1. Background and Significance C. B. C. A. B. 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 Conclusions 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 Inclusion Criteria ­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 Aims Dexmedetomidine (DEX) is a highly selective α2- agonist 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. Dose Level Bolus mcg/kg Infusion mcg/kg/hr Low (n=12)0.350.25 Medium (n=12)0.700.50 High (n=12)1.000.75 Demographics ParameterEstimate (SE%) CL (mL/min/kg 0.75 ) 31.2 (5.4) Q (mL/min/kg 0.75 ) 181.4 (27.1) V 1 (L/kg) 1.1 (15.1) V 2 (L/kg 1 ) 1.5 (6.4) Total bypass effect1.2 (25.6) Patient Population Clearance (mL/kg/min) Volume of Distribution (L/kg) Adults 1 9.01.6 Children 2 13 – 16.81.8 – 2.3 Study Population31.22.6 1 Hospira, Precedex Product Label 2004 2 Petroz GC, et al. Anesthesiology 2006. 105:1098–1110 Population Predicted vs. Observed Concentration Observed Plasma Concentrations (pg/mL) Population Predicted Plasma Concentration (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 Design and Conduct Dose escalation study Loading dose immediately followed by a continuous intravenous infusion (CIVI) Dexmedetomidine infusion ≤ 24 hours Acknowledgements Results Clinical and Translational Research Center Nursing Cardiac Center and Cardiac ICU Staff Carey Roth Bayer James Lee Di Wu Zombor Zoltani Results 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 Individual Predicted vs. Observed Concentration Individual Predicted Plasma Concentration (pg/mL) Observed Plasma Concentrations (pg/mL) Methods Validated liquid chromatography & tandem mass spectrometry assay 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 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 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 Semi-logarithmic Concentration – Time Profile Time from end of infusion (minutes) ● Dose Level 1 ■ Dose Level 2 ▲ Dose Level 3 Dexmedetomidine Plasma Concentration (pg/mL) Final model: CL = θ CL * (WT/ 7.0) 0.75 Q = θ Q * (WT/ 7.0) 0.75 *(TBYP/58) θTBYP V1 = θ V1 V2 = θ V2 * (WT/ 7.0) 1 Bottom line – 0.25 mcg/kg/hour without a bolus 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 Simulated Plasma DEX Concentrations Individual Predicted Plasma Concentration (pg/mL) Minutes CL influenced by weight Q influenced by weight and total bypass time V 2 influenced by weight No difference in single or two ventricle physiology Pattern of Inter-individual Error in Clearance vs. Weight Without allometric relationship With allometric relationship Inter-individual Error Weight (kg) Inter-individual Error Dosing Level 1Dosing Level 2Dosing Level 3Overall Age (months), median (range) 9.3 (3.3-20.4)7.8 (3.9-18.5) 7.2 (2.6-19.6) 7.8 Weight (kg) 7.5 (5.3-11.9)7.0 (5.4-10.2) 6.9 (5.1-11.2) 7.0 Gender Female Male 5757 6666 5757 16 20 Surgical procedure Two ventricle physiology Atrial septal defect repair CAVC 1 repair RV – PA 2 conduit revision Subaortic membrane resection PAPVR 3 repair Rastelli Ross-Kono Tetralogy of Fallot repair VSD 4 repair Single ventricle physiology Bidirectional Glenn (BDG 5 ) BDG 5 & DKS 6 BDG 5 & TAPVR 7 repair Kawashima Hemi-Fontan 11325 11325 1111141211111412 1121311211213112 17 19 Cardiopulmonary bypass (min) Total bypass Cross-clamp Circulatory arrest 52.5 (16-70), n=12 19 (8-53), n=9 28, n=1 60 (24-99), n=12 29 (13-61), n=10 15 (2-31), n=5 58 (28-169), n=12 26 (17-90), n=11 25 (17-89), n=7 58 26 25 1 CAVC – Common atrioventricular canal 2 RV-PA – Right ventricle-pulmonary artery 3 PAPVR – Partial anomalous pulmonary venous return 4 VSD – Ventricular septal defect 5 BDG – Bidirectional Glenn 6 DKS – Damus-Kaye-Stansel 7 TAPVR – Total anomalous pulmonary venous return