Methods of treating pediatric patients with dexmedetomidine

Abstract

To provide methods of providing sedation or analgesia to a pediatric patient.SOLUTION: The presently disclosed subject matter relates to methods of administering an effective amount of dexmedetomidine to a pediatric patient in order to reduce the incidence of neurological damage. More specifically, the presently disclosed subject matter relates to methods of providing sedation or analgesia to a pediatric patient by administering a dexmedetomidine infusion and optionally a loading dose. The dexmedetomidine can be administered before, during or after surgery.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] 1. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 61 / 547,626, filed October 14, 2011, U.S. Application No. 13 / 343,693, filed January 4, 2012, and U.S. Application No. 13 / 471,403, filed May 14, 2012, the disclosures of which are incorporated herein by reference in their entireties. 2. Field of the Invention The presently disclosed subject matter relates to methods of providing safe and effective sedative and / or analgesic agents to pediatric patients. More particularly, the presently disclosed subject matter relates to reducing, preventing, and / or ameliorating neurological damage in pediatric patients by administering dexmedetomidine. [Background technology]

[0002] 3. Background of the Invention Sedation is an important component of pediatric patient care in the intensive care unit (ICU), not only for the physiological well-being of the pediatric patient, but also for patient safety and the safety of caregivers. Benzodiazepines and opioids, such as fentanyl or morphine, are frequently administered to produce sedation and analgesia in pediatric intensive care units (PICUs). Propofol has been shown to cause serious, life-threatening metabolic alterations in children, including circulatory collapse, and is not indicated for continuous intensive care sedation in the pediatric population. (See Propofol Injectable Emulsion [Package Insert]. Lake Forest, IL: Hospira, Inc.: 2008). Long-term administration of benzodiazepines and opioids can lead to the development of tolerance and physical dependence. Midazolam sedation can cause oversedation in some pediatric patients, alternating with subsedation and paradoxical agitation. (See Midazolam Hydrochloride [Package Insert]. Lake Forest, IL: Hospira, Inc.: 2005). Recent reports of apoptosis and neurodevelopmental abnormalities from gamma-aminobutyric acid (GABA) agonists in neonatal and infant animal models highlight concerns about sedating neonates and infants with benzodiazepines. (See Young et al. Brit J Pharma 2005;146:189-197; and Sander et al. Brit J Anaesth 2008;101(5):597-609.) Concomitant administration of opioids further complicates management of pediatric patients due to respiratory depressant effects. Thus, there is a significant unmet need for safe and effective sedation and analgesia for pediatric patients. Dexmedetomidine (Precedex®) is a highly selective alpha-2 adrenergic agonist with sedative, analgesic, and anxiolytic effects. Dexmedetomidine is currently approved by the FDA for sedation of initially intubated, mechanically ventilated adult patients in intensive care settings and is also approved for sedation of non-intubated adult patients as a component of monitored anesthesia therapy during surgical or diagnostic procedures. Because dexmedetomidine has minimal effect on respiratory drive, it is the only sedative agent approved in the United States for administration as a continuous infusion in non-intubated ICU patients. Sedation with dexmedetomidine has been widely studied in adult patients in the ICU. When used in combination with opioids or benzodiazepines, dexmedetomidine often allows for a reduction in the dose of other medications, reducing the risk of respiratory depression. Summary of the Invention [Problem to be solved by the invention]

[0003] 4. Summary of the Invention The present invention relates to a method for sedation or analgesia in a pediatric patient in need of sedation or analgesia, comprising administering dexmedetomidine to the patient, wherein the dexmedetomidine is administered in an amount effective to reduce the incidence of neurological damage. [Means for solving the problem]

[0004] In one embodiment, dexmedetomidine is administered at a concentration of about 0.01 to about 2.5 μg / kg / hour, the child is about 17 years of age or younger, the dexmedetomidine is administered as a continuous infusion for a period of less than about 36 hours, and the dexmedetomidine is administered in an amount effective to reduce the incidence of neurological damage. In certain embodiments, the pediatric patient is a preterm newborn, hi one embodiment, the gestational age of the pediatric patient ranges from about 7 months to about 11 months. In certain embodiments, the pediatric patient is intubated before, during, or after administration of dexmedetomidine. In one embodiment, the pediatric patient is critically ill. In particular embodiments, dexmedetomidine is administered parenterally. In certain embodiments, dexmedetomidine is administered by intravenous infusion. In certain embodiments, the neuronal damage is cell degeneration or neuroapoptosis. In one embodiment, the neuronal damage occurs within a cortical lamina selected from the group consisting of layer I and layer II. In certain embodiments, dexmedetomidine is administered preoperatively. In particular embodiments, dexmedetomidine is administered postoperatively. In specific embodiments, dexmedetomidine is administered post-cardiopulmonary bypass. In one embodiment, the pediatric patient is an age selected from the group consisting of about 12 to about 17 years old and about 2 years old or younger. In certain embodiments, administration of dexmedetomidine reduces the need for rescue medication. In one embodiment, the rescue medication is a sedative. In a specific embodiment, the rescue medication is an analgesic. In certain embodiments, administration of dexmedetomidine is initiated with a first loading dose before a maintenance dose. In one embodiment, no initial loading dose is administered. [Brief explanation of the drawings]

[0005] [Figure 1]1 shows the mean plasma concentrations of dexmedetomidine over time for the fully evaluable population of Example 3. [Figure 2] 1 shows plasma clearance with respect to age for the fully evaluable cohort of Example 3. [Figure 3] 1 shows plasma clearance in relation to body weight for the fully evaluable population of Example 3. [Figure 4] 1 shows weight-adjusted plasma clearance versus age for the fully evaluable population of Example 3. [Figure 5] 1 shows weight-adjusted volume of distribution versus age for the fully evaluable population of Example 3. [Figure 6] 1 shows the predicted mean curve of AUC generated using a power-fit model for Example 3. [Figure 7] 1 shows the predicted mean curve of AUC0-t generated using a power fitting model for Example 3. [Figure 8] 1 shows the predicted mean curve of Cmax generated using a power fitting model for Example 3. [Figure 9] 10 shows the predicted mean curve of Css generated using a power-fit model for Example 3. [Figure 10] Shown is the mean Ramsay Sedation Score (RSS) vs. AUC0-∞ for the fully evaluable population. [Figure 11] The mean Ramsay Sedation Score (RSS) vs. Css for the fully evaluable population is shown. [Figure 12] Representative 5x and 10x magnification photomicrographs of TUNEL staining of the frontal cortex of a newborn monkey are shown. [Figure 13] Representative 5x and 10x magnification photomicrographs of activated caspase 3 staining in the frontal cortex of a neonatal monkey are shown. [Figure 14] Representative 20x magnification photomicrographs of activated caspase 3 staining in the frontal cortex of a neonatal monkey are shown. [Figure 15] Representative 20x magnification photomicrographs of silver staining of the frontal cortex of a neonatal monkey are shown. [Figure 16A-1]1 shows a line graph of plasma dexmedetomidine concentrations versus time since start of loading dose infusion for each treatment group in the studies of Examples 1, 3, and 5. [Figure 16A-2] 1 shows a line graph of plasma dexmedetomidine concentrations versus time since start of loading dose infusion for each treatment group in the studies of Examples 1, 3, and 5. [Figure 16B-1] 1 shows a line graph of plasma dexmedetomidine concentrations versus time since start of loading dose infusion for each treatment group in the studies of Examples 1, 3, and 5. [Figure 16B-2] 1 shows a line graph of plasma dexmedetomidine concentrations versus time since start of loading dose infusion for each treatment group in the studies of Examples 1, 3, and 5. [Figure 16C] 1 shows a line graph of plasma dexmedetomidine concentrations versus time since start of loading dose infusion for each treatment group in the studies of Examples 1, 3, and 5. [Figure 17A-1] 1 shows a line graph of dexmedetomidine concentration versus time since indicated end of maintenance infusion for each treatment group in the studies of Examples 1, 3, and 5. [Figure 17A-2] 1 shows a line graph of dexmedetomidine concentration versus time since indicated end of maintenance infusion for each treatment group in the studies of Examples 1, 3, and 5. [Figure 17B-1] 1 shows a line graph of dexmedetomidine concentration versus time since indicated end of maintenance infusion for each treatment group in the studies of Examples 1, 3, and 5. [Figure 17B-2] 1 shows a line graph of dexmedetomidine concentration versus time since indicated end of maintenance infusion for each treatment group in the studies of Examples 1, 3, and 5. [Figure 17C] 1 shows a line graph of dexmedetomidine concentration versus time since indicated end of maintenance infusion for each treatment group in the studies of Examples 1, 3, and 5. [Figure 18A-1] FIG. 1 shows semi-log scatter plots of dose-normalized dexmedetomidine plasma concentrations versus time since end of maintenance infusion for the studies of Examples 1, 3, and 5. [Figure 18A-2]FIG. 1 shows semi-log scatter plots of dose-normalized dexmedetomidine plasma concentrations versus time since end of maintenance infusion for the studies of Examples 1, 3, and 5. [Figure 18B] FIG. 1 shows semi-log scatter plots of dose-normalized dexmedetomidine plasma concentrations versus time since end of maintenance infusion for the studies of Examples 1, 3, and 5. [Figure 19A-1] 1 shows goodness-of-fit plots of individual predicted dexmedetomidine Cp basic structure models for the combined datasets of Examples 1, 3, and 5. [Figure 19A-2] 1 shows goodness-of-fit plots of individual predicted dexmedetomidine Cp basic structure models for the combined datasets of Examples 1, 3, and 5. [Figure 19B-1] 1 shows goodness-of-fit plots of individual predicted dexmedetomidine Cp basic structure models for the combined datasets of Examples 1, 3, and 5. [Figure 19B-2] 1 shows goodness-of-fit plots of individual predicted dexmedetomidine Cp basic structure models for the combined datasets of Examples 1, 3, and 5. [Figure 20] 9 shows 90% prediction intervals derived from 1000 simulated data sets overlaid on observed dexmedetomidine concentrations versus time since end of maintenance infusion for Examples 1, 3, and 5. [Figure 21] 1 shows a comparison of the 5th, 50th, and 95th percentiles of predicted corrected observed data and model-based simulated data for Examples 1, 3, and 5. [Figure 22A-1] 1 shows goodness-of-fit plots of the final population pharmacokinetic model for the entire population of data from Examples 1, 3, and 5. [Figure 22A-2] 1 shows goodness-of-fit plots of the final population pharmacokinetic model for the entire population of data from Examples 1, 3, and 5. [Figure 22B-1] 1 shows goodness-of-fit plots of the final population pharmacokinetic model for the entire population of data from Examples 1, 3, and 5. [Figure 22B-2] 1 shows goodness-of-fit plots of the final population pharmacokinetic model for the entire population of data from Examples 1, 3, and 5. [Figure 22C-1] 1 shows goodness-of-fit plots of the final population pharmacokinetic model for the entire population of data from Examples 1, 3, and 5. [Figure 22C-2] 1 shows goodness-of-fit plots of the final population pharmacokinetic model for the entire population of data from Examples 1, 3, and 5. [Figure 22D-1] 1 shows goodness-of-fit plots of the final population pharmacokinetic model for the entire population of data from Examples 1, 3, and 5. [Figure 22D-2] 1 shows goodness-of-fit plots of the final population pharmacokinetic model for the entire population of data from Examples 1, 3, and 5. [Figure 23-1] Geometric means and 95% confidence intervals of individual Bayesian estimates of dexmedetomidine clearance plotted at the midpoint of each age group are shown. [Figure 23-2] Corresponding weight-adjusted estimates of dexmedetomidine clearance are shown (each plot has a typical value versus age line based on a population model for each parameter superimposed on it). [Figure 24-1] Geometric means and 95% confidence intervals of individual Bayesian estimates of dexmedetomidine volume of distribution plotted at the midpoint of each age group are shown. [Figure 24-2] The corresponding weight-adjusted estimates of dexmedetomidine volume of distribution are shown (each plot has a line superimposed on it representing typical values ​​versus age based on a population model for each parameter). [Figure 25-1] 1 shows pairwise scatter plots of the between-individual variance terms from the final model of Example 6. [Figure 25-2] 1 shows pairwise scatter plots of the between-individual variance terms from the final model of Example 6. [Figure 25-3] 1 shows pairwise scatter plots of the between-individual variance terms from the final model of Example 6. [Figure 25-4] 1 shows pairwise scatter plots of the between-individual variance terms from the final model of Example 6. [Figure 25-5] 1 shows pairwise scatter plots of the between-individual variance terms from the final model of Example 6. [Figure 25-6]1 shows pairwise scatter plots of the between-individual variance terms from the final model of Example 6. [Figure 26] 9 shows the 95% confidence intervals of individual Bayesian estimates expressed as a percent of the geometric mean of the weight-adjusted CL of dexmedetomidine for each age group as determined from the analysis performed in Example 6. [Figure 27] 9 shows the 95% confidence intervals of individual Bayesian estimates expressed as a percent of the geometric mean of the weight-adjusted volume of distribution of dexmedetomidine for each age group as determined from the analysis performed in Example 6. [Figure 28] 9 shows the 95% confidence intervals of individual Bayesian estimates expressed as a percent of the geometric mean of the weight-adjusted CL of dexmedetomidine for each age group as determined from the analysis performed in Example 8. [Figure 29] 9 shows the 95% confidence intervals of individual Bayesian estimates expressed as a percent of the geometric mean of the weight-adjusted volume of distribution of dexmedetomidine for each age group as determined from the analysis performed in Example 8. [Figure 30A] 1 shows the goodness-of-fit plot for the final population pharmacokinetic model of dexmedetomidine in Example 8. [Figure 30B] 1 shows the goodness-of-fit plot for the final population pharmacokinetic model of dexmedetomidine in Example 8. [Figure 30C] 1 shows the goodness-of-fit plot for the final population pharmacokinetic model of dexmedetomidine in Example 8. [Figure 30D] 1 shows the goodness-of-fit plot for the final population pharmacokinetic model of dexmedetomidine in Example 8. [Figure 30E] 1 shows the goodness-of-fit plot for the final population pharmacokinetic model of dexmedetomidine in Example 8. [Figure 30F] 1 shows the goodness-of-fit plot for the final population pharmacokinetic model of dexmedetomidine in Example 8. [Figure 30G] 1 shows the goodness-of-fit plot for the final population pharmacokinetic model of dexmedetomidine in Example 8. [Figure 30H]1 shows the goodness-of-fit plot for the final population pharmacokinetic model of dexmedetomidine in Example 8. [Figure 31A] Prediction-corrected visual predictive check results for dexmedetomidine concentration versus time since IV termination are shown. [Figure 31B] Prediction-corrected visual predictive check results are shown for dexmedetomidine concentration versus time elapsed after IV completion. [Figure 32-1] Geometric means and 95% confidence intervals for Bayesian estimates of dexmedetomidine clearance and weight-adjusted clearance for specific age groups are shown overlaid with typical values ​​based on population models of clearance and weight-adjusted clearance. [Figure 32-2] Geometric means and 95% confidence intervals for Bayesian estimates of dexmedetomidine clearance and weight-adjusted clearance for specific age groups are shown overlaid with typical values ​​based on population models of clearance and weight-adjusted clearance. [Figure 33-1] Geometric means and 95% confidence intervals for Bayesian estimates of dexmedetomidine volume of distribution and weight-adjusted volume of distribution for specific age groups are shown overlaid with typical values ​​based on a population model of volume of distribution and weight-adjusted volume of distribution. [Figure 33-2] Geometric means and 95% confidence intervals for Bayesian estimates of dexmedetomidine volume of distribution and weight-adjusted volume of distribution for specific age groups are shown overlaid with typical values ​​based on a population model of volume of distribution and weight-adjusted volume of distribution. [Figure 34A] Predicted mean curves of AUC0-inf generated using a power fitting model are shown. [Figure 34B] Predicted mean curves of AUC0-t generated using a power fitting model are shown. [Figure 34C] Predicted mean curves for Cmax generated using a power fitting model are shown. [Figure 35]A linear plot illustrating the mean dexmedetomidine concentrations over time is shown (time points: 1 = pre-dose, 2 = end of bolus, 3 = 30 minutes after start of infusion, 4 = 60 minutes after start of infusion, 5 = 2 hours after start of infusion, 6 = 4-6 hours after start of infusion, 7 = 6 hours after start of infusion, 8 = 12 hours after start of infusion, 8.1 = 23 hours after start of infusion, 9 = 30-15 minutes before end of infusion, 10 = end of infusion, 11 = 15 minutes after end of infusion, 12 = 30 minutes after end of infusion, 13 = 60 minutes after end of infusion, 14 = 2 hours after end of infusion, 15 = 4 hours after end of infusion, 16 = 8 hours after end of infusion, 17 = 12 hours after end of infusion, 18 = 15-18 hours after end of infusion, 19 = 24 hours after end of infusion). [Figure 36A] Age-related clearance is shown. [Figure 36B] Age-related weight-adjusted clearance is shown. DETAILED DESCRIPTION OF THE INVENTION

[0006] 6. Detailed Description of the Invention The present invention relates to a method for sedation or analgesia in a pediatric patient in need thereof, comprising administering dexmedetomidine to the pediatric patient, wherein the dexmedetomidine is administered in an amount effective to reduce the incidence of nerve damage. For clarity, and not by way of limitation, this detailed description is divided into the following subsections: 6.1 Definitions; 6.2 Pharmaceutical preparations; 6.3 Patient population; and 6.4 Treatment Methods.

