infusion ≤ 24 hours
Bolus
mcg/kg
Infusion
mcg/kg/hr
Low (n=12)
0.35
0.25
Medium (n=12)
0.70
0.50
High (n=12)
1.00
0.75
Dose Level
Methods
Dosing Level 1
Dosing Level 2
9.3 (3.3-20.4)
7.8 (3.9-18.5)
Age (months), median (range)
Aims
Inclusion Criteria
Pattern of Inter-individual Error in Clearance vs. Weight
A.
Dosing Level 3
7.2 (2.6-19.6)
6.9 (5.1-11.2)
Overall
Weight (kg)
7.5 (5.3-11.9)
7.0 (5.4-10.2)
Gender
Female
5
6
5
Male
7
6
7
Surgical procedure
Two ventricle physiology
Atrial septal defect repair
1
1
CAVC repair
1
2
RV – PA conduit revision
1
Subaortic membrane resection
1
3
PAPVR repair
1
Rastelli
1
1
Ross-Kono
1
Tetralogy of Fallot repair
3
1
2
VSD4 repair
2
1
Single ventricle physiology
Bidirectional Glenn (BDG5)
5
4
3
5
6
BDG & DKS
1
5
7
BDG & TAPVR repair
1
Kawashima
1
Hemi-Fontan
2
2
Cardiopulmonary bypass (min)
52.5 (16-70), n=12 60 (24-99), n=12 58 (28-169), n=12
Total bypass
19 (8-53), n=9
29 (13-61), n=10 26 (17-90), n=11
Cross-clamp
28, n=1
15 (2-31), n=5
25 (17-89), n=7
Circulatory arrest
– Common atrioventricular canal
– Right ventricle-pulmonary artery
3PAPVR – Partial anomalous pulmonary venous return
4VSD – Ventricular septal defect
Without allometric relationship
7.0
16
20
17
Weight (kg)
19
5BDG
2RV-PA
6DKS
B.
•
•
•
•
58
26
25
Simulations
• Final model was used to perform 500 simulations for an infant with a weight of 7.0 kg
who received 58 minutes of cardiopulmonary bypass with a fixed rate infusion of 0.25
mcg/kg/hour:
- No bolus dose
- 0.35 mcg/kg bolus
- 0.75 mcg/kg bolus
• Median plasma concentrations were plotted against time to assess the impact of the
bolus dose on the time to steady state concentration
CL (mL/min/kg0.75)
31.2 (5.4)
Q
(mL/min/kg0.75)
Patient Population
Adults1
Clearance
(mL/kg/min)
Volume of
Distribution
(L/kg)
9.0
1.6
13 – 16.8
1.8 – 2.3
31.2
2.6
181.4 (27.1)
Children2
V1 (L/kg)
1.1 (15.1)
V2 (L/kg1)
1.5 (6.4)
Study Population
1Hospira,
Total bypass effect
1.2 (25.6)
2Petroz
Precedex Product Label 2004
GC, et al. Anesthesiology 2006. 105:1098–1110
▲ Dose Level 3
• Middle line – Bolus of 0.35 mcg/kg
over ten min followed by 0.25
mcg/kg/hr
• Top line - Bolus of 0.75 mcg/kg over
ten min followed by 0.25 mcg/kg/hour
Time from end of infusion (minutes)
Minutes
Safety Monitoring
• Cardiovascular events
- 3 subjects with increased cardiac ischemia possibly related to study drug not clinically significant (Dose 1, n = 2; Dose 3 n = 1)
- 1 subject developed intermittent accelerated junctional rhythm possibly related to study drug not clinically significant (Dose 2)
- 1 subject developed intermittent complete heart block with bradycardia possibly related to study drug resulting in discontinuation of infusion (Dose 2)
• 1 subject in Dose 3 developed oversedation and hypopnea requiring discontinuation of infusion
• No evidence of elevated transaminases, ocular dryness or clinically significant adrenal suppression
• Drop-outs
- 1 subject experienced hypotension with ongoing post-operative bleeding during administration of bolus dose without initiation of infusion
- 1 subject was removed from study due to leakage of peripheral IV catheter
Conclusions
Population Predicted vs. Observed Concentration Individual Predicted vs. Observed Concentration
•
•
•
•
•
•
Individual Predicted
Plasma Concentration (pg/mL)
Covariate analysis
• Covariate analysis included age, weight, total cardiopulmonary bypass time, cross
clamp time, and circulatory arrest time as continuous variables and ventricular
physiology (single or two ventricles) as a categorical variable
Estimate (SE%)
Population Predicted
Plasma Concentration (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
Parameter
• Bottom line – 0.25 mcg/kg/hour
without a bolus
■ Dose Level 2
CL influenced by weight
Q influenced by weight and total bypass time
V2 influenced by weight
No difference in single or two ventricle physiology
Validated liquid chromatography & tandem mass spectrometry assay
Simulated Plasma DEX Concentrations
● Dose Level 1
Final model:
CL = θCL * (WT/ 7.0)0.75
Q = θQ * (WT/ 7.0)0.75 *(TBYP/58) θTBYP
V1 = θV1
V2 = θV2* (WT/ 7.0)1
Weight (kg)
Semi-logarithmic Concentration – Time Profile
– Bidirectional Glenn
– Damus-Kaye-Stansel
7TAPVR – Total anomalous pulmonary venous return
1CAVC
With allometric relationship
7.8
Inter-individual Error
Demographics
Individual Predicted
Plasma Concentration (pg/mL)
Dexmedetomidine (DEX) is a highly selective α2agonist with hypnotic, analgesic and anxiolytic
properties. In intubated adults, it provides sedation
while preserving respiratory function facilitating
extubation. Only limited pharmacokinetic (PK) data
is available for pediatric patients.
Results
C.
C.
Inter-individual Error
Results
Dexmedetomidine
Plasma Concentration (pg/mL)
Background and Significance
Observed Plasma Concentrations (pg/mL)
Dexmedetomidine appears to be safe in infants with congenital heart disease following open heart surgery
The were no serious adverse events attributed to study drug
In infants following open heart surgery, dexmedetomidine clearance and volume of distribution is higher than reported values in older children
Single versus two-ventricle physiology did not impact dexmedetomidine pharmacokinetics
Without an appropriate loading dose, time to steady state concentration is approximately 6 hours after the initiation of a continuous infusion
Simulations suggest that a ratio of the bolus dose to continuous infusion rate of 3:1 is required to achieve steady state concentrations rapidly
Acknowledgements
Observed Plasma Concentrations (pg/mL)
• Clinical and Translational Research Center Nursing
• Cardiac Center and Cardiac ICU Staff
• Carey Roth Bayer
• James Lee
• Di Wu
• Zombor Zoltani