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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