[0007] 6.1 Definition The terms used in this specification generally have their ordinary meanings in the art, within the context of this invention and within the specific context in which each term is used. Particular terms are discussed below, or elsewhere in this specification, to provide further guidance to the practitioner in describing the compositions and methods of the invention and how to make and use them. According to the present invention, the term "dexmedetomidine" as used herein refers to a substantially pure, optically active dextrorotatory stereoisomer of medetomidine, either as the free base or as a pharmaceutically acceptable salt. In one non-limiting embodiment, dexmedetomidine has the formula (S)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole. Pharmaceutically acceptable salts of dexmedetomidine can include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Preferably, the dexmedetomidine salt is dexmedetomidine HCl. In other non-limiting embodiments, dexmedetomidine comprises the structure shown in Formula I:

[0008] [ka] Formula I

[0009] The term "pharmaceutical composition" as used in accordance with the present invention relates to a composition that can be formulated in any conventional manner using one or more pharmaceutically acceptable carriers or excipients. As used herein, "pharmaceutically acceptable" means one approved by a regulatory agency of the Federal or State government or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias for mammalian, more particularly human, use. The term "dosage" is intended to encompass formulations expressed in units of μg / kg / hour, μg / kg / day, mg / kg / day, or mg / kg / hour. A dosage is the amount of an ingredient administered according to a particular administration regimen. A "dose" is the amount of drug administered to a mammal in a unit volume or mass, e.g., an absolute unit amount expressed in mg of drug. The dose depends on the concentration of the drug in the formulation, e.g., moles / liter (M), mass / volume (m / v), or mass / mass (m / m). These two terms are closely related, as a particular dosage may result from a single-dose or multiple-dose administration regimen of the formulation. The specific meaning in each case will be clear from the context. The terms "therapeutically effective dose," "effective amount," and "therapeutically effective amount" refer to an amount sufficient to produce a desired effect. In some non-limiting embodiments, a "therapeutically effective dose" refers to an amount sufficient to reduce, and most preferably prevent, a clinically significant impairment in the activity, function, and response of the host by at least about 15%, preferably at least 50%, more preferably at least 90%. Alternatively, a therapeutically effective amount is sufficient to bring about an improvement in a clinically significant condition in the host. These parameters will depend on the severity of the condition being treated, other actions being taken, such as dietary modification, the subject's weight, age, and sex, and other criteria that one of ordinary skill in the art can readily determine using standard good medical practice. In other non-limiting embodiments, a therapeutic response can be any response that a user (e.g., a clinician) would recognize as an effective response to the therapy. Thus, a therapeutic response will typically be the induction of a desired effect, such as sedation or analgesia.

[0010] As used herein, the term "intensive care unit" or "ICU" means any setting that provides intensive care. As used herein, the term "gestational age" is calculated as the time elapsed since the first day of the last menstrual period. If the pregnancy is achieved using assisted reproductive techniques, the gestational age is calculated by adding two weeks to the gestational age calculated above. As used herein, the term "pediatric patient" refers to a human patient 17 years of age or younger. In certain non-limiting embodiments, the patient is 16 years of age or younger, or 15 years of age or younger, or 14 years of age or younger, or 13 years of age or younger, or 12 years of age or younger, or 11 years of age or younger, or 10 years of age or younger, or 9 years of age or younger, or 8 years of age or younger, or 7 years of age or younger, or 6 years of age or younger, or 5 years of age or younger, or 4 years of age or younger, or 3 years of age or younger, or 2 years of age or younger, or 1 year of age or younger, or 6 months of age or younger, or 4 months of age or younger, or 2 months of age or younger, or 1 month of age or younger. In particular embodiments, the pediatric patient is between about 12 and 17 years of age. In one embodiment, the pediatric patient has an age selected from the group consisting of about 12 to about 17 years of age and about 2 years of age or younger. In one embodiment, the pediatric patient was released from the womb immediately prior to administration of dexmedetomidine. In certain embodiments, the "pediatric patient" is a preterm newborn. As used herein, the term "preterm newborn" refers to a child born before 37 weeks from the start of the last menstrual period. If the pregnancy is achieved using assisted reproductive techniques, the child is a preterm newborn if calculated by adding two weeks to the gestational age calculated above. In certain embodiments, the pediatric patient has a gestational age of about 20 weeks to about 44 weeks, or about 20 weeks to about 40 weeks, or about 20 weeks to about 38 weeks, or about 20 weeks to about 36 weeks, or about 20 weeks to about 34 weeks, or about 20 weeks to about 30 weeks, or about 20 weeks to about 28 weeks, or about 20 weeks to about 24 weeks. In certain embodiments, the pediatric patient has a gestational age of about 36 weeks to about 44 weeks, or about 36 weeks to about 42 weeks, or about 36 weeks to about 40 weeks, or about 36 weeks to about 38 weeks. As used herein, the term "neurologic injury" refers to various types of neurocognitive, psychocognitive, and / or neuromotor or movement disorders, or combinations thereof, which are discussed in more detail below.

[0011] As used herein, the term "reducing the incidence" means reducing the severity, reducing the number, preventing or delaying the development of one or more of the incidences, or a combination thereof. The terms "about" or "approximately" mean within an acceptable error range for a particular value, as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 3 or more than 3 standard deviations, depending on the practice of the art. Alternatively, "about" can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold of a value.

[0012] 6.2 Pharmaceutical Compositions Pharmaceutical compositions of dexmedetomidine suitable for parenteral administration may be in the form of suppositories, solutions, or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending agents, stabilizers, solubilizing agents, and / or dispersing agents. The form may be sterile and fluid. It may be stable under the conditions of manufacture and storage and preserved against the contaminating action of microorganisms such as bacteria and fungi. Alternatively, dexmedetomidine may be in sterile powder form for reconstitution with a suitable vehicle prior to use. The pharmaceutical composition may be presented in unit-dose form in ampoules or other unit-dose or multi-dose containers. Alternatively, the pharmaceutical composition may be stored in a lyophilized state, requiring only the addition of a sterile liquid carrier, e.g., water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, or tablets. In some non-limiting embodiments, the dexmedetomidine composition is formulated as a liquid. In certain non-limiting embodiments, the dexmedetomidine liquid composition contains dexmedetomidine, or a pharmaceutically acceptable salt thereof, at a concentration of from about 0.005 μg / mL to about 100 μg / mL, or from about 0.005 μg / mL to about 50 μg / mL, or from about 0.005 μg / mL to about 25 μg / mL, or from about 0.005 μg / mL to about 15 μg / mL, or from about 0.005 μg / mL to about 10 μg / mL, or about 0.005 μg / mL to about 10 μg / mL. 0.005μg / mL to about 7μg / mL, or about 0.005μg / mL to about 5μg / mL, or about 0.005μg / mL to about 4μg / mL, or about 0.005μg / mL to about 3μg / mL, or about 0.005μg / mL to about 2μg / mL, or about 0.005μg / mL to about 1μg / mL, or about 0.005μg / mL to about 0.5μg / mL, or about 0.005μg / mL to about 0.05μg / mL. In certain non-limiting embodiments, the dexmedetomidine liquid composition comprises dexmedetomidine, or a pharmaceutically acceptable salt thereof, at a concentration of about 0.5 μg / mL, or about 1.0 μg / mL, or about 2.0 μg / mL, or about 4.0 μg / mL. In one embodiment, the dexmedetomidine composition is a premixed formulation that does not need to be reconstituted or diluted prior to administration to a patient, as disclosed in U.S. Patent Application No. 13 / 343,672, filed January 4, 2012, entitled "Dexmedetomidine Premixed Formulation," the entire contents of which are incorporated herein by reference. Suitable excipients for dexmedetomidine compositions include preservatives, suspending agents, stabilizers, dyes, buffers, antibacterial agents, antifungal agents, and isotonic agents, such as sugars or sodium chloride. As used herein, the term "stabilizer" refers to a compound optionally used in the pharmaceutical compositions of the present invention to avoid the need for sulfites and to extend shelf life. Non-limiting examples of stabilizers include antioxidants. The pharmaceutical composition may contain one or more pharmaceutically acceptable carriers. The carrier may be a solvent or dispersion medium. Non-limiting examples of pharmaceutically acceptable carriers include water, saline, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), oil, and suitable mixtures thereof. Parenteral formulations can be sterilized. Non-limiting examples of sterilization techniques include filtration through a bacteria-retaining filter, terminal sterilization, incorporation of sterilizing agents, irradiation, heating, vacuum drying, and freeze-drying.

[0013] 6.3 Patient population The presently disclosed subject matter includes administering dexmedetomidine to a pediatric patient. In certain embodiments, the pediatric patient is intubated. The pediatric patient can be intubated before, during, or after administration of dexmedetomidine. The pediatric patient can be intubated via nasal, endotracheal, direct oral laryngoscopy, or fiberoptic routes, or via tracheotomy. In certain embodiments, the patient is seriously ill. In one embodiment, the pediatric patient suffers from one or more medical conditions. In certain embodiments, the medical condition is a lung disorder, a brain disorder, a heart disorder, a liver disorder, a kidney disorder, an eye or ear disorder, a gastrointestinal disorder, or a skin disorder. Non-limiting examples of lung disorders include respiratory distress syndrome, pneumonia, bronchopulmonary dysplasia, apnea of ​​prematurity, and pneumothorax. Non-limiting examples of brain disorders include intraventricular hemorrhage and cerebral palsy. Non-limiting examples of liver disorders include jaundice. Non-limiting examples of heart disorders include cardiac ischemia and patent ductus arteriosus. Non-limiting examples of eye disorders include retinopathy of prematurity, myopia, and strabismus. Non-limiting examples of other medical conditions include heroin withdrawal, cocaine withdrawal, fetal alcohol syndrome, HIV-positive status, and Tay-Sachs disease. In one embodiment, the patient has undergone surgery. The patient may undergo surgery before, during, and / or after administration of dexmedetomidine. In certain embodiments, dexmedetomidine is administered before surgery. In one embodiment, dexmedetomidine is administered before surgery to reduce the incidence of nerve damage. In some embodiments, dexmedetomidine is administered before and during surgery. In particular embodiments, dexmedetomidine is administered before and after surgery. In certain embodiments, dexmedetomidine is administered during and after surgery. In particular embodiments, dexmedetomidine is administered before, during, and after surgery. Surgery means any manual or operative procedure or manipulation for the treatment or prevention of disease, injury, or deformity. Surgery is usually performed by a doctor, surgeon, or dentist in a hospital or other medical facility. Pediatric patients undergoing surgery may be hospitalized or may be outpatients, e.g., outpatient surgery. Surgery may be conservative (e.g., surgery to preserve or remove a diseased or damaged organ, tissue, or limb with minimal risk) or radical (e.g., surgery designed to remove an entire area of ​​locally widespread disease and adjacent zones of lymphatic drainage).

[0014] Non-limiting examples of surgery include surgery performed on the cardiovascular system, including the heart and blood vessels; surgery performed on the musculoskeletal system, including the bones and muscles; surgery performed on the respiratory system, including the trachea and lungs; surgery performed on the integumentary system, including the skin and nails; surgery performed on the mediastinum and diaphragm; surgery performed on the digestive system, including the esophagus, stomach, gallbladder, and intestines; surgery performed on the urinary system, including the kidneys and bladder; surgery performed on the male reproductive system; surgery performed on the female reproductive system; surgery performed on the endocrine system, including the pituitary gland, adrenal glands, and endocrine thyroid gland; surgery performed on the nervous system, including the brain, spinal cord, and peripheral nerves; surgery performed on the eye and ocular adnexa; and surgery performed on the auditory system. Non-limiting examples of surgeries performed on the cardiovascular system include repair of congenital heart disease after birth and heart transplant surgery. Non-limiting examples of surgeries performed on the musculoskeletal system include fracture repair, scoliosis surgery, and tendon lengthening. Non-limiting examples of surgeries performed on the respiratory system include lung transplants, thoracotomy, and pneumothorax surgery. Non-limiting examples of surgeries performed on the integumentary system include burn treatment and skin grafting. Non-limiting examples of surgeries performed on the mediastinum and diaphragm include repair of congenital diaphragmatic hernia and removal of mediastinal cysts and tumors. Non-limiting examples of surgeries performed on the digestive system include bowel resection and treatment of pyloric stenosis. Non-limiting examples of surgeries performed on the urinary system include kidney transplants and treatment of bladder diverticula. Non-limiting examples of surgeries performed on the male reproductive system include treatment of undescended testes. Non-limiting examples of surgeries performed on the female reproductive system include ovarian cystectomy. Non-limiting examples of surgeries performed on the endocrine system include treatment of hyperparathyroidism. Non-limiting examples of surgeries performed on the nervous system include laminectomy and corpus callosotomy. Non-limiting examples of surgeries performed on the eyes include strabismus surgery. Non-limiting examples of surgeries performed on the auditory system include cochlear implant surgery. Further non-limiting examples of surgeries include tonsillectomy, cleft lip and palate repair, treatment of lymphangioma, tracheoesophageal fistula repair, surgery for neuroblastoma, and treatment of esophageal atresia. In one embodiment, the patient has undergone cardiopulmonary bypass.

[0015] 6.4 Treatment method As noted above, the therapeutic methods of the present invention relate to methods of sedation or analgesia in a pediatric patient comprising administering dexmedetomidine to the pediatric patient, wherein the dexmedetomidine is administered in an amount effective to reduce the incidence of nerve damage. Dexmedetomidine for use in the present invention can be administered by any suitable route, including parenteral, intravenous, and oral routes. Non-limiting examples of parenteral administration routes include intravenous, intramuscular, subcutaneous, intraperitoneal, or intrathecal routes. Parenteral administration may be by intermittent bolus injection of the formulation, or by intravenous or intraperitoneal administration from an external (e.g., intravenous bag) or internal (e.g., biodegradable implant, bioartificial organ) reservoir. See, e.g., U.S. Patent Nos. 4,407,957 and 5,798,113, each of which is incorporated herein by reference in its entirety. Pulmonary delivery methods and devices are described, for example, in U.S. Patent Nos. 5,654,007, 5,780,014, and 5,814,607, each of which is incorporated herein by reference in its entirety. Other useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, pump delivery, encapsulated cell delivery, liposome delivery, needle-delivered injections, needle-free injections, nebulizers, aerosolizers, electroporation, and transdermal patches. Needle-free injection devices are described in U.S. Patent Nos. 5,879,327; 5,520,639; 5,846,233 and 5,704,911, the entire specifications of which are incorporated herein by reference. In yet another non-limiting embodiment, the therapeutic compound can be delivered in a controlled or sustained release system. For example, the compound or composition can be administered using intravenous infusion, continuous infusion, an implantable osmotic pump, or other modes of administration. In one embodiment, a pump can be used (Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et al., 1980, Surgery 88:507; Saudek et al., 1989, N. Engl. J. Med. 321:574). In another embodiment, polymeric materials can be used (Langer and Wise eds., 1974, Medical Applications of Controlled Release, CRC Press: Boca Raton, Fla; Smolen and Ball eds., 1984, Controlled Drug Bioavailability, Drug Product Design and Performance, Wiley, NY; Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem., 23:61; Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol., 25:351; (See Howard et al., 9189, J. Neurosurg. 71:105.) In yet another embodiment, a controlled release system can be placed in proximity to the therapeutic target, i.e., the brain, so that only a fraction of the systemic dose is required (see, e.g., Goodson, 1984, in (See Medical Applications of Controlled Release, Vol. 2, pp. 115-138).

[0016] In certain embodiments, dexmedetomidine is administered as a continuous intravenous dose to a pediatric patient at a concentration of about 0.005 μg / kg / hr to about 50 μg / kg / hr, or about 0.005 μg / kg / hr to about 25 μg / kg / hr, or about 0.005 μg / kg / hr to about 15 μg / kg / hr, or about 0.005 μg / kg / hr to about 5 μg / kg / hr, or about 0.005 μg / kg / hr to about 2 μg / kg / hr, or about 0.005 μg / kg / hr to about 1.5 μg / kg / hr, or about 0.005 μg / kg / hr to about 1 μg / kg / hr, or about 0.005 μg / kg / hr to about 0.5 μg / kg / hr, or about 0.005 μg / kg / hr to about 0.25 μg / kg / hr. In preferred, non-limiting embodiments, the concentration is about 0.025 μg / kg / hour to about 2.0 μg / kg / hour. In specific embodiments, dexmedetomidine is administered as a continuous intravenous dose to a pediatric patient at a concentration of about 0.005 μg / kg / hour to about 50 μg / kg / hour, or about 0.025 μg / kg / hour to about 50 μg / kg / hour, or about 0.05 μg / kg / hour to about 50 μg / kg / hour, or about 0.01 μg / kg / hour to about 50 μg / kg / hour, or about 0.2 μg / kg / hour to about 50 μg / kg / hour, or about 0.25 μg / kg / hour to about 50 μg / kg / hour, or about 0.5 μg / kg / hour. The dose is administered at a concentration of about 0.7 μg / kg / hour to about 50 μg / kg / hour, or about 1.0 μg / kg / hour to about 50 μg / kg / hour, or about 1.5 μg / kg / hour to about 50 μg / kg / hour, or about 2.0 μg / kg / hour to about 50 μg / kg / hour, or about 5.0 μg / kg / hour to about 50 μg / kg / hour, or about 10 μg / kg / hour to about 50 μg / kg / hour, or about 20 μg / kg / hour to about 50 μg / kg / hour. In certain embodiments, dexmedetomidine is administered to a pediatric patient as a continuous intravenous dose of about 0.01 μg / kg / hr, or about 0.025 μg / kg / hr, or about 0.05 μg / kg / hr, or about 0.1 μg / kg / hr, or about 0.2 μg / kg / hr, or about 0.25 μg / kg / hr, or about 0.3 μg / kg / hr, or about 0.4 μg / kg / hr, or about 0.5 μg / kg / hr, or about 0.6 μg / kg / hr, or about 0.7 μg / kg / hr, or about 0.75 μg / kg / hr, or about 0.8 μg / kg / hr, or about 0.9 μg / kg / hr or about 1.0 μg / kg / hr, or about 1.1 μg / kg / hr, or about 1.2 μg / kg / hr, or about 1.3 μg / kg / hr, or about 1.4 μg / kg / hr, or about 1.5 μg / kg / hr, or about 1.6 μg / kg / hr, or about 1.7 μg / kg / hr, or about 1.8 μg / kg / hr, or about 1.9 μg / kg / hr, or about 2.0 μg / kg / hr, or about 2.1 μg / kg / hr, or about 2.2 μg / kg / hr, or about 2.3 μg / kg / hr, or about 2.4 μg / kg / hr, or about 2.5 μg / kg / hr.In certain embodiments, dexmedetomidine is administered as a continuous intravenous dose of about 3.0 μg / kg / hr, or about 3.5 μg / kg / hr, or about 4.0 μg / kg / hr, or about 4.5 μg / kg / hr, or about 4.0 μg / kg / hr, or about 4.5 μg / kg / hr, or about 5.0 μg / kg / hr, or about 5.5 μg / kg / hr, about 6.0 μg / kg / hr, or about 6.5 μg / kg / hr, or about 7.0 μg / kg / hr, or about 7.5 μg / kg / hr, About 8.0 μg / kg / hour, or about 8.5 μg / kg / hour, or about 9.0 μg / kg / hour, or about 9.5 μg / kg / hour, or about 10 μg / kg / hour, or about 11 μg / kg / hour, or about 12 μg / kg / hour, or about 13 μg / kg / hour, or about 14 μg / kg / hour, or about 15 μg / kg / hour, or about 16 μg / kg / hour, or about 17 μg / kg / hour, or about 18 μg / kg / hour, or about 19 μg / kg / hour or about 20 μg / kg / hr, or about 21 μg / kg / hr, or about 22 μg / kg / hr, or about 23 μg / kg / hr, or about 24 μg / kg / hr, or about 25 μg / kg / hr, or about 27.5 μg / kg / hr, or about 30 μg / kg / hr, or about 32.5 μg / kg / hr, or about 35 μg / kg / hr, or about 40 μg / kg / hr, or about 45 μg / kg / hr, or about 50 μg / kg / hr. In certain embodiments, dexmedetomidine is administered as a continuous intravenous dose over about 1 to about 10 minutes, or about 1 to about 20 minutes, or about 1 to about 30 minutes, or about 1 to about 2 hours, or about 1 to about 3 hours, or about 1 to about 4 hours, or about 1 to about 5 hours, or about 1 to about 6 hours, or about 1 to about 7 hours, or about 1 to about 8 hours, or about 1 to about 9 hours, or about 1 to about 10 hours, or about 1 to about 11 hours, or about 1 to about 12 hours, or about 1 to about 13 hours, or about 1 to about 14 hours, or about 1 to about 15 hours, or about 1 to about 16 hours, or about 1 to about 17 hours, or about 1 to about 18 hours, or about 1 to about 19 hours, or about 1 to about 20 hours, or about 1 to about 21 hours, or about 1 to about 22 hours, or about 1 to about 23 hours, or about 1 to about 24 hours. In preferred, non-limiting embodiments, dexmedetomidine is administered over a period of about 6 to about 24 hours. In certain embodiments, dexmedetomidine is administered as a continuous dose over a period of about 6 hours, or about 7 hours, or about 8 hours, or about 9 hours, or about 10 hours, or about 11 hours, or about 12 hours, or about 13 hours, or about 14 hours, or about 15 hours, or about 16 hours, or about 17 hours, or about 18 hours, or about 19 hours, or about 20 hours, or about 21 hours, or about 22 hours, or about 23 hours, or about 24 hours.

