Pharmacokinetic Study of Intranasal Dexmedetomidine in Pediatric Patients With Congenital Heart Disease

Phase 1

Terminated

Conditions: Congenital Heart Disease
Dexmedetomidine

Interventions: Drug: Dexmedetomidine

Registration Number: NCT03417999

Lead Sponsor: Children's Hospital of Philadelphia

Brief Summary: The main objectives of the study are to determine peak plasma drug concentration levels and corresponding time of dexmedetomidine following intranasal administration in children age ≥1 mo to ≤ 6 yr with congenital heart disease undergoing an elective diagnostic or interventional cardiac catheterization procedure.

Detailed Description: The high anxiety levels that children may experience during the preoperative period may be associated with negative medical, psychological, and social consequences. To reduce this stress, and to facilitate separation from parents and the induction of anesthesia, children are often given a sedative prior to undergoing a procedure. Dexmedetomidine is a highly selective a2-adrenergic receptor agonist with sedative, anxiolytic, and analgesic properties. While off-label in its use, the administration of dexmedetomidine by the intranasal route has become a popular and effective technique for sedation in children because it is non-invasive, easy to administer, well tolerated, and relatively fast in onset. Despite this, little consistent data have been published on its onset time, duration of action, or optimal dose. The only available pharmacokinetic (PK) data on dexmedetomidine in pediatric patients is in children who were administered IV dexmedetomidine. We are proposing a prospective open-label inter-subject cohort dose-escalation pharmacokinetic study to obtain peak dexmedetomidine drug concentration level in plasma and the corresponding time point following intranasal administration in the pediatric patient with cardiac disease.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 28

Inclusion Criteria

Male or female subjects age ≥1 mo to ≤6 yo.
Subjects must have congenital heart disease.
American Society of Anesthesiology (ASA) Physical Status 1-3.
Subjects scheduled for elective cardiac interventional or diagnostic catheterization anticipated to last ≥ 3hours.
Subjects spontaneously ventilating with a natural airway scheduled for elective cardiac interventional or diagnostic catheterization anticipated to last ≥ 2 hours.
Subjects must have reliable intravascular access from which to draw blood samples.

Exclusion Criteria

History of allergic reaction or sensitivity to dexmedetomidine.
Nasal pathology preventing the administration of drug.
Patients that are on maintenance medications that could inhibit or induce the CYP2A6 enzyme.
Cardiac conduction abnormalities defined as second or third degree heart block or pacemaker dependence.
Bradycardia, defined by age, upon arrival in the preoperative care area.
Hepatic dysfunction defined as a history of hepatic dysfunction AND an Alanine Aminotransferase (ALT) value greater than 2 times normal in the 6 months prior to study drug administration.
The subject has received dexmedetomidine or clonidine within 1 week of the study date.
BMI >30.
Patients previously enrolled in this study.
Any investigational drug use within 30 days prior to enrollment.
Wards will not be eligible.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort 2	Dexmedetomidine	* Dexmedetomidine 4 μg/kg * Under general oral endotracheal anesthesia * 7 subjects age \>2 yo and ≤ 6 yo
Cohort 1	Dexmedetomidine	Cohort 1A: * Dexmedetomidine 2 μg/kg * Under general oral endotracheal anesthesia * 7 subjects age \>2 yo and ≤ 6 yo * 7 subjects age ≥1 mo and ≤2 yo Cohort 1B: * Dexmedetomidine 2 μg/kg * Under sedation with a natural airway * 7 subjects age \>2 yo and ≤ 6 yo * 7 subjects age ≥1 mo and ≤2 yo

Primary Outcome Measures

Name	Time	Method
Time of Peak Drug Concentration Level of Dexmedetomidine	Up to 5 hours - 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, and 300 minutes post drug administration	Following the administration of atomized intranasal dexmedetomidine, serum samples will be drawn at 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240 and 300 minutes post drug administration. The time of peak drug concentration will be determined based on this data.
Dose-limiting Toxicities (DLT) and/or Maximum Plasma Level > 1000 pg/mL	Subjects were monitored for 6 hours after the administration of study drug.	Dose-limiting toxicities (DLT) include bradycardia, hypotension, new intraventricular conduction abnormality or any serious adverse event possibly, probably, or definitely related to intranasal dexmedetomidine administration that occured after the administration of the intranasal dexmedetomidine and through the completion of PK sampling. Bradycardia, hypotension, or new intraventricular conduction abnormalities that occured after the administration of intravenous dexmedetomidine given by the primary anesthesia team as part of usual clinical care were not considered DLTs but were considered an adverse event. Any events that could not be explained by the intervention that the patient was undergoing were assumed to be related to the study drug.
Number of Samples Obtained Per Subject	Up to 5 hours - 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, and 300 minutes post drug administration	Following the administration of atomized intranasal dexmedetomidine, serum samples will be drawn at 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240 and 300 minutes post drug administration. This is the number of samples obtained per subject.
Serum Drug Concentration Levels of Dexmedetomidine	Up to 5 hours - 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, and 300 minutes post drug administration	Following administration of atomized intranasal dexmedetomidine, serum samples will be obtained at the following times post administrations: 0, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, and 300 minutes. Peak concentration will be determined based on this data.