[0017] In certain non-limiting embodiments, the administration of dexmedetomidine includes an initial loading dose administered before a second maintenance dose. When administered as a loading dose followed by a maintenance dose, the loading dose can be from about 0 μg / kg to about 5 μg / kg, or from about 0.005 μg / kg to about 4.5 μg / kg, or from about 0.005 μg / kg to about 3 μg / kg, or from about 0.005 μg / kg to about 2.5 μg / kg, or from about 0.005 μg / kg to about 2 μg / kg, or from about 0.005 μg / kg to about 1.5 μg / kg, or from about 0.005 μg / kg to about 1 μg / kg, or from about 0.005 μg / kg to about 0.5 μg / kg, or from about 0.005 μg / kg to about 0.25 μg / kg, or from about 0 μg / kg to about 0.4 μg / kg. In preferred, non-limiting embodiments, the loading dose is about 0 μg / kg to about 1.0 μg / kg. In specific embodiments, the loading dose is about 0.01 μg / kg, or about 0.025 μg / kg, or about 0.05 μg / kg, or about 0.1 μg / kg, or about 0.2 μg / kg, or about 0.25 μg / kg, or about 0.3 μg / kg, or about 0.35 μg / kg, or about 0.4 μg / kg, or about 0.5 μg / kg, or about 0.6 μg / kg, or about 0.7 μg / kg, or about 0.8 μg / kg, or about 0.9 μg / kg, or about 1 μg / kg. 0.0 μg / kg, or about 1.1 μg / kg, or about 1.2 μg / kg, or about 1.3 μg / kg, or about 1.4 μg / kg, or about 1.5 μg / kg, or about 1.6 μg / kg, or about 1.7 μg / kg, or about 1.8 μg / kg, or about 1.9 μg / kg, or about 2.0 μg / kg, or about 2.1 μg / kg, or about 2.2 μg / kg, or about 2.3 μg / kg, or about 2.4 μg / kg, or about 2.5 μg / kg.In certain embodiments, the loading dose is about 3.0 μg / kg, or about 3.5 μg / kg, or about 4.0 μg / kg, or about 4.5 μg / kg, or about 4.0 μg / kg, or about 4.5 μg / kg, or about 5.0 μg / kg, or about 5.5 μg / kg, about 6.0 μg / kg, or about 6.5 μg / kg, or about 7.0 μg / kg, or about 7.5 μg / kg, About 8.0 μg / kg, or about 8.5 μg / kg, or about 9.0 μg / kg, or about 9.5 μg / kg, or about 10 μg / kg, or about 11 μg / kg, or about 12 μg / kg, or about 13 μg / kg, or about 14 μg / kg, or about 15 μg / kg, or about 16 μg / kg, or about 17 μg / kg, or about 18 μg / kg, or about 19 μg / kg kg, or about 20 μg / kg, or about 21 μg / kg, or about 22 μg / kg, or about 23 μg / kg, or about 24 μg / kg, or about 25 μg / kg, or about 27.5 μg / kg, or about 30 μg / kg, or about 32.5 μg / kg, or about 35 μg / kg, or about 40 μg / kg, or about 45 μg / kg, or about 50 μg / kg. In certain embodiments, the loading dose is less than about 0.5 μg / kg, or less than about 0.45 μg / kg, or less than about 0.4 μg / kg, or less than about 0.35 μg / kg, or less than about 0.3 μg / kg, or less than about 0.25 μg / kg, or less than about 0.2 μg / kg, or less than about 0.15 μg / kg, or less than about 0.1 μg / kg, or less than about 0.05 μg / kg, or less than about 0.01 μg / kg. In certain embodiments, no loading dose is administered. The loading dose can be administered over about 1 to about 5 minutes, or about 1 to about 10 minutes, or about 1 to about 15 minutes, or about 1 to about 20 minutes, or about 1 to about 25 minutes, or about 1 to about 30 minutes, or about 1 to about 45 minutes, or about 1 to about 60 minutes. The loading dose can be followed by a maintenance dose over the time period described above for a single sustained dose. In a preferred, non-limiting embodiment, the loading dose is administered over about 10 to about 20 minutes. In specific embodiments, the loading dose is administered over about 5 minutes, or about 7.5 minutes, or about 10 minutes, or about 12.5 minutes, or about 15 minutes, or about 20 minutes, or about 25 minutes, or about 30 minutes, or about 35 minutes, or about 40 minutes, or about 45 minutes, or about 50 minutes, or about 55 minutes, or about 60 minutes. In certain non-limiting embodiments, when administered as a single continuous loading or maintenance dose, dexmedetomidine is administered over about 1 hour to about 7 days, or about 1 hour to about 4 days, or about 1 hour to about 48 hours, or about 1 hour to about 36 hours, or about 1 hour to about 24 hours, or about 1 hour to about 12 hours. In specific non-limiting embodiments, dexmedetomidine is administered as a continuous infusion for less than about 72 hours, or less than about 48 hours, or less than about 36 hours, or less than about 24 hours, or less than about 18 hours, or less than about 12 hours, or less than about 6 hours, or less than about 3 hours, or less than about 1 hour, or less than about 30 minutes.

[0018] In certain non-limiting embodiments, the methods reduce the amount of rescue medication required. In one embodiment, the rescue medication is a non-dexmedetomidine sedative. In specific embodiments, the disclosed methods reduce the amount of sedative rescue medication required by about 5% to about 100%, or about 5% to about 75%, or about 5% to about 50%, or about 5% to about 25%, or about 5% to about 15%. In certain embodiments, the sedative rescue drug is a benzodiazepine. Non-limiting examples of benzodiazepines include clonazepam, diazepam, estazolam, flunitrazepam, lorazepam, midazolam, nitrazepam, oxazepam, triazolam, temazepam, chlordiazepoxide, and alprazolam. In certain embodiments, the sedative drug is a barbital. Non-limiting examples of barbital drugs include amobarbital, pentobarbital, secobarbital, and phenobarbital. Other examples of sedative drugs include chloral hydrate, eszopiclone, zaleplon, zolpidem, and zopiclone. In certain embodiments, the rescue medication is an analgesic medication. In certain embodiments, the method reduces the amount of analgesic rescue medication required. In specific embodiments, the disclosed method reduces the amount of analgesic rescue medication required by about 5% to about 100%, or about 5% to about 75%, or about 5% to about 50%, or about 5% to about 25%, or about 5% to about 15%. In one embodiment, the analgesic is an opioid. Non-limiting examples of opioids include codeine, oxycodone, hydrocodone, fentanyl, morphine, buprenorphine, hydromorphone, methadone, tramadol, meperidine, oxymorphone, and pentazocine. In certain embodiments, the analgesic is an N-methyl-D-aspartate antagonist (NDMA). Non-limiting examples of NDMA include ketamine, nitrous oxide, and xenon. Other examples of analgesics include clonidine, desflurane, isoflurane, and sevoflurane. Rescue medication may be administered perorally, parenterally, nasally (e.g., as a powder), rectally (e.g., as a suppository), or topically.

[0019] In one embodiment, the disclosed method reduces the incidence of neuronal damage. In certain embodiments, the disclosed method reduces the incidence of neuronal damage in one or more regions of the brain. Non-limiting examples of brain regions in which the incidence of neuronal damage is reduced include the cerebral cortex, basal ganglia, olfactory bulb, hypothalamus, thalamus, epithalamus, midbrain, pons, cerebellum, and medulla. Non-limiting causes of neurological damage include, but are not limited to, administration of sedatives or analgesics, seizures, asphyxiation, epilepsy, concussion, cerebral hemorrhage, cord shock, drowning, tumors, immunotherapy, chemotherapy, iatrogenic free radical toxicity, injury, ataxia, surgery, cardiopulmonary bypass, cerebral palsy, cerebral ischemia, cerebral anoxic injury, autoimmune neurodegeneration, myocardial ischemia, myocardial infarction, stroke, atherosclerosis, acute respiratory failure, coronary artery bypass surgery, ulcerative colitis, traumatic brain injury, spinal cord injury, spinal muscular atrophy, vertebral disease, decompression sickness, fetal alcohol syndrome, hepatitis B, hepatitis C, hepatitis G, yellow fever, dengue fever, encephalitis, liver disease, primary cirrhosis, kidney disease, pancreatitis, polycystic kidney disease, Helicobacter pylori (H. pylori)-associated gastric and duodenal ulcer disease, HIV infection, toxoplasmosis, rubella, cytomegalovirus, tuberculosis, meningitis, juvenile diabetes, lichen planus, uveitis, Behcet's disease, pure red cell aplasia, aplastic anemia, amyotrophic lateral sclerosis, multiple sclerosis, nephrotic syndrome, and combinations thereof. In certain non-limiting embodiments, the resulting neurological damage includes various types of neurocognitive, psychocognitive, and / or neuromotor or movement disorders, or combinations thereof. Such disorders can be functional or ability delays, functional or ability disruptions, loss of function or ability, inability to develop or learn new abilities, and the like. Non-limiting examples of neurocognitive and / or psychocognitive disorders include learning, memory, executive function, and visuospatial ability disorders. Non-limiting examples of neuromotor disorders include strength, balance, mobility disorders, and combinations thereof. In other non-limiting embodiments, the neurological damage includes developmental delays, cerebral palsy, intellectual disability, visual impairment, hearing loss, autism, motor paralysis, hemiplegia, distortion conditions, stress conditions, neurological dysfunction such as convulsions, seizures, muscle rigidity, nervous tension, and anxiety, and the like, and combinations thereof (see, e.g., Hintz et al. Pediatrics. 2005 Jun;115(6):1645-51).

[0020] Neurological disorders include, but are not limited to, cognitive impairments ... Scale of Intelligence. San Antonio: The Psychological Corp., 1989), the Randt Memory Test Short Story Module (Randt C, Brown E. Administration manual: Randt Memory Test. New York: Life Sciences, 1983), the Digit Span subtest and the Digit Symbol Task subtest of the Wechsler Adult Intelligence Scale-Revised. subtest)(Wechsler D. The Wechsler Adult Intelligence Scale-Revised (WAIS-R). San Antonio, Tex.: Psychological Corporation, 1981), Revised Benton Visual Retention Test (Benton Revised Visual Retention Test)(Benton AL, Hansher K. Multilingual aphasia examination. Iowa City: University of Iowa Press, 1978), and Trail Making Test Making Test)(Part B)(Reitan R M. Validity of the Trail Making Test Neurological damage can be assessed by well-established criteria, such as the Bayley Scales of Infant Development (BSID-II) Mental Development Index assessment, the BSID-II Psychomotor Development Index assessment, and the BSID-II Neurological Development Index assessment. Development Index assessment, Denver Developmental Screening Test Developmental Screening Test, magnetic resonance imaging, vision testing, and hearing testing. Other tests include standardized interactions and / or observations, such as standardized assessments of socialization, hand-eye coordination, motor control, ability to understand and use sounds and words, and ability to recognize sounds and words.

[0021] Non-limiting examples of reducing the incidence of nerve injury include reducing the severity of one or more incidences of nerve injury, reducing the number of one or more incidences of nerve injury, preventing the onset of one or more incidences of nerve injury, or delaying the onset of one or more incidences of nerve injury, or a combination thereof. In one non-limiting embodiment, reducing the incidence of nerve injury includes a better score or rating, as measured by one of the above tests or assessments, than if the pediatric patient had not been administered the effective amount of dexmedetomidine. In certain embodiments, the neuronal damage is cell degeneration or neuronal apoptosis. As used herein, the term "cell degeneration" refers to cell death as a result of a stimulus, trauma, a pharmaceutical composition, or a pathological process. As used herein, the term "neuronal apoptosis" or "neuronal apoptosis" refers to neuronal cell death associated with programmed cell death. In certain embodiments, the method reduces the incidence of neuronal apoptosis. Non-limiting examples of cells that can be protected by the disclosed methods include neurons and glial cells. Non-limiting examples of neurons that can be protected by the disclosed methods include Renshaw cells, Purkinje cells, hippocampal basket cells, cerebellar basket cells, cortical basket cells, cortical interneurons, cerebellar interneurons, pyramidal cells, granule cells, anterior horn cells, and motor neurons. Non-limiting examples of glial cells that can be protected by the disclosed methods include neurolemmocytes, satellite cells, microglia, oligodendroglia, and astroglia. In certain embodiments, neuronal damage includes cell atrophy, margination-induced chromatin condensation, formation of membrane-enclosed apoptotic bodies, and Ash neuronal necrosis. In one embodiment, administration of dexmedetomidine reduces the incidence of neuronal damage in the cortical lamina. In certain embodiments, this reduction occurs in one or more of cortical lamina layers I-IV. In one embodiment, the reduction in neuronal damage occurs in cortical lamina layer I. In particular embodiments, the reduction in neuronal damage occurs in cortical lamina layer II. In certain embodiments, this reduction occurs in both cortical lamina layers I and II. [Example]

[0022] 7. Working Example The following examples are merely illustrative of the disclosed subject matter and should not be construed as limiting the scope of the invention in any way. Example 1: Dexmedetomidine study in neonates Initial study of 30 patients A 30-subject, open-label, multicenter safety, efficacy, and pharmacokinetic study of dexmedetomidine was conducted in neonates with a gestational age of ≥28 to ≤44 weeks who required a minimum of 6 hours of sedation in an intensive care setting. This study investigated the efficacy, pharmacokinetics, and safety of three different dose levels of dexmedetomidine in neonates with a gestational age of ≥28 to ≤44 weeks administered as a continuous infusion for a minimum of 6 hours and up to 24 hours after a loading dose in a neonatal intensive care unit (NICU), cardiac intensive care unit (CICU), or PICU. Gestational age (weeks) was calculated as the time elapsed from the first day of the last menstrual period to the date of enrollment. If pregnancy was achieved using assisted reproductive techniques, 2 weeks were added to the above calculation to calculate gestational age. Patients selected for this study were initially intubated and mechanically ventilated preterm neonates born at ≥28 to <36 weeks' gestational age and full-term neonates born at ≥36 to ≤44 weeks' gestational age. The former were assigned to Group I, and the latter to Group II. Subjects weighed >1000 g at enrollment. In this population, the neonatal cardiovascular system possesses characteristics that may be adversely affected by the use of dexmedetomidine. Unlike older infants, children, and adults, the neonatal myocardium is unable to increase contractility and cardiac output in response to metabolic demands. Instead, neonates are highly dependent on their own heart rate to increase cardiac output. As a result, dexmedetomidine's known bradycardic effect may reduce cardiac output in neonates. For this reason, the dose selected for study in this population was intentionally lower than that typically used for sedation of older pediatric patients. Although lower doses were expected to reduce the adverse effects of bradycardia, due to the high lipid solubility and potentially high cerebrospinal fluid concentrations of dexmedetomidine, the immaturity of the blood-brain barrier in this population may enhance the sedative properties of dexmedetomidine; therefore, a minimum dose of 0.05 μg / kg loading dose followed by 0.05 μg / kg / hour maintenance dose over 10 or 20 minutes was expected to produce some sedation in mechanically ventilated subjects in this age group. The highest dose, 0.2 μg / kg loading dose followed by 0.2 μg / kg / hour, was expected not to cause bradycardic effects. Each subject received a loading dose of dexmedetomidine over 10 or 20 minutes, followed by an appropriate continuous infusion maintenance dose of dexmedetomidine for a minimum of 6 hours but not more than 24 hours. The dose level administered to each subject is shown in Table 1 below. Subjects were assigned to dose levels sequentially.

[0023] TIFF0007818561000002.tif31108

[0024] The dexmedetomidine administered was from Hospira, The dexmedetomidine was Precedex® dexmedetomidine HCl injection manufactured by Hospira, Inc. Dexmedetomidine hydrochloride (HCl) injection (100 μg / mL, base) was supplied to the infusion study site by Hospira. The study drug was prepared (diluted) by the on-site pharmacy. The dexmedetomidine loading dose was diluted with 0.9% sodium chloride or 5% dextrose in water to one of the following concentrations: 4 μg / mL solution, 2 μg / mL solution, 1 μg / mL solution, or 0.5 μg / mL solution. Dexmedetomidine was infused using a controlled infusion device. To ensure accurate infusion, dexmedetomidine was not administered directly into the pulmonary artery. Dexmedetomidine was administered as a two-stage infusion. A 10- or 20-minute loading dose of dexmedetomidine was followed by a continuous fixed maintenance dose of dexmedetomidine for a minimum of 6 hours and up to 24 hours after surgery. Dexmedetomidine for the maintenance infusion was diluted to the same concentration as the dexmedetomidine loading dose. For both the loading and maintenance infusions, dexmedetomidine was administered at the insertion site of the IV catheter to prevent drug overflow. Dexmedetomidine was administered through an IV line designated for dexmedetomidine. The most recent body weight measured before dexmedetomidine initiation was used to calculate sedative doses. Because dexmedetomidine lasts up to 24 hours, there was no need to adjust the dose for daily weight fluctuations. Exposure to dexmedetomidine by gestational age is summarized in Table 2 (loading dose), Table 3 (maintenance dose), and Table 4 (total dose / hour; exposure times <6 hours, <12 hours, <24 hours, >0 to <6 hours, ≥6 to <12 hours, ≥12 to <24 hours, and ≥24 hours). Median exposure to dexmedetomidine is summarized in Tables 2 to 4 below. Median data were selected due to data variability. Median dexmedetomidine exposure was highest in age group II, dose level 3. In age group I, two subjects received infusions lasting >0 to <6 hours, ≥6 to <12 hours, and ≥12 to <24 hours, respectively. In age group II, the majority of subjects (n = 17, 70.8%) received infusions lasting ≥6 to <12 hours, with a median duration of just over 6 hours (370 minutes). Subjects in dose level 3 received the longest maintenance infusion in age group II, with a median of 961.5 minutes (16 hours) compared with the other two cohorts in age group II, which had medians of 360.0 to 365.0 minutes (approximately 6 hours). All subjects completed treatment receiving a minimum of 6 hours of maintenance infusion.

[0025] Table 2. Median burden of dexmedetomidine exposure TIFF0007818561000003.tif44106 a Age group I = gestational age ≥28 to <36 weeks; age group II = ≥36 to ≤44 weeks. b The units are μg / kg for loading dose and μg / kg / hour for maintenance dose (continuous infusion).

[0026] Table 3. Median Maintenance Doses of Dexmedetomidine Exposure TIFF0007818561000004.tif4498 a Age group I = gestational age ≥28 to <36 weeks; age group II = ≥36 to ≤44 weeks. b The units are μg / kg for loading dose and μg / kg / h for maintenance dose (continuous infusion).

[0027] Table 4. Median Total Dose of Dexmedetomidine Exposure TIFF0007818561000005.tif93106 aAge group I = gestational age ≥28 to <36 weeks; age group II = ≥36 to ≤44 weeks. b The units are μg / kg for loading dose and μg / kg / hour for maintenance dose (continuous infusion).

[0028] Subjects in age group I received a median total loading dose of 0.07 μg over a median duration of 10 minutes and a median total maintenance dose of 1.30 μg over 1407.5 minutes (23.5 hours). Subjects in age group II received a median total loading dose of 0.18-0.70 μg over 10 minutes and a median total maintenance dose of 1.08-12.20 μg over 360-961.5 minutes (6-16 hours). The Neonatal Pain, Agitation, and Sedation Scale (Neonatal Pain, Agitation, and Sedation Scale) was developed to assess sedation and pain / agitation in neonates. Efficacy assessment was performed by assessing sedation frequency using the Neonatal Patient Assessment Scale (N-PASS). The N-PASS includes five criteria for assessing neonatal sedation level, pain, and agitation. The indicators are: 1) crying / irritability, 2) behavior / state, 3) facial expression, 4) limbs / tone, and 5) vital signs (i.e., HR, RR, SBP, DBP, and SpO2). Whenever possible, the same investigator or designee obtained N-PASS scores according to the activity schedule shown in Table 5. All N-PASS assessments were monitored with an assessment of the presence of paradoxical reactions (marked agitation). Agitation was protocol-defined and occurred when either the crying / irritability or behavior / state criteria merited a score of 2. For each of the five criteria, subjects were assigned a single numerical value: −2, −1, 0, +1, or +2. Subjects could have some criteria scores on the negative sedation side and other criteria on the positive pain / agitation side, but for any single criterion, they would receive a score on either the sedation or pain side, but not both. If the subject's gestational age was <30 weeks, a pain score of 1 was added.

[0029] Table 5. N-PASS-Neonatal Pain, Agitation and Sedation Scale TIFF0007818561000006.tif129113

[0030] Rescue morphine or fentanyl and / or midazolam could be given if a total N-PASS score >3 or indicated by clinical judgment. The dexmedetomidine infusion could be continued during or after extubation of the subject, with a minimum duration of dexmedetomidine of 6 hours and a maximum duration of infusion of 24 hours. Efficacy measures included the use of rescue medications for sedation or analgesia during the dexmedetomidine infusion (frequency and amount used). Rescue medications for sedation (midazolam) and pain (fentanyl or morphine) were administered as needed during dexmedetomidine administration based on the results of the N-PASS sedation / pain scale. An N-PASS total score >3 indicated the need for rescue therapy, and the choice of sedative or analgesic rescue medication was left to the investigator's discretion. For any bolus administration of rescue therapy, the following sequence of events occurred: an N-PASS score was obtained before rescue medication administration and within 5 minutes after midazolam administration. The rescue medication for sedation was midazolam, and the rescue medication for pain was either fentanyl or morphine. Midazolam was administered at the recommended dose of 0.05–0.15 mg / kg per dose based on pediatric labeling. Rescue fentanyl for pain was administered as a 0.5–2 μg / kg bolus or a 1–2 μg / kg / hour continuous infusion. For fentanyl infusions, N-PASS was recorded immediately before the start of the infusion. Rescue morphine was administered as a 0.025–0.1 mg / kg bolus or a 0.01–0.02 mg / kg / h infusion. For morphine infusions, N-PASS was recorded immediately before the start of the infusion. Summary statistics for the loading and maintenance infusion doses of dexmedetomidine are shown in Table 5A below.

[0031] Table 5A. Summary statistics for dose-related data TIFF0007818561000007.tif159110

[0032] Safety measures included collection of adverse events (AEs), heart rate (HR in beats per minute [bpm]), systolic blood pressure (SBP in millimeters of mercury [mmHg]), diastolic blood pressure (DBP in millimeters of mercury [mmHg]), mean arterial pressure (MAP in millimeters of mercury [mmHg]), oxygen saturation by pulse oximetry (percent SpO2), and respiratory rate (RR in breaths / min [breaths / min]) or ventilator settings, laboratory results, and electrocardiogram (ECG) monitoring. Arterial, venous, or peripheral blood samples (0.15 mL each) were obtained for pharmacokinetic analysis at six or seven protocol-specified times depending on body weight for subjects in age group I (gestational ages ≥28 weeks to <36 weeks) and at seven protocol-specified times for subjects in age group II (gestational ages ≥36 weeks to ≤2 weeks). Chemistry, hematology, and urinalysis samples were obtained for clinical testing according to the following scheduled study activities: at screening, 5 hours after maintenance but before discontinuation of dexmedetomidine, and within 24 hours after discontinuation of dexmedetomidine infusion. Additionally, subjects on s / p CPB had a sample taken for ALT levels after CPB but within 1 hour of initiating dexmedetomidine (this constituted baseline ALT). All blood and urine samples were collected in appropriately labeled tubes and sent to a local laboratory for analysis. Liver function tests (LFTs) were obtained before and after treatment and compared for evidence of liver dysfunction. LFTs were obtained during the following periods: at screening, 5 hours after maintenance but before discontinuation, and as close as 24 hours after infusion discontinuation or the day of discharge, whichever occurred first. Additionally, subjects on s / p CPB had a sample taken for ALT levels after CPB but within 1 hour of starting the dexmedetomidine infusion. This constituted the baseline ALT and was not used as an exclusion criterion. Liver function tests were defined as follows: aspartate aminotransferase (AST), ALT, alkaline phosphatase, and total bilirubin. Hepatotoxicity was defined by an ALT >156 U / L or a ≥30% increase from screening, whichever was greater. SAS TMStatistical analyses were performed using a statistical software system (SAS Institute, Inc., Cary, NC), version 9.1. Unless otherwise specified, all statistical tests were two-sided, and a p-value ≤ 0.0500 after rounding to four decimal places was considered statistically significant. Missing data were generally not imputed. For continuous variables, N, mean, median, SD, minimum, Q1, Q3, and maximum are presented. Means and medians are presented to one decimal place as well as raw values. Standard deviations (SDs) are presented to two decimal places as well as raw values. For categorical variables, N and percentages are presented. All percentages are reported to one decimal place. For final statistics, treatment differences were assessed by age group for continuous variables using two-way analysis of variance (ANOVA) when the assumption of normal distribution was valid, or by nonparametric tests when this assumption was not met. For regular categorical variables, the Cochran-Mantel-Haenszel (CMH) test was used. When treatment differences were significant, pairwise comparisons between dose levels were performed. All efficacy variables were analyzed for dexmedetomidine. Dexmedetomidine was effective in sedating critically ill, initially intubated, and mechanically ventilated preterm infants ≥ 28 to < 36 weeks. No subjects in age group I received rescue midazolam for sedation during the dexmedetomidine infusion. At doses up to 0.2 μg / kg / h used in this study, dexmedetomidine was moderately effective in sedating full-term neonates. In age group II, a total of 4 subjects (16.7%) received rescue midazolam (mean dose 0.22 mg / kg) for sedation during the dexmedetomidine infusion. Most preterm infants in age group I did not require additional medication for pain during the dexmedetomidine infusion. One subject (16.7%) in age group I received rescue medication for analgesia during the test infusion. In contrast, most full-term neonates (58.3%) in age group II received rescue medication for analgesia during the test infusion. The increased analgesic requirements in age group II, especially at dose level 3, likely reflect a higher proportion of postoperative surgical subjects. All dose levels spent only a short time with a total N-PASS score >3, suggesting that most subjects were adequately sedated and did not experience signs of pain / agitation. In general, trends in mean changes from baseline in vital signs were not clinically meaningful.

[0033] Preterm infants with gestational ages ≤28 to <36 weeks appeared to have lower clearance than term neonates, resulting in higher dose-adjusted exposures. These parameters were fully evaluated at one dose level (0.05 μg / kg) in age group I (≥28 to <36 weeks gestational age) and at all three dose levels (0.05 μg / kg, 0.1 μg / kg, and 0.2 μg / kg) in age group II (≥36 to ≤44 weeks gestational age). Younger subjects appeared to have lower clearance (0.41 L / hr / kg at the 0.05 μg / kg dose level in age group I) than older subjects (0.61 L / hr / kg at the 0.05 μg / kg dose level in age group II), resulting in higher dose-adjusted exposures. This finding is difficult to interpret because pharmacokinetic data were not available at the 0.1 and 0.2 μg / kg dose levels in younger subjects. The results of the pharmacokinetic analysis included the steady-state, weight-adjusted volume of distribution (Vssw) and apparent terminal half-life (t 1 / 2 ) suggest that dexmedetomidine exposure was similar across dose levels and age groups. Furthermore, within older subjects (age group II), dexmedetomidine exposure appeared to be proportional to dose. Dose proportionality could not be assessed within younger subjects (age group I). This finding is difficult to interpret because pharmacokinetic data were not available at 0.1 μg / kg and 0.2 μg / kg in younger subjects. The lower clearance and higher concentrations in this age group compared with full-term neonates (four subjects required midazolam for sedation and 14 subjects required rescue medication for analgesia) are consistent with the higher efficacy observed in preterm neonates (none required rescue midazolam for sedation and one subject required rescue medication for analgesia). V ssw and t 1 / 2 was similar across dose levels and age groups.

[0034] Dexmedetomidine was safe and well tolerated in both age groups and at all doses. The observed adverse effect profile was typical of critically ill, high-risk pediatric populations and postoperative surgical patients. Two subjects (33.3%) in age group I and 15 subjects (62.5%) in age group II experienced treatment-emergent adverse effects. Only one subject in age group I, dose level 1, reported a treatment-emergent adverse effect. Events reported by more than one subject in age group II were hypokalemia, hypokalemia, irritability, atelectasis, and pleural effusion. These events were more common and expected in postoperative open cardiac surgery patients. Time to successful extubation was examined using Kaplan-Meier estimates in Precedex-exposed subjects. The results in this section were not considered further because they were not clinically meaningful due to the high variability of medical history factors. Most treatment-emergent adverse effects were judged to be unrelated to treatment, and only two subjects (age group II) in this study experienced treatment-emergent adverse effects that were judged to be treatment-related. No treatment-emergent severe adverse effects were reported. Two subjects in each age group experienced treatment-emergent moderate adverse effects, and all other subjects experienced treatment-emergent mild adverse effects. There were no treatment-emergent severe adverse effects leading to death, treatment-emergent other severe adverse effects, or treatment-emergent adverse effects leading to dexmedetomidine discontinuation. There were no dose-limiting toxicities (persistent bradycardia, persistent hypotension, or respiratory depression) leading to dexmedetomidine discontinuation. In general, mean changes from baseline were not clinically significant for laboratory parameters, vital signs, physical examination, or ECG. Dexmedetomidine was effective in sedating critically ill, initially intubated, mechanically ventilated preterm infants. No subjects in age group I received rescue midazolam for sedation during the study infusion. At doses up to 0.2 μg / kg / h used in this study, dexmedetomidine was moderately effective in sedating term neonates. Most preterm infants in age group I did not require additional medication for pain during the dexmedetomidine infusion. In contrast, many full-term neonates in age group II (58.3%) received rescue medication for analgesia during the study infusion. The increased analgesic requirements in age group II, especially at dose level 3, likely reflect a higher rate of postoperative surgical subjects. Preterm infants appeared to have lower plasma clearance than full-term neonates, resulting in higher titration exposure and greater efficacy. No subjects discontinued the study due to treatment-emergent adverse events. Dexmedetomidine was safe and well tolerated in both age groups and at all doses. The observed adverse effect profile was typical of the critically ill, high-risk pediatric population studied.

[0035] Additional cohort of 6 patients After initiating the study with the original 30 patients, six additional patients were enrolled and completed the study (hereafter the "Additional Cohort"). The study protocol for the additional cohort study was as described above. The additional six patients were neonates with a gestational age of ≥ 28 weeks to < 36 weeks who required sedation within an intensive care setting for a minimum of six hours. These six patients were at dose level 2 and received a loading dose of 0.1 μg / kg and a maintenance dose of 0.1 μg / kg. The dose levels for each age group for the total 36 patients who received dexmedetomidine in this study are shown in Table 6 below.

[0036] Table 6. Dose levels for each age group TIFF0007818561000008.tif34105

[0037] The mean gestational age of the six subjects in the supplemental cohort was 32.5 weeks. Three were male and three were female. The mean weight was 1.71 kg, and the mean height was 42.75 cm. The reasons for intubation were respiratory disease in five subjects and sepsis in one subject. All six subjects in the supplemental cohort received prior therapy before entering the study; the most common of these were anti-infectives, nutritional products, and midazolam or fentanyl. All six subjects received concomitant therapy; the most common of these were anti-infectives and nutritional products. All six subjects received a variety of therapies after dexmedetomidine infusion. None of the six subjects in the supplemental cohort required rescue midazolam or morphine during the dexmedetomidine infusion. Only one subject (16.7%) required rescue analgesia during the dexmedetomidine infusion and received 20 μg (0.98 μg / kg) fentanyl. This subject's dexmedetomidine infusion duration was 6.5 hours. This subject had a history of respiratory distress syndrome requiring intubation as well as gastroschisis requiring surgical silo placement, both of which were ongoing at the time of examination. The only subject requiring rescue analgesia due to a total N-PASS score of less than 3 was the subject, who received 0.25 hours of infiltration IV. The geometric means of the plasma pharmacokinetic parameters of dexmedetomidine after the loading and maintenance doses in the Study Addendum cohort (age group I, dose level 2) are shown in Table 7 below.

[0038] Table 7. Geometric mean plasma pharmacokinetic parameters of additional cohort patients TIFF0007818561000009.tif72107

[0039] The weight-adjusted clearance (CLw) of DEX in two subjects evaluated in the additional cohort was similar to that in one subject evaluated at age group I, dose level 1, and was again lower than that observed in age group II subjects. Consistent with the difference in clearance, the dose-adjusted area under the concentration-time curve from zero to infinity, AUC(0-infinity), evaluated in the additional cohort (n=2) was 4.6-fold higher (2102.55 vs. 461.04 pg / mL h) than that calculated across all dose levels for age group II (n=12). Similarly, the steady-state concentration (C ss ) was higher in the supplemental cohort than at the same dose level in age group II (369.67 vs. 170.53 pg / mL). However, the maximum concentration (C max ) was actually lower in the supplemental cohort for the same dose level in age group II, 107.22 vs. 122.43 pg / mL, respectively. The steady-state weight-adjusted volume of distribution (V ssw ) was slightly greater in the supplemental cohort compared to the same dose level in age group II (3.79 vs. 2.85 L / kg), and the apparent terminal elimination half-life (t 1 / 2 ) was longer in the supplemental cohort, at 8.32 vs. 4.77 hours, respectively. Dexmedetomidine was safe and well tolerated in both age groups and at all doses, including the booster cohort. The adverse effect profile observed in the booster cohort is representative of the critically ill, high-risk pediatric population. Limited information from preterm neonates makes interpretation of the effect of age on dexmedetomidine pharmacokinetics difficult. However, based on two dose levels (0.05 and 0.1 μg / kg) tested in age group I of the original 30-patient cohort and in an additional cohort, clearance appeared to be lower in preterm neonates (n = 3) than in term neonates (n = 12), resulting in a 4.4- to 4.6-fold greater total exposure (AUC). This finding suggests that preterm neonates in age group I, dose levels 1 and 2 have higher C than full-term neonates. ssThe lower clearance and higher concentrations in preterm neonates are consistent with the greater efficacy observed in preterm neonates at both dose levels (none of the subjects required rescue midazolam for sedation and 2 subjects required rescue medication for analgesia) compared to full-term neonates (4 subjects required rescue midazolam for sedation and 14 subjects required rescue medication for analgesia). C max and AUC(0-last) appeared to be lower in the supplemental cohorts compared to the same dose level in the Age Group II population. These values ​​were as follows: max The mean clearance, mean concentration, and mean efficacy of the 20-month-old neonates were 107.22 vs. 122.43 pg / mL, respectively, and the AUC(0-last) was 708.09 vs. 813.26 pg / mL, respectively. Lower clearance, higher concentrations, and greater efficacy were observed in the additional cohort of preterm neonates, consistent with what was observed in other cohorts of preterm neonates compared with full-term neonates in the original cohort of 30 patients. Most preterm neonates in age group I in the data set of the additional cohort and the original 30-patient cohort did not require additional medication for pain during the dexmedetomidine infusion. One subject (13.7%) at each dose level in age group I received rescue medication for analgesia during the study infusion. In contrast, in the original 30-patient cohort, many full-term neonates in age group II (58.3%) received rescue medication for analgesia during the study infusion. The high analgesic requirements in age group II, especially at dose level 3, likely reflect the high proportion of postoperative surgical subjects. Subjects in the data set of the additional cohort and the original 30-patient cohort spent a short time with a total N-PASS score >3, indicating that most subjects were adequately sedated and did not exhibit signs of pain / agitation. In general, trends in changes from baseline in vital signs in the additional cohort and interim analysis data were not clinically meaningful. Median exposure to dexmedetomidine is summarized in Table 8 below. Median data were selected due to data variability. Subjects in age group I, dose level 2 had a lower median total maintenance dose and median duration of dexmedetomidine exposure compared to age group I, dose level 1 from the interim analysis: specifically, 1.14 μg vs. 1.30 μg, with a median duration of 375.0 minutes (6.25 hours) vs. 1407.5 minutes (23.5 hours), respectively. Subjects in age group I, dose level 2 had a lower median total maintenance dose compared to age group II from the interim analysis of the same dose level, but similar median duration of dexmedetomidine exposure: specifically, 1.14 μg vs. 1.87 μg, with a median duration of 375.0 minutes (6.25 hours) vs. 365.0 minutes (6.1 hours), respectively. Five of the six subjects received infusions lasting ≥6 to <12 hours, with a median total dose of 1.26 μg and a median duration of 380 minutes (6.3 hours), and one subject received an infusion lasting ≥12 to <24 hours, with a median total dose of 4.06 μg and a median duration of 1285.0 minutes (21.4 hours). All subjects completed treatment receiving a minimum 6-hour maintenance infusion.

[0040] Table 8. Doses and median duration of dexmedetomidine exposure JPEG0007818561000010.jpg79108

[0041] There was intersubject variability in most hematological tests. In general, no evidence of systematic changes was found for any hematological, chemistry, or urinalysis variables. Treatment-emergent adverse events attributed to laboratory results included hypoalbuminemia (n = 3) and the following events, which occurred in one subject each: hyperbilirubinemia, increased unconjugated blood bilirubin, hypoproteinemia, hypocalcemia, hematuria, and hyperglycemia. All of these laboratory parameters were judged to be unrelated to dexmedetomidine and are typical of this preterm neonatal population. Physical examination data were collected. The most common abnormal findings at physical examination and after dexmedetomidine administration were pulmonary / respiratory. There were no abnormal, clinically significant electrocardiogram results at physical examination or during or after dexmedetomidine administration. Total fluid input ranged from 49.1 to 162.6 mL, and total fluid output ranged from 30 to 224 mL. In general, there were no clinically meaningful changes from baseline in laboratory parameters, vital signs, physical examination, or electrocardiogram results in the additional cohort. All six subjects in the additional cohort experienced treatment-emergent adverse events. These are shown in Table 9 below. Of the 18 treatment-emergent adverse events, only hypoalbuminemia (n=3) was reported by more than one subject. Most treatment-emergent adverse events were judged to be unrelated to treatment. Only mild treatment-emergent adverse events were judged to be related to dexmedetomidine. One subject experienced two treatment-emergent adverse events judged to be related to treatment. One subject experienced three severe treatment-emergent adverse events; two subjects each experienced one moderate treatment-emergent adverse event. None of these severe or moderate events were judged to be related to dexmedetomidine. All other events were mild. There were no treatment-emergent serious adverse events resulting in death, one subject experienced three serious treatment-emergent adverse effects, and no subjects discontinued dexmedetomidine as a result of a treatment-emergent adverse event. No dose-limiting toxicities (persistent bradycardic, persistent hypotension, or respiratory depression) leading to discontinuation of dexmedetomidine emerged under treatment.

[0042] Table 9. Summary of Treatment-Emergent Adverse Events by System Organ Class and Preferred Term JPEG0007818561000011.jpg116109

[0043] The mean gestational ages in Group I - Levels 1 and 2 were 30.3 and 32.5 weeks, respectively, and the mean gestational age in Group II - Levels 1-3 was 38.7 weeks. Most patients experienced adequate levels of sedation, with only four patients (17%) in Group II receiving rescue sedation with midazolam (0.22 ± 0.26 mg / kg). Two patients (17%) in Group I and 11 patients (46%) in Group II received rescue analgesia with fentanyl. Additionally, four patients (21%) in Group II received rescue morphine. Dexmedetomidine clearance (CL) was significantly increased in Group I, Levels 1 and 2, respectively. w ) were 0.41 and 0.29 L / hr / kg, and the maximum plasma concentration (C max ) were 102 and 107 pg / mL, and the volume of distribution (V ssw ) were 2.7 and 3.8 L / kg, and the disappearance t 1 / 2 In Group 2, Levels 1, 2, and 3, the CL w are 0.61, 0.64 and 0.73 L / hr / kg, and C max were 78, 122, and 325 pg / mL, and V ssw are 1.4, 2.8 and 2 L / kg, and t 1 / 2 Group I had a 4.5-fold longer total exposure (AUC) than Group II, with a lower CL w was observed. The observed safety profile was typical of critically ill high-risk pediatric patient populations and postoperative surgical patients. Adverse events were reported in 8 (67%) patients in Group I and 15 (62%) patients in Group II, but only 2 (8%) patients had these adverse events considered related to dexmedetomidine. No patients had serious adverse events related to dexmedetomidine or adverse events requiring discontinuation of dexmedetomidine. The conclusions about the overall efficacy of this study were not affected by the update with additional cohorts. Dexmedetomidine was effective in sedating critically ill, initially intubated, mechanically ventilated preterm infants ≥ 28 to < 36 weeks in the additional cohorts and in the original 30-patient cohort. No subjects in the original 30-patient cohort or additional cohorts in age group I, dose levels 1 or 2, received rescue midazolam for sedation during the dexmedetomidine infusion. In the original 30-patient cohort, dexmedetomidine was effective in sedating full-term neonates at doses up to 0.2 μg / kg / hour used in this study. In age group II, a total of 4 subjects (16.7%) received rescue midazolam for sedation during the dexmedetomidine infusion (mean dose 0.22 mg / kg). In the additional cohort and interim analysis data, most preterm neonates in age group I did not require additional rescue medication for pain during the dexmedetomidine infusion. One subject (16.7%) in each dose level in age group I received rescue medication for analgesia during the study infusion. In contrast, in the interim analysis, many full-term neonates (58.3%) in age group II received rescue medication for analgesia during the study infusion. The increased analgesic requirements in age group II, especially at dose level 3, likely reflect a higher proportion of postoperative surgical subjects. Subjects in the additional cohort and interim analysis data spent a short time with a total N-PASS score >3, indicating that most subjects were adequately sedated and did not exhibit signs of pain / agitation. In the additional cohort of preterm neonates, lower clearance, higher concentrations, and greater efficacy were observed compared to the term neonates in the interim analysis, consistent with what was observed in other cohorts of preterm neonates in the interim analysis. Subjects in the additional cohort of age group I, dose level 2 had a lower median total maintenance dose and duration of dexmedetomidine exposure compared with age group I, dose level 1 in the interim analysis. Subjects in this additional cohort also had a lower median total maintenance dose, but similar duration of dexmedetomidine exposure, compared with age group II at the same dose level.

[0044] Example 2: Dexmedetomidine Study in Pediatric Intensive Care Unit Subjects A 175-subject, randomized, double-blind, dose-controlled, multicenter study of dexmedetomidine in initially intubated and mechanically ventilated pediatric subjects in a pediatric intensive care unit setting was conducted. The study examined the efficacy, pharmacokinetics, and safety of four different dose levels of dexmedetomidine. Subjects ranged in age from 1 month to less than 17 years. For preterm neonates, age was adjusted to 3 months of actual birth age based on gestational age. Subjects were mechanically ventilated before and during dexmedetomidine initiation, and subjects were expected to require a minimum of 6 hours of continuous intravenous (IV) sedation. Subjects could be intubated via nasal, endotracheal, or tracheostomy. Subjects were required to meet the American College of Anesthesiologists (ABA) 1, 2, 3, or 4 criteria at the time of initiation of dexmedetomidine infusion. They also had an American Society of Anesthesiologists (ASA) classification and a University of Michigan Sedation Scale (UMSS) score of 1, 2, 3, or 4. Subjects were randomized into one of two treatment groups. Within each treatment group, stratification was performed according to the presence or absence of cardiopulmonary bypass (CPB). The treatment groups are shown in Table 10 below. A total of 89 subjects were randomized into Group 1 (low dose) and 86 subjects were randomized into Group 2 (high dose). Of course, 83 subjects in the low dose group and 81 subjects in the high dose group received randomized dexmedetomidine for at least 6 hours.

[0045] TIFF0007818561000012.tif31101

[0046] The median age for the combined age group was 10.7 months (range: 0.9 months to 16.3 years) in the low-dose group and 14.7 months (range: 1.3 months to 16.2 years) in the high-dose group. Height and weight were similar across dose groups and by underlying condition (median height for combined age group: low-dose 68.0 cm, high-dose 76.5 cm; median weight for combined age group: low-dose 8.1 kg, high-dose 8.5 kg). Overall, there were slightly more males than females (low-dose, 59.6% males; high-dose, 55.8% males). Most subjects had severe illness (ASA 2016) from severe congenital cardiopulmonary disease. Demographics were similar between treatment groups (P3). Patients were further assigned to age group I or II. The number of subjects in each subgroup is shown in Table 11 below.

[0047] Table 11. Number of subjects in each subgroup JPEG0007818561000013.jpg25103Dx=Diagnosis a The Dex dose was loading dose (LD) = 0.2 / maintenance dose (MD) = 0.025-0.5 μg / kg / hour. b The Dex dose was LD = 0.3 / MD = 0.05-0.5 μg / kg / hour. c The Dex dose was LD = 0.5 / MD = 0.1-0.7 μg / kg / hour. d The Dex dose was LD = 0.6 / MD = 0.2-1.4 μg / kg / hour. e Age group I = ≥ 1 month to < 24 months; f Age group II = ≥ 24 months to < 17 years

[0048] In age group I, the median age was 8.51 months (low dose) and 9.75 months (high dose); in age group II, the median age was 6.32 years (low dose) and 7.57 years (high dose). Subjects in both age groups and both dexmedetomidine dose groups had similar screening ASA classifications, with the majority of subjects having high-risk P3 for severe systemic disease. Subjects undergoing open cardiac surgery were mostly high-risk P3, with similar numbers of subjects in the low-dose (72.2%) and high-dose (73.0%) dexmedetomidine groups. All subjects (100.0%) in the high-dose group and all but one subject in the low-dose group received at least one concomitant medication during the study; concomitant medication use was similar across dose groups. Concomitant medications taken by at least 50.0% of subjects in any dose group (whose use is permitted as rescue medications by protocol) other than midazolam, fentanyl, and morphine included furosemide, acetaminophen, potassium chloride, and heparin. As expected in s / p CPB groups after open cardiac surgery, >90% of subjects received inotropic support postoperatively. Inotropic therapy with milrinone and dobutamine was similar in both the low-dose and high-dose dexmedetomidine s / p CPB groups. Subjects received a random loading dose of dexmedetomidine over 10 or 20 minutes followed by an appropriate maintenance dose of dexmedetomidine. Each subject received a continuous infusion maintenance dose of dexmedetomidine for a minimum of 6 hours but not more than 24 hours. The dexmedetomidine administered was from Hospira, The dexmedetomidine was Precedex® dexmedetomidine HCl injection, manufactured by Inc. For subjects undergoing s / p CPB, the low-dose dexmedetomidine group was titrated to 0.025-0.5 μg / kg / hour and the high-dose dexmedetomidine group was titrated to 0.1-0.7 μg / kg / hour; for all other subjects, the low-dose dexmedetomidine group was titrated to 0.05-0.5 μg / kg / hour and the high-dose dexmedetomidine group was titrated to 0.2-1.4 μg / kg / hour. The dexmedetomidine continuous infusion was administered for a minimum duration of 6 hours and a maximum duration of 24 hours. The dexmedetomidine administered was from Hospira, The dexmedetomidine was Precedex® dexmedetomidine HCl injection manufactured by Hospira, Inc. Dexmedetomidine hydrochloride (HCl) injection (100 μg / mL, base) was supplied to the infusion study site by Hospira. The study drug was prepared (diluted) by the on-site pharmacy. The optional loading dose of dexmedetomidine was diluted with 0.9% sodium chloride or 5% dextrose in water to one of the following concentrations: a 4 μg / mL solution for the high-dose group and a 2 μg / mL solution for the low-dose group. Dexmedetomidine was infused using a controlled infusion device. Dexmedetomidine could be administered through an IV line designated for dexmedetomidine, through a designated IV line for dexmedetomidine attached to a Y-site adapter, or through a designated side port if given through a central line. No other medications were administered as boluses through the dexmedetomidine infusion line. The same syringe or bag used for the loading dose could be used for the maintenance dose by simply changing the infusion rate.

[0049] If rescue midazolam was required, the dexmedetomidine dose was increased and the need for additional midazolam after dexmedetomidine administration was reassessed. If rescue pain medication was required, patients were initially treated with an increased dexmedetomidine infusion rate, followed by fentanyl or morphine at age-specific doses or as a continuous infusion. Subjects receiving continuous infusions of fentanyl or morphine before randomization were allowed to continue these infusions throughout study drug administration if necessary. A baseline score for UMSS was obtained before the start of the drug infusion. The UMSS scale is shown in Table 12 below. If a loading dose was administered, UMSS scores were obtained immediately before the loading dose and at 5 and 10 minutes during the loading dose. If the loading dose was administered over 20 minutes, UMSS scores were obtained at 15 minutes. If no loading dose was administered, UMSS scores were obtained at the start of the maintenance infusion and at 5, 10, 15, 30, and 60 minutes during the first hour. UMSS scores were obtained every 4 hours during the remainder of the maintenance infusion. If a rescue medication was administered, UMSS scores were measured immediately before and 5 minutes after administering the rescue medication. UMSS scores were also obtained immediately before and 5 minutes after any non-pharmacological intervention, such as swaddling, holding, or rocking.

[0050] Table 12. University of Michigan Sedation Scale JPEG0007818561000014.jpg37107

[0051] Chemistry, hematology, and urinalysis samples were obtained for clinical testing. A baseline cortisol level test was performed before the initiation of dexmedetomidine administration. For CPB subjects, this blood draw was obtained within 90 minutes of the initiation of postoperative dexmedetomidine. An ACTH stimulation test was performed at the end of the dexmedetomidine infusion. Safety measures included collection of adverse events (AEs), heart rate (HR in beats per minute [bpm]), systolic blood pressure (SBP in millimeters of mercury [mmHg]), diastolic blood pressure (DBP in millimeters of mercury [mmHg]), mean arterial pressure (MAP in millimeters of mercury [mmHg]), oxygen saturation by pulse oximetry (percent SpO2), and respiratory rate (RR in breaths / min [breaths / min]) or ventilator settings, laboratory results, and electrocardiogram (ECG) monitoring. SAS TMStatistical analyses were performed using a statistical software system (SAS Institute, Inc., Cary, NC), version 9.1. Unless otherwise specified, all statistical tests were two-sided, and a p-value ≤ 0.0500 after rounding to four decimal places was considered statistically significant. In general, missing data were not imputed. For continuous variables, N, mean, median, SD, minimum, Q1, Q3, and maximum are presented. Means and medians are presented to one decimal place as well as raw values. Standard deviations (SD) are presented to two decimal places as well as raw values. For categorical variables, N and percentages are shown. All percentages are reported to one decimal place.

[0052] Dexmedetomidine exposure was highest at the high dose and generally greater in other diagnostic groups. The mean maintenance dose (μg / kg / hour) of low-dose dexmedetomidine was 0.33 μg / kg / hour in s / p CPB subjects requiring a slightly lower maintenance infusion to maintain target sedation. Similarly, in the high-dose dexmedetomidine group, the mean maintenance infusion was 0.59 μg / kg / hour in s / p CPB subjects requiring a lower maintenance infusion. The median duration of maintenance infusion was 1215.0 minutes (20.3 hours) in the low-dose group and 1127.5 minutes (18.8 hours) in the high-dose group. The median total loading dose was higher in ASA P3 and P4 subjects than in P1 and P2 subjects. The median total maintenance dose was similar in ASA P1 and P2 and P3 and P4 subjects. Median dexmedetomidine exposure is shown in Table 13 below. Exposure times are shown in Table 14 below.

[0053] [Table 1-1]

[0054] [Table 1-2]

[0055] [Table 2-1]

[0056] [Table 2-2]

[0057] Overall, subjects in the high-dose dexmedetomidine group were clinically better sedated than those in the low-dose dexmedetomidine group, with 54.3% of high-dose subjects not requiring rescue midazolam compared with 44.6% in the low-dose dexmedetomidine group, although this difference was not statistically significant (p=0.2751). By age, a smaller proportion of subjects in age group II did not require rescue midazolam for sedation compared with age group I in both dexmedetomidine dose groups, although this difference was not statistically significant (p=0.6723). In both dose groups, subjects undergoing open cardiac surgery with CPB received more rescue midazolam than other diagnostic groups. The greatest difference between treatment groups was in cardiac surgery subjects, with more subjects in both age groups receiving high-dose dexmedetomidine than in the low-dose dexmedetomidine group and not requiring midazolam rescue sedation. This difference was 22.73% but was not statistically significant (p=0.0974). Table 15 contains the number and percent of subjects who did not require rescue midazolam for sedation during treatment. Table 16 contains the difference between treatment groups in the proportion of subjects who did not require rescue midazolam for sedation during treatment.

[0058] Table 15. Number and Percentage of Subjects Who Did Not Require Rescue Midazolam for Sedation During Intubation JPEG0007818561000019.jpg98109 a Number and percent of subjects who did not require rescue midazolam for sedation based on achieving and maintaining a target UNSS range of 1 to 3 while intubated. b Age group I = ≥ 1 month to < 24 months c Age group II = ≥ 24 months to < 17 years

[0059] Table 16. Differences between treatment groups in the proportion of subjects who did not require rescue midazolam for sedation during the intubated treatment period JPEG0007818561000020.jpg130111 a Subjects who did not require rescue midazolam for sedation based on achieving and maintaining a target UNSS range of 1 to 3 while intubated. b Mean difference between treatment groups in the proportion of subjects who did not require rescue midazolam for sedation based on achieving and maintaining a target UNSS range of 1 to 3 while intubated. c P values ​​for risk differences for 2 × 2 tables from chi-squared tests with correction for continuity. d Age group I = ≥ 1 month to < 24 months e Age group II = ≥ 24 months to < 17 years

[0060] All age and diagnosis groups receiving high-dose dexmedetomidine were in the target UMSS range 87.8-99.2% of the time compared with 85.5-99.0% of the time in the low-dose dexmedetomidine group. There were no statistical differences between dexmedetomidine dose groups in the absolute time or percentage of time in UMSS ranges 1-3. All age and diagnosis groups receiving low-dose dexmedetomidine were outside the target UMSS range 1.0-14.5% of the time compared to 0.8-12.2% of the time in the high-dose dexmedetomidine groups. There were no statistical differences between dexmedetomidine dose groups in the absolute time or percentage of time subjects were outside the target sedation range (UMSS<1 or UMSS>3). Overall, more rescue midazolam for sedation (total dose and dose / kg) was required in the low-dose dexmedetomidine group than in the high-dose dexmedetomidine group, but the difference was not statistically significant.For the combined age group, 46 / 83 subjects (55.4%) in the low-dose dexmedetomidine group required rescue midazolam for sedation compared with 37 / 81 subjects (45.7%) in the high-dose dexmedetomidine group. For subjects who required rescue midazolam, the median total amount of rescue midazolam required for sedation while intubated during the treatment period was 1.965 mg (range: 0.19-30.80 mg) in the low-dose group and 2.00 mg (range: 0.10-13.20 mg) in the high-dose group; the median rescue midazolam dose per kg was 0.266 mg / kg (range: 0.02-1.49 mg / kg) in the low-dose group and 0.179 mg / kg (range: 0.02-1.11 mg / kg) in the high-dose group. Results were similar across age groups. For the combined age group, 53 / 83 subjects (63.9%) in the low-dose dexmedetomidine group and 44 / 81 subjects (54.3%) in the high-dose dexmedetomidine group received rescue fentanyl for analgesia while intubated during the treatment period. For subjects receiving rescue fentanyl, the median total amount of rescue fentanyl required for analgesia was 46.00 μg (range: 1.50-593.00 μg) in the low-dose group and 35.13 μg (range: 1.50-750.00 μg) in the high-dose group; the median amount of rescue fentanyl required per kg for analgesia was 4.13 μg / kg (range: 0.10-83.52 μg / kg) in the low-dose group and 3.25 μg / kg (range: 0.08-35.98 μg / kg) in the high-dose group.

[0061] For the combined age group, 35 / 83 subjects (42.2%) in the low-dose group and 32 / 81 subjects (39.5%) in the high-dose dexmedetomidine group received rescue morphine for analgesia while intubated during the treatment period. For subjects who received rescue morphine, the median total rescue morphine dose required for analgesia was 1.80 mg (range: 0.25-20.50 mg) in the low-dose dexmedetomidine group and 1.63 mg (range: 0.32-15.00 mg) in the high-dose dexmedetomidine group; the median rescue morphine dose per kg was 0.20 mg / kg (range: 0.03-4.10 mg / kg) in the low-dose dexmedetomidine group and 0.17 mg / kg (range: 0.05-0.57 mg / kg) in the high-dose dexmedetomidine group. The difference in time to first rescue medication was not statistically significant; the median time from start of dexmedetomidine infusion to first dose of rescue medication was 1.6 hours (95% CI: 0.93, 3.38) in the low-dose dexmedetomidine group and 2.0 hours (95% CI: 1.07, 3.75) in the high-dose group. The time to extubation was estimated from the first end of mechanical ventilation within the dexmedetomidine infusion period up to the 24-hour follow-up. If dexmedetomidine was discontinued because the subject's ventilator settings were unavailable and no longer needed for sedation, the extubation time was estimated as the last day / hour of dexmedetomidine. As described above, subjects for whom the time to extubation could not be measured were excluded from the analysis. If extubation was successful, the subject was considered to have had the event. Subjects who were not extubated were censored; the censoring time was set to the subject's last observation during the corresponding evaluable period. This censoring time will represent the subject's withdrawal from the study, death, or last recorded observation during the evaluable period, whichever occurred first. The median time to successful extubation was 23.8 hours (95% CI: 18.55, N / A) in the low-dose dexmedetomidine group and 20.5 hours (95% CI: 17.13, 23.33) in the high-dose dexmedetomidine group; the difference was not statistically significant.

[0062] In general, moderate or severe adverse events were more common in the low-dose dexmedetomidine group than in the high-dose dexmedetomidine group, and more actual events were reported in age group I than in age group II; in age group I, 17 subjects (27.0%; 30 events) and 10 subjects (16.7%; 17 events) in the low-dose and high-dose groups, respectively, experienced moderate and severe treatment-related adverse events; in age group II, 8 subjects (30.8%; 13 events) and 6 subjects (23.1%; 9 events) in the low-dose and high-dose groups, respectively, experienced moderate and severe treatment-related adverse events. Overall, 5 / 175 subjects (2.9%) reported a total of 7 severe treatment-related adverse events; all severe treatment-related adverse events were reported in the low-dose dexmedetomidine group. Reported severe treatment-related adverse events were myocarditis, fever, status epilepticus, dyspnea, ventricular fibrillation, chest pain, and wheezing. Severe myocarditis events were also considered serious treatment-related adverse events. Treatment-related adverse events experienced by two or more subjects in the dose groups in age group I were hypotension (three subjects [4.8%] and five subjects [8.3%] in the low-dose and high-dose dexmedetomidine groups, respectively), agitation (two subjects [3.2%] and four subjects [6.7%]), and bradycardia (two subjects [3.2%] and two subjects [3.3%]), and hypertension (two subjects [3.2%] in the low-dose dexmedetomidine group); and in age group II, hypotension (two subjects [7.7%] in the high-dose group). Serious treatment-related adverse events and treatment-related adverse events leading to dexmedetomidine or study discontinuation were reported only in age group I. Two serious treatment-related adverse events were reported in this study: myocarditis (1 subject, low dose) and apnea (1 subject, high dose); both events were considered probably or probably related to dexmedetomidine. Seven subjects (4.0%) experienced a total of eight treatment-related adverse events that led to discontinuation of dexmedetomidine: decreased respiratory rate and respiratory acidosis (1 subject each, low dose), and bradycardia, medical device electrical failure. The following adverse events occurred: electrical finding, endotracheal intubation complications, agitation, apnea, and hypotension (1 subject each, high dose). Two subjects experienced treatment-related adverse events leading to study discontinuation (oxygen desaturation and agitation [1 subject, high dose] and hypotension [1 subject, low dose]). Four deaths occurred, all unrelated to dexmedetomidine. No subjects discontinued dexmedetomidine due to death.

[0063] The median amounts of sedative rescue midazolam and rescue fentanyl and morphine (total and per kg) were not statistically significantly different between the low-dose and high-dose dexmedetomidine groups, but the total and per kg amounts of sedative rescue midazolam, analgesic rescue fentanyl, and analgesic rescue morphine tended to be higher in the low-dose dexmedetomidine group. This study demonstrates that dexmedetomidine was clinically effective in sedating critically ill, initially intubated infants and children after major cardiac and noncardiac surgery with CPB. A non-significant (p = 0.2751) dose-response effect was observed, regardless of age, with more subjects (54.3%) in the high-dose dexmedetomidine group than in the low-dose dexmedetomidine group (44.6%) not requiring rescue midazolam to maintain target sedation. High-dose dexmedetomidine was most effective in cardiac surgery subjects (s / p CPB), with more subjects in both age groups receiving high-dose dexmedetomidine than low-dose dexmedetomidine not requiring midazolam rescue sedation (p = 0.0974, difference = 22.73%). All age and diagnosis groups receiving high-dose dexmedetomidine were within the target UMSS range (1–3) 87.8–99.2% of the time compared with 85.5–99.0% of the time in the low-dose dexmedetomidine group; the difference was not statistically significant.

[0064] Example 3: Pharmacokinetics of dexmedetomidine in pediatric patients This study characterizes the pharmacokinetic and pharmacodynamic profiles of dexmedetomidine administered as a continuous IV infusion after an intravenous (IV) loading dose in pediatric subjects. A 56-subject, open-label, multicenter, ascending-dose study of dexmedetomidine was conducted in initially intubated, mechanically ventilated pediatric subjects requiring sedation in an intensive care setting and expected to require a minimum of 6 hours but not more than 24 hours of continuous IV sedation. The study investigated the pharmacokinetics and pharmacodynamics of dexmedetomidine. Subjects were at least 2 years old and less than 17 years old. Subjects were divided into two age groups: Group I consisted of children at least 2 years old and less than 6 years old, and Group II consisted of children at least 6 years old and less than 17 years old. Within each group there were four escalating dose levels (Table 17). Subject disposition and study demographics are shown in Table 18. A total of 69 subjects were enrolled in the study, of which 59 received dexmedetomidine (either dose) and were included in the safety population (26 in Group I and 33 in Group II). A total of 56 subjects completed the study (26 in Group I and 30 in Group II). Three patients in Group II were prematurely discontinued from the study due to protocol deviations (one subject each from dose levels 1, 2, and 3). The fully evaluable population consisted of 57 subjects who received study drug infusion for at least 5 hours (26 in Group I, 31 in Group II). Two subjects in Group II were excluded from the fully evaluable population. Subjects in Group I were primarily male (57.7%) and Caucasian (88.5%) with a mean (SD) age of 3.7 (1.12) years. As shown in Table 18, subjects in Group II were primarily female (63.6%) and Caucasian (72.7%) with a mean (SD) age of 10.3 (3.24) years.

[0065] Table 17. Study design JPEG0007818561000021.jpg34106Abbreviation: DEX = dexmedetomidine

[0066] Table 18. Subject Demographics - Safety Population JPEG0007818561000022.jpg48108Abbreviation: DEX = dexmedetomidine

[0067] The dexmedetomidine administered to subjects was Precedex® dexmedetomidine HCl injection (manufactured and supplied by Hospira, Inc.). Dexmedetomidine hydrochloride (HCl) injection (100 μg / mL, base) was supplied to the infusion study site. The on-site pharmacy prepared (diluted) the study drug to 4 μg / mL in 0.9% sodium chloride and did not refrigerate. Dexmedetomidine was administered as a two-stage IV infusion through a designated IV line using a controlled infusion device and was not administered directly into the pulmonary artery. Dexmedetomidine was administered at four escalating dose levels as a two-stage IV infusion, including a 10-minute loading dose infusion followed immediately by a continuous fixed maintenance dose for a minimum of 6 hours and a maximum of 24 hours. Each dose increase was determined by tolerability of the previous dose. After subjects completed the dexmedetomidine maintenance infusion, the post-infusion procedure began and continued for 24 hours. The primary evaluation was to estimate the dexmedetomidine pharmacokinetic parameters for each age group at each dose level, including AUC (area under the plasma concentration-time curve), C max (maximum observed plasma concentration), C ss (steady-state concentration), CL (plasma clearance), V ss (steady-state volume of distribution) and t 1 / 2 (terminal half-life) was included. Safety monitoring included treatment-emergent adverse events (TEAEs) (severity, related to study drug), vital signs, clinical laboratory results, and electrocardiogram (ECG) and physical examination findings. After discontinuation of all other sedative and analgesic medications, a dexmedetomidine infusion was initiated and subjects achieved a Ramsay Sedation Scale (RSS) of 2, 3, or 4. The RSS is a clinically derived scale used to quantify the depth of anesthesia and has been used in children ranging in age from 1 month to 18 years. The RSS is shown in Table 19 below. Rescue medications (midazolam or fentanyl) were administered as needed for sedation and analgesia, respectively, based on the results of the sedation (RSS) and analgesia (Face, Legs, Activity, Cry, and Consolability [FLACC]) scales during study drug administration. After discontinuation of the dexmedetomidine infusion, further sedation and analgesia were provided by standard of care.

[0068] TIFF0007818561000023.tif31105

[0069] First, the RSS was administered, followed immediately by the Richmond Agitation-Sedation Scale (Richmond Agitation-Sedation Scale) The level of sedation was assessed using the RAS (Random Agitation and Sedation Scale). The RASS has been used and validated to quantify the depth of anesthesia in adults in an ICU environment, but has not been validated in infants and children. The purpose of using the RASS in this study was to evaluate its suitability for children aged 2 to less than 17 years. The RASS scale is shown in Table 20 below.

[0070] Table 20. Richmond Agitation-Sedation Scale (RASS) JPEG0007818561000024.jpg53107

[0071] Based on RSS and RASS scores and clinical judgment, additional rescue sedation with IV midazolam was administered if subjects were not fully sedated. For subjects 6 months to 5 years of age, the midazolam dose was 0.05 to 0.1 mg / kg. For subjects 6 to 12 years of age, the midazolam dose was 0.025 to 0.05 mg / kg. Subjects over 12 years of age received 1 mg / kg midazolam. Pain was assessed using the Face, Legs, Activity, Cry, and Mood (FLACC) scale. The FLACC scale is a valid and reliable observational tool used as a measure of pain in children ranging in age from 2 months to 18 years. The FLACC scale is shown below in Table 21.

[0072] Table 21. Face, Legs, Activity, Crying, and Mood Scales JPEG0007818561000025.jpg63116

[0073] While receiving the dexmedetomidine infusion, rescue fentanyl IV was administered at a recommended dose of 0.25–1 μg / kg as needed to treat pain based on clinical judgment or a FLACC score greater than 4. FLACC scores were recorded before and within 5 minutes after any rescue fentanyl administration. Each of the five FLACC scale categories was assigned a score of 0–2, resulting in a total score of 0–10. 96.6% of study subjects received premedication medications, defined as medications received within 48 hours before the start of the study drug infusion. The most frequently used premedication medications reported by subjects were from the nervous system (94.9%), gastrointestinal and metabolic (83.1%), and musculoskeletal (79.7%) drug classes and included the following: fentanyl citrate (81.4%), midazolam (66.1%), magnesium sulfate (28.8%), ranitidine (28.8%), and vecuronium (27.1%). Concomitant medications were defined as infusion and non-infusion medications received throughout the study drug infusion and post-study drug administration periods. All subjects (100%) in the enrolled population received concomitant non-infusion medications, and 39.0% of subjects received infusion medications. The most frequently reported concomitant non-infusion medications were from the nervous system (100%), gastrointestinal and metabolic (98.3%), and systemic anti-infective (96.6%) drug classes and included the following: fentanyl citrate (88.1%), midazolam (67.8%), magnesium sulfate (35.6%), and cephalothin (32.2%). The most frequently reported concomitant infusion medications were from the cardiovascular system (30.5%), blood and blood-forming organs (28.8%), nervous system (23.7%), and gastrointestinal and metabolic (22.0%) drug classes and included the following: milrinone (23.7%), papaverine (20.3%), heparin (18.6%), fentanyl citrate (6.8%), and midazolam (5.1%).

[0074] Subjects receiving continuous IV fentanyl infusions were allowed to resume these infusions after the initiation of a dexmedetomidine infusion. Subjects receiving continuous fentanyl infusions had a FLACC score recorded immediately before and within 5 minutes after any change in fentanyl infusion dose. Subjects had to be intubated first when dexmedetomidine treatment was initiated. As soon as subjects met site-specific respiratory criteria, they could undergo tracheal extubation at any time after the start of the loading dose. Dexmedetomidine infusion could be continued during and after the extubation process. Sedation levels and vital signs were monitored and recorded during the peri-extubation period. Pharmacokinetic and safety measures monitored included: sedation level (via RSS and RASS scores), heart rate (HR), blood pressure (BP), respiratory rate (RR), and oxygen saturation (SpO2) by pulse oximetry. BP, HR, SpO2, and RR were recorded simultaneously with the RSS, RASS, and FLACC scales before the loading dose, 5 and 10 minutes during the loading dose, and every hour during the maintenance infusion, as close as possible to the scheduled pharmacokinetic sampling time (up to 5 minutes before). Cardiac monitoring was continued. Five hours into the maintenance infusion, but before the infusion was discontinued, a 12-lead ECG was obtained. After discontinuation of the infusion, HR, BP, RR, and SpO2 were recorded every 15 minutes for the first hour, every 30 minutes for the second hour, every hour for the third hour, and every 4 hours thereafter until the final pharmacokinetic sample was obtained. Vital signs were obtained up to 5 minutes before the pharmacokinetic sample. The dexmedetomidine infusion rate was not titrated during this study. After discontinuation of the dexmedetomidine infusion, further sedation and analgesia were provided per standard of care, but dexmedetomidine was not restarted until after the final pharmacokinetic sample was obtained. Venous or arterial blood samples were collected for plasma dexmedetomidine concentration determination. Blood samples were collected into heparinized vacutainer tubes for pharmacokinetic analysis via a peripheral vein, central vein, peripherally inserted central venous catheter (PICC), or arterial line. The arterial line had to already be in place as part of standard care for sample collection. In no case was an arterial line placed solely for the purpose of collecting pharmacokinetic samples. Furthermore, all pharmacokinetic samples were collected consistently from either venous or arterial access throughout the duration of the study; interchangeability of venous and arterial blood samples was not permitted. Blood samples were collected at the following time points: within 30 minutes before the start of the loading dose; within 5 minutes before the end of the loading dose and simultaneously with the start of the maintenance infusion; 0.5, 1, 2, and 4–6 hours after the start of the maintenance infusion; within 30 minutes before the end of the maintenance infusion, which must be within 24 hours of the start of the maintenance infusion; 10 minutes after the end of the maintenance infusion; and 0.5, 1, 2, 4, and 10 hours after the end of the maintenance infusion. For pharmacokinetic analysis, venous blood samples (1 mL) were collected in heparinized tubes at the site opposite the infusion site (e.g., left arm vs. right arm). Samples were not taken from the second lumen of the multilumen catheter through which the drug was administered. Heparinized tubes were also used to collect arterial blood samples (1 mL).

[0075] Pharmacokinetic analysis was performed using model-independent methods. The primary evaluation was the assessment of dexmedetomidine pharmacokinetics for the fully evaluable population. As used herein, the "fully evaluable population" refers to pediatric subjects who received at least 5 hours of dexmedetomidine infusion. As used herein, the term "safety population" refers to pediatric subjects who received any amount of dexmedetomidine. Pharmacokinetic parameters were evaluated using non-compartmental methods, including the area under the plasma concentration-time curve (AUC), C max (maximum observed plasma concentration), CL (plasma clearance), C ss (steady-state concentration), V ss (steady-state volume of distribution) and t 1 / 2 (terminal half-life). Additional parameters were determined as appropriate. Plasma concentrations and resulting pharmacokinetic parameters were summarized by descriptive statistics, number of subjects, arithmetic mean, SD, coefficient of variation (CV), median, and range (maximum and minimum). Dose proportionality was assessed between the administered dose levels using AUC and C max For this evaluation, a power analysis approach and data visualization techniques were used. The primary evaluation was the assessment of dexmedetomidine pharmacokinetics. For the primary analysis, pharmacokinetic analyses were summarized for each age group by dose level in the fully evaluable population. Data from all fully evaluable subjects were included in this analysis. Pharmacokinetic parameters were assessed using non-compartmental methods. Summary statistics for pharmacokinetic parameters were tabulated. Only subjects with sufficient pharmacokinetic and pharmacodynamic data to calculate pharmacokinetic and pharmacodynamic parameters were included in the analysis population. To identify pharmacokinetic variations between different dose levels and different age groups, plots of mean plasma dexmedetomidine concentration versus time curves by dose level were generated for each age group during and after study drug infusion. Overlay plots of individual plasma dexmedetomidine concentration versus time were generated by dose level. ss , C max , V ss ,CL,AUC,t 1 / 2 , time of maximum concentration (t max ), terminal elimination rate constant (terminal elimination rate constant)(λz), distribution volume (V d ), and weight-adjusted CL and V d Descriptive statistics for V were summarized by dose level for each age group. Within each dose level, differences in these pharmacokinetic parameters between age groups were assessed using two-sample t-tests. Overall dose levels were assessed by age group using two-way analysis of variance. Additionally, pooled data from all dose levels within each age group were used to assess V ss and CL were also summarized, and differences between age groups were assessed using two-sample t tests. V using pooled data from all dose levels and age groups ss and CL vs. age (years) and V ss Scatter plots of CL versus body weight (kg) were visually generated. The relationships between these pharmacokinetic parameters, adjusted for body weight or dose, were assessed by linear or nonlinear regression analysis based on the results of dose-proportionality analysis. Pharmacokinetic analyses were summarized by dose level for each age group for the fully evaluable population as the primary analysis and the safety population as a secondary analysis. The following descriptive statistics were summarized by dose level for each age group: RSS5, RSS avg, N (%) of subjects who received rescue midazolam, time to first use of rescue midazolam, total amount of rescue midazolam, N (%) of subjects who received rescue fentanyl, total amount of rescue fentanyl, N (%) of subjects who switched to alternative sedation or analgesia therapy, time to successful extubation, and change from baseline in mean, maximum, and minimum values ​​of HR, SBP, DBP, MAP, RR, SpO2 during and after infusion. As used herein, the term "baseline" means immediately before dexmedetomidine loading. Subdescriptive statistics were also summarized for subjects receiving dexmedetomidine alone and for subjects receiving dexmedetomidine with concomitant administration of midazolam or fentanyl: RSS5, RSS avg , N (%) of subjects who switched to alternative sedation or analgesic therapy, time to extubation, and change from baseline in mean, maximum, and minimum values ​​of HR, SBP, DBP, MAP, RR, and SpO2 during and after infusion. These analyses were performed for each age group using pooled data from all dose levels within that age group. Additionally, time to first rescue medication for sedation and time to successful extubation were assessed using the Kaplan-Meier method. Successful extubation was assessed by comparing treatment groups and / or subjects receiving dexmedetomidine alone and those receiving dexmedetomidine in combination with midazolam or fentanyl using the log-rank and Wilcoxon tests.

[0076] The relationship between sedation level and plasma concentrations, additional sedative requirements, and the effects of dexmedetomidine alone and coadministration of midazolam or fentanyl on sedation, HR, and BP were analyzed.Subsequent pharmacokinetic and pharmacodynamic association assessment and modeling were performed to identify covariates that may further explain interindividual variability in pharmacokinetic and pharmacodynamic parameters. Statistical analyses, summary tabulations, and data listings were performed or prepared using SAS® software, version 9.1. Pharmacokinetic parameters were calculated using the computer program WinNonlin (version 5.1 or higher - PharSight, Mountainview, CA). A summary of the proportion of subjects stratified by dose level and age group who were intubated and concurrently received rescue midazolam for sedation during the treatment period for the fully evaluable population is shown in Table 22. A summary of the total weight-adjusted amounts of rescue medications (midazolam, fentanyl) required for sedation and analgesia while intubated during the treatment period for the fully evaluable population is shown in Table 23. A summary of the total amount of rescue medications (midazolam, fentanyl) required for sedation and analgesia while intubated during the treatment period for the fully evaluable population is shown in Table 24. Across all treatment groups in the fully evaluable population, except for the dose level 4 treatment group, a smaller proportion of subjects in Group II received rescue midazolam for sedation compared to Group I (37.5% vs. 50.0%, 42.9% vs. 66.7%, 25.0% vs. 50.0%, and 25.0% vs. 16.7% for dose levels 1, 2, 3, and 4 treatment groups for Group II vs. Group I, respectively, respectively). The differences between age groups in the number of subjects receiving rescue midazolam were not statistically significant in any treatment group for both the fully evaluable and safety populations.For the entire safety population, there were no statistically significant differences between dose level groups in the total amount of rescue medication required for sedation or analgesia in intubated subjects.

[0077] Table 22. Summary of the Proportion of Subjects Who Received Rescue Midazolam for Sedation During the Treatment Period While Intubated, Stratified by Dose Level and Age Group - Fully Evaluable Population JPEG0007818561000026.jpg4796 Abbreviations: CMH = Cochran-Mantel-Haenszel; midazolam = midazolam a Differences between age groups I and II within dose levels using Fisher's exact probability test. b Cochran-Armitage trend test within age groups P value of trend test). c Overall Cox-Mantel-Haenszel test by age group. Note: Group I: age ≥ 2-6 years; Group II: age ≥ 6-17 years. Note: Dose Level 1 - Dex LD=0.25 / CD=0.2 μg / kg / hr Dose level 2 - Dex LD=0.50 / CD=0.4μg / kg / hour Dose level 3 - Dex LD=1.00 / CD=0.7μg / kg / hour Dose level 4 - Dex LD=1.00 / CD=2.00μg / kg / hour

[0078] Table 23. Summary of weight-adjusted total rescue medications (midazolam, fentanyl) required for sedation and analgesia while intubated during the treatment period - Fully evaluable population JPEG0007818561000027.jpg74106Abbreviations: CD = continuous dose; DEX = dexmedetomidine; LD = loading dose; MAX = maximum; midazolam = midazolam; Min = minimum Note: Dose Level 1 - Dex LD=0.25 / CD=0.2 μg / kg / hr Dose level 2 - Dex LD=0.50 / CD=0.4μg / kg / hour Dose level 3 - Dex LD=1.00 / CD=0.7μg / kg / hour Dose level 4 - Dex LD=1.00 / CD=2.00μg / kg / hour a Within each dose level, descriptive statistics were calculated based on the total number of subjects who were intubated and whether or not they used any amount of rescue medication for sedation during the treatment period. b P values ​​obtained from Proc NPAR1WAY for the specified test.

[0079] Table 24. Summary of total amount of rescue medication (midazolam, fentanyl) required for sedation and analgesia while intubated during the treatment period - fully evaluable population JPEG0007818561000028.jpg74112Abbreviations: CD = continuous dose; DEX = dexmedetomidine; LD = loading dose; MAX = maximum; midazolam = midazolam; Min = minimum Note: Dose Level 1 - Dex LD=0.25 / CD=0.2 μg / kg / hr Dose level 2 - Dex LD=0.50 / CD=0.4μg / kg / hour Dose level 3 - Dex LD=1.00 / CD=0.7μg / kg / hour Dose level 4 - Dex LD=1.00 / CD=2.00μg / kg / hour a Within each dose level, descriptive statistics were calculated based on the total number of subjects who were intubated and whether or not they used any amount of rescue medication for sedation during the treatment period. b P values ​​obtained from Proc NPAR1WAY for the specified test.

[0080] As shown in Table 25, time to first rescue medication for sedation and analgesia in the fully evaluable population demonstrated a trend reflecting longer median times to first rescue medication with increasing dose levels at similar time intervals in the dose level 2 and 3 treatment groups (2.2 and 2.5 hours), but shorter times to first rescue medication in the dose level 1 treatment group (1.0 hour) and longer times to first rescue medication in the dose level 4 treatment group (7.8 hours). As shown in Table 26, this trend was not statistically significant (P=0.2391 Log-Rank). A comparable trend was observed in the safety population, except that the effect was not monotonic. The dose level 2 treatment group had a slightly longer time to rescue medication (2.5 hours) than the dose level 3 treatment group (2.4 hours).

[0081] Table 25. Summary of time to first dose of sedative and analgesic rescue medication (hours) JPEG0007818561000029.jpg4190Abbreviations: CD = sustained dose; DEX = dexmedetomidine; LD = loading dose; MAX = maximum; midazolam = midazolam; Min = minimum Note: Dose Level 1 - Dex LD=0.25 / CD=0.2 μg / kg / hr Dose level 2 - Dex LD=0.50 / CD=0.4μg / kg / hour Dose level 3 - Dex LD=1.00 / CD=0.7μg / kg / hour Dose level 4 - Dex LD=1.00 / CD=2.00μg / kg / hour a Within each dose level, descriptive statistics were calculated based on the total number of subjects who were intubated and whether or not they used any amount of rescue medication for sedation during the treatment period. b P values ​​obtained from Proc NPAR1WAY for the specified test. c P values ​​obtained from log-rank and Wilcoxon tests for differences between treatment groups (using PROC LIFETEST at stratum dose levels). d CI lower limit only, no upper limit

[0082] JPEG0007818561000030.jpg90122

[0083] In Group I, the mean total dose was 30.9200, 100.1147, 94.0000, and 663.5800 μg for dose level 1, 2, 3, and 4 treatment groups, respectively, with exposure generally increasing with increasing dose level, except for the dose level 3 treatment group, which showed a slight decrease. In Group II, the mean total dose was 73.1150, 236.9350, 269.2444, and 586.2825 μg for dose levels 1, 2, 3, and 4, respectively. Exposure increased with increasing dose level for all treatment groups in Group II. Total exposure to dexmedetomidine for the safety population is shown in Table 27 below.

[0084] Table 27. Total Exposure to Dexmedetomidine - Safety Population JPEG0007818561000031.jpg2698

[0085] Summary statistics for the loading and maintenance infusion doses of dexmedetomidine are shown below in Table 27A. Table 27A. Summary statistics for dose-related data JPEG0007818561000032.jpg156105 TIFF0007818561000033.tif29101

[0086] The mean dexmedetomidine concentration profiles (over time) for dose levels 1 and 2 were similar and generally stable over the same time period as shown in Figure 1. In the dose level 3 treatment group, the mean plasma dexmedetomidine concentration showed a sharp increase at the end of the loading dose compared to the other dose levels. This sharp increase was the result of an excessively high plasma dexmedetomidine concentration at the end of the loading dose in the dose level 3 treatment group subject (subject 123009). Subject 123009 had a mean area under the concentration-time curve (AUC) from time zero to the last measurable concentration. 0-t ) = 116910.2 μg / mL / hour and the area under the concentration-time curve from time zero to time infinity (AUC 0-∞ ) = 117264.1 μg / mL / hour, and C max = 28804.30 μg / mL. The mean plasma concentration of dexmedetomidine tended to increase with increasing dose level. The highest mean plasma concentration was observed in the dose level 4 treatment group. Mean concentration, AUC, and C at the end of the maintenance infusion ss , and C max The values ​​increased with increasing dose. The mean half-life values ​​for dose levels 1, 2, 3, and 4 treatment groups (combined across all age groups) were 1.546, 1.743, 2.045, and 2.145 hours, respectively. The apparent increase in half-life with increasing dose level is due to the large number of concentrations used to calculate half-life for low dose levels below the limit of quantitation. As shown in Table 28, the pharmacokinetic parameter V d (p=0.0046), weight adjustment V dStatistically significant differences were observed between Groups I and II within each dose level for CL (p=0.0040), CL (p=0.0078), and weight-adjusted CL (p=0.0094).

[0087] Table 28. Summary of statistically significant differences between Group I and Group II subjects within each dose level for pharmacokinetic parameters - Fully evaluable population JPEG0007818561000034.jpg72109Abbreviations: CD = sustained dose; CL = plasma clearance; DEX = dexmedetomidine; LD = loading dose; PK = pharmacokinetics; V d =distribution volume Note: Dose Level 1 - Dex LD=0.25 / CD=0.2 μg / kg / hr Dose level 2 - Dex LD=0.50 / CD=0.4μg / kg / hour Dose level 3 - Dex LD=1.00 / CD=0.7μg / kg / hour Dose level 4 - Dex LD=1.00 / CD=2.00μg / kg / hour

[0088] Statistically significant differences (p<0.05) in PK parameters were observed in AUC 0-t , C max , t 1 / 2 , AUC 0-∞ , C ss and λz by dose level and C ss (p=0.0167), C max (p=0.0053), V d (p=0.0089) and CL (p=0.0125), as well as weight-adjusted V d (p=0.0055) and CL (p=0.0190) were observed by age. Descriptive statistics were used to summarize the pharmacokinetic parameters of dexmedetomidine in the fully evaluable population and are shown in Table 29. Similar results were obtained in subjects undergoing cardiopulmonary bypass.

[0089] Table 29. Summary of Pharmacokinetic Parameters - Fully Evaluable Population JPEG0007818561000035.jpg142101 JPEG0007818561000036.jpg14699 JPEG0007818561000037.jpg56103Abbreviation:λz=terminal disappearance rate constant;AUC 0-∞ = area under the concentration-time curve from time zero to time infinity; AUC 0-t = area under the concentration-time curve from time zero to the last measurable concentration; CD = sustained dose; CL = plasma clearance; C max = maximum observed plasma concentration; C ss = steady-state concentration; CV = coefficient of variation; DEX = dexmedetomidine; LD = loading dose; Max = maximum; Min = minimum; T max t = time of maximum concentration; 1 / 2 = terminal elimination half-life; V d =distribution volume;V ss = steady-state volume of distribution. Note: Dose Level 1 - Dex LD=0.25 / CD=0.2 μg / kg / hr Dose level 2 - Dex LD=0.50 / CD=0.4μg / kg / hour Dose level 3 - Dex LD=1.00 / CD=0.7μg / kg / hour Dose level 4 - Dex LD=1.00 / CD=2.00μg / kg / hour

[0090] Plasma clearance with respect to age, weight with respect to age, and weight-adjusted clearance are shown in Figures 2-4, respectively. Weight-adjusted clearance in 2-year-old patients was approximately 1 L / h / kg and decreased with age to a value approximating that observed in adults (0.6 L / kg / h). Pharmacokinetic analysis was performed on dose levels 1, 2, 3, and 4 of the treatment groups and on AUC and C max A dose-proportional and linear relationship was demonstrated between the AUC and the α- and β-blockers. 0-∞ , AUC 0-t , C max , and C ss The predicted mean curves for each are shown in Figures 6 to 9. As the dose increases, the AUC and C max increased (Figure 1 and Table 29). AUC of dexmedetomidine 0-∞ and AUC 0-tThe C of dexmedetomidine was positively linear across dose levels 1, 2, 3, and 4. max The apparent t of dexmedetomidine was positively linear across dose levels 1, 2, and 3, with a slight decrease in dose level 4. 1 / 2 were 1.546, 1.743, 2.045, and 2.145 hours for dose levels 1, 2, 3, and 4, respectively. There was no statistically significant difference in the pharmacokinetic parameter V between Groups I and II. d (p=0.0046), weight adjustment V d This was only observed for V (p=0.0040), CL (p=0.0078), and weight-adjusted CL (p=0.0094). Weight-adjusted clearance decreased with age to a value approximating that observed in adults. d Or weight adjustment V d No significant increase or decrease was observed. Two-way analysis of variance (ANOVA) was used to evaluate the pharmacokinetic parameter AUC for the main effect of dose level. 0-t , AUC 0-∞ , C ss , C max , λz, and t 1 / 2 and C ss , C max , V d , weight adjustment V d Statistically significant differences were observed for the main effects of age for CL, CL, and weight-adjusted CL. However, there were no statistically significant dose level by age group interactions for any pharmacokinetic parameter. A summary of key pharmacokinetic parameters for the fully evaluable population is shown in Table 30 below.

[0091] Table 30. Summary of important pharmacokinetic parameters in the fully evaluable population JPEG0007818561000038.jpg7998 Abbreviation: λz=terminal disappearance rate constant; AUC 0-∞ = area under the concentration-time curve from time zero to time infinity; AUC 0-t = area under the concentration-time curve from time zero to the time of the last measurable concentration; CL = plasma clearance; C max = maximum observed plasma concentration; Css = steady-state concentration; DEX = dexmedetomidine; LD = loading dose; t 1 / 2 = terminal elimination half-life; V d = distribution volume. a Results of two-way analysis of variance (ANOVA) to assess the effect of dose level on age group on PK parameters. Note: Dose Level 1 - Dex LD=0.25 / CD=0.2 μg / kg / hr Dose level 2 - Dex LD=0.50 / CD=0.4μg / kg / hour Dose level 3 - Dex LD=1.00 / CD=0.7μg / kg / hour Dose level 4 - Dex LD=1.00 / CD=2.00μg / kg / hour

[0092] Pharmacokinetic parameters measured in Groups I and II included sedation level, number of subjects receiving rescue medication (midazolam and fentanyl), amount of rescue medication required for sedation and analgesia, vital signs (HR, SBP, DBP, MAP, RR, and SpO2), time to successful extubation, and RSS. avg and AUC 0-∞ and C ss The comparison was between RSS scores (e.g., RSS5 and RSS avg ) were generally similar between Groups I and II regardless of dose level, but RSS5 and RSS6 in the dose level 4 treatment group in Group II were avg Scores were slightly higher in Groups I and II compared to the other treatment groups. In subjects receiving dexmedetomidine only, RSS5 and RS scores were significantly higher across treatment groups in Group II compared to Group I. Savg In subjects receiving dexmedetomidine and midazolam or fentanyl concomitantly, the RSS scores were 5 and 6. avg Scores were generally similar among subjects in all treatment groups and across age groups except for subjects in the Group II, Dose Level 4 treatment group. RSS5 and RSS avg Score (RSS5=4.5 and RSS avgRSS5 score range = 4.5) was slightly higher than the other treatment groups (RSS5 score range = 2.5-3.7) in arms I and II of the fully evaluable population. Similar results were observed in the safety population. As noted above, one subject in the dose level 3 treatment group had extremely high plasma concentrations at the end of the loading infusion. Plasma concentration data for this subject were obtained using AUC and C ss Figures 10 and 11 show the RSS avg and AUC and C ss The mean AUC value of 117,264.1 μg / hr / mL and C value of 5743.55 μg / mL were excluded from the analysis. ss In this subject, AUC and C ss RSSavg increased with the increase in Across all treatment groups, a smaller percentage of subjects in Group II received rescue midazolam for sedation compared with Group I. Fewer subjects in the dose-level 4 treatment group required rescue medication compared with the other three dose-level treatment groups. Due to the higher sedation levels in this treatment group, the time to administration of the first dose of rescue medication was also longer in this treatment group in the dose-level 4 treatment group. The differences between these age groups in the number of subjects receiving rescue midazolam were not statistically significant at any dose level in any age group. The amount of rescue medication required for sedation and analgesia during treatment was similar across all dose levels. No statistically significant differences were observed in the amount of midazolam or fentanyl used as rescue medication for sedation or analgesia between treatment groups in the safety population. In general, the majority of treated subjects across age groups and dose levels required the coadministration of midazolam or fentanyl with dexmedetomidine, with the exception of the dose level 4 treatment group in Group II, in which 3 of 8 subjects received coadministration of midazolam or fentanyl. In the fully evaluable population, median time to extubation increased with dose. While time intervals were similar (0.6-1.7 hours) for dose level 1, 2, and 3 treatment groups, time to extubation was longer for the dose level 4 treatment group (6.8 hours). This effect was not statistically significant (p=0.3041). Similar results were seen for the safety population. A summary of times to successful extubation for the fully evaluable population is shown in Table 31 below.

[0093] Table 31. Summary of Time to Successful Extubation - Fully Evaluable Population JPEG0007818561000039.jpg3795Abbreviations: CD = sustained dose; CI = confidence interval; DEX = dexmedetomidine; LD = loading dose; Note: Kaplan-Meier estimates, log-rank and Wilcoxon tests were used to summarize time to successful extubation. Note: Dose Level 1 - Dex LD=0.25 / CD=0.2 μg / kg / hr Dose level 2 - Dex LD=0.50 / CD=0.4μg / kg / hour Dose level 3 - Dex LD=1.00 / CD=0.7μg / kg / hour Dose level 4 - Dex LD=1.00 / CD=2.00μg / kg / hour Note: If extubation was successful, the subject is considered to have the event. If the subject does not complete / discontinues treatment, the subject is censored. a Median time from start of Dex infusion to successful extubation (hours). b 95% CI for median. c P values ​​by log-rank and Wilcoxon tests for differences between treatment groups (using PROC LIFETEST at stratum dose levels).

[0094] Clinically insignificant trends were observed in the mean changes from baseline in HR, SBP, DBP, MAP, RR, or SpO2 in Group I and Group II subjects during and after infusion. Similarly, clinically insignificant trends were observed in the mean changes from baseline in HR, SBP, DBP, or MAP in subjects stratified by whether or not they underwent cardiopulmonary bypass. Treatment-related adverse events occurred primarily during the loading dose and only at dose levels 3 and 4. The most frequently reported treatment-emergent non-drug-related adverse effects in both age groups were pyrexia, vomiting, hypokalemia, and hypertension. In Group I (26 subjects), treatment-related TEAEs were bradycardic (2 subjects), hypotension (1 subject), sedation (2 subjects), and hypertension (1 subject). In Group II (33 subjects), treatment-related TEAEs were bradycardic (1 subject), sedation (1 subject), hypertension (5 subjects), and chills (1 subject). The majority of these adverse effects were considered unrelated to the study drug and were mild or moderate in intensity. Numerical differences were observed in several hematological, chemistry, and urinalysis parameters, with trends for increases or decreases in lymphocytes, neutrophils, platelets, ALP, AST, and bilirubin between treatment groups. Although numerical changes occurred, clinically meaningful trends in mean changes from baseline in HR, SBP, DBP, MAP, RR, and SpO2 between treatment groups were not observed. Respiratory rate was unaffected. Similar results were obtained in subjects stratified by whether or not they underwent cardiopulmonary bypass. The change from baseline in SBP tended to increase from dose levels 1 to 4 for subjects who underwent CPB. These differences were not statistically significant. No similar observations were noted in subjects who did not undergo CPB. With the exception of a slightly higher SBP observed in subjects undergoing CPB in the dose-level 4 treatment group, the four dose levels of dexmedetomidine studied were generally well tolerated in this study, and no clinically meaningful differences were observed in the safety profile of dexmedetomidine between dose levels. No clinically meaningful changes from baseline were observed in laboratory test results during or after the infusion across treatment groups. Hematology results that showed significant numerical changes from baseline included lymphocytes, neutrophils, and platelets. Chemistry results that showed significant numerical changes from baseline included alkaline phosphatase (ALP), aspartate aminotransferase (AST), and bilirubin. The majority of reported ECG findings were normal or abnormal but not clinically significant. The majority of subjects had unremarkable physical examination findings in all body system categories except the cardiopulmonary body system. No clinically meaningful changes were observed in vital signs, laboratory results, or ECGs during and after the infusion in any treatment group. In general, dexmedetomidine was well tolerated in intubated, mechanically ventilated pediatric patients in this study. No deaths were reported. One subject experienced a seizure that was considered mild and unrelated to study drug. Drug-related treatment-emergent adverse events (TEAEs) were reported at dose levels 3 and 4, as shown in Table 32.

[0095] Table 32. Drug-Related Treatment-Emergent Events (by Preferred Term) - Safety Population JPEG0007818561000040.jpg96108Abbreviations: DEX = dexmedetomidine; TEAE = treatment-emergent adverse events. Medical Regulatory Glossary Investigator adverse event (AE) terms were coded into preferred terms using the MedDRA Dictionary for Regulatory Activities (MedDRA) version 11.0. Percentages are based on the number of subjects in each treatment group by age group. Subjects are counted once within each system organ class or for each preferred term and may have multiple TEAEs. Any event assessed as unknown related, unlikely related, possibly, probably / probably, or definitely related to the study drug is relevant. If a subject experienced the same TEAE more than once, the most likely association to study drug was summarized. Note: Dose Level 1 - Dex LD=0.25 / CD=0.2 μg / kg / hr Dose level 2 - Dex LD=0.50 / CD=0.4μg / kg / hour Dose level 3 - Dex LD=1.00 / CD=0.7μg / kg / hour Dose level 4 - Dex LD=1.00 / CD=2.00μg / kg / hour

[0096] Example 4: Effects of dexmedetomidine in the prenatal cynomolgus monkey brain This study was conducted to determine the potential neuroapoptotic effects of dexmedetomidine in the prenatal cynomolgus monkey brain by administering dexmedetomidine to pregnant monkeys. The overall objective of this study was to demonstrate that dexmedetomidine, an anesthetic with a mechanism of action different from that of isoflurane or ketamine, does not induce neuroapoptosis in the prenatal cynomolgus monkey brain. The objectives of the immunohistochemical analysis in this study were to histopathologically evaluate and characterize regions of interest and to characterize and compare test article-induced apoptosis between groups. The monkey model used was that described in Slikker et al. Tox. Sci. 2007; 98(1), 145-58, the entire contents of which are incorporated herein by reference. Pregnant females with a gestational age of 120±7 days received a 12-hour intravenous infusion of dexmedetomidine followed by removal of fetuses after a 6-hour post-infusion observation period. Fetal brains were collected by cesarean section. Treatment groups are shown in Table 33 below.

[0097] JPEG0007818561000041.jpg43122

[0098] After treatment, the animals were sacrificed, and brain tissue was perfused and fixed in 10% neutral-buffered formalin. Serial unstained brain sections were prepared at 50–70 μm thickness using a vibratome microtome, yielding approximately 800 sections per brain. Fixed brain tissue from 20 animals was processed. For each animal, approximately 25 interval sections per brain were stained with the following stains: hematoxylin and eosin (H&E), silver stain, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and activated caspase 3 (AC3). The American College of Veterinary Pathologists (AVC) performed a series of imaging studies, including the use of image analysis to assess and compare the incidence and distribution of apoptotic cells within TUNEL-stained and AC3-stained sections. Sections were evaluated by board-certified pathologists from the American College of Pathologists (ACVP). Fixed tissues were macroscopically trimmed, processed, oriented, embedded in paraffin, and sectioned to approximately 35-40 μm thickness. Each brain was carefully oriented and macroscopically trimmed into individual blocks to ensure symmetry across animals. Six serial blocks were prepared for each brain, spanning the entire frontal cortex. Approximately 100 unstained ultrathin sections were cut in each block for a total of approximately 600 sections per animal. For each block, section levels 1, 25, 50, and 100 were selected for staining. Evaluation was performed to ensure the selected section levels and to ensure good correlation across animals. Evaluation was also performed to confirm that ketamine-induced lesions were confined to layers 1 and 2 of the frontal cortex in all animals, as reported by Slikker, and that the pathogen was consistently distributed in this region. Approximately 25 serial sections from each brain were stained using one of the following techniques. H&E staining was used to define general histology and morphology. Silver staining was used to visualize neurodegeneration. TUNEL is a method for detecting DNA fragments by labeling the ends of nucleic acids. AC3, detected by IHC antibody staining, is a marker of apoptotic cells. After staining, tissues were evaluated under a light microscope by a certified veterinary pathologist. All procedures were in accordance with CBI SOPs; details are kept in the study records. A modified silver staining method was used for brain sections. See Xuemin Ye et al. 2001, Brain Research Protocols 8, 104-112, the entire contents of which are incorporated herein by reference. Briefly, sections were degreased in xylene and rehydrated in alcohol. The following steps were used: rehydration in 50, 75, and 97% 1-propanol for at least 5 minutes each; esterification in sulfuric acid / 1-propanol for 16 hours at 56°C; rehydration in 50 and 25% 1-propanol followed by two 5-minute changes of distilled water; washing in 1% acetic acid for exactly 10 minutes; placing the sections in developer until they turned brown (approximately 6-8 minutes); finishing the development by washing in 1% acetic acid (30 minutes); dehydration, clearing, and covering. For activated caspase-3 staining, tissues were deparaffinized, hydrated, and subjected to heated citrate buffer antigen retrieval. Tissues were stained using a DAKO automated stainer. Tissues were reacted with peroxidase and two protein blocks. After rinsing with buffer, tissues were incubated with a 1:275 dilution of AC-3 (Abcam) for 60 minutes at room temperature, followed by incubation with Envision goat anti-rabbit secondary antibody (Envision) for 30 minutes. Immunoreactivity was visualized with DAB and counterstained with hematoxylin. Both positive (human tonsil) and negative (human uterus) tissues were included, in addition to tissues stained with an irrelevant antibody and saline. For TUNEL staining, tissues were deparaffinized, hydrated, and subjected to heated citrate buffer antigen retrieval. Tissues were stained with a DAKO automated stainer or with Trevigen. Manual staining was performed using the TACS 2TdT-DAB In Situ Apoptosis Detection Kit. Both positive (human tonsil) and negative (human uterus) tissues were included, in addition to tissues stained with an irrelevant antibody and saline. Widespread regions of the frontal cortex and multiple levels throughout the frontal cortex were examined, with particular emphasis on its laminae. Brain tissue residues on the slides were also examined for any other lesions. Representative photomicrographs were taken. The study's pathologist, a veterinary pathologist certified by the American College of Veterinary Pathologists (ACVP), qualitatively examined H&E-silver stained, TUNEL, and AC3 sections. Lesion incidence and severity (presence of apoptosis and cytotoxicity) were scored using a generally accepted industry scoring system: 0 = normal, 1 = minimal, 2 = mild, 3 = moderate; and 4 = severe. Severity scoring of treatment-related findings is shown below in Table 34. Massive neuroapoptotic lesions in the cortex were present in the ketamine-treated group, while minimal changes were seen in the dexmedetomidine-treated group, especially in the low (therapeutic) dose group.

[0099] Table 34. Summary of neuroapoptotic lesion severity scoring JPEG0007818561000042.jpg59123

[0100] Severity scoring of treatment-related findings is shown in Table 34. Representative photomicrographs of TUNEL staining of the frontal cortex are shown in Figure 12. Representative photomicrographs of AC3 staining of the frontal cortex are shown in Figures 13 and 14. Representative photomicrographs of silver staining of the frontal cortex are shown in Figure 15. In Group 1, untreated brains, examination of HE-, silver-, TUNEL-, and AC3-stained sections from the frontal cortex demonstrated no or rare, scattered damaged and apoptotic cells within the layers of the frontal cortex. There was some low-intensity positive nuclear AC3 staining, particularly within the white matter, indicating normal fetal development. There were a few TUNEL-positive cells in other regions of the brain, but there were no significant differences between control and treated brains. In Group 2, the ketamine-treated group, examination of HE, silver, TUNEL, and AC3 sections from the frontal cortex demonstrated a dramatic increase in moderate to large numbers of damaged and apoptotic cells compared to untreated and dexmedetomidine-treated brains. AC3 marks neurons undergoing apoptotic degeneration after exposure to apoptosis-inducing drugs such as isoflurane. AC3-stained cells are also the same cells stained by silver dye, which marks dead or dying cells. AC3 also reveals whether cells are in an early or advanced state of degeneration and what type of cells are undergoing degeneration (Bambrink, 2010). In the early state, degenerating cells can be visualized microscopically due to the presence of large amounts of AC3 protein in the cell bodies and processes. After cell death, cell bodies become condensed and clustered. Both of these morphologies were abundantly visible in ketamine-treated brains but minimally visible in the dexmedetomidine-treated group. The lesions seen in this study were characterized by moderately multifocal amounts of necrolytic debris, degenerated axons, and cell bodies and apoptotic nuclei within laminae I–VI of the cortex, with the most intense staining in layers I and II. Affected cell types included γ-aminobutyric acidergic inhibitory interneurons (layer II) and cells with the morphology and branching pattern of small pyramidal neurons (presumably glutamatergic, projecting to visible neurons in the contralateral hemisphere) (Bambrink, 2010). Affected large multipolar neurons (commonly in layers V and VI), large and small pyramidal neurons (layers IV and V), and interneurons within layer II were also evident. These observations are very similar to those described by Bambrink, 2010, using isoflurane-treated rhesus monkeys. There were also sporadic AC-3 positive cells scattered within the deeper white matter in all groups, including controls. In Group 3, i.e., the low-dose dexmedetomidine group, HE, silver, TUNEL, and AC3-stained sections from the frontal cortex demonstrated fewer damaged and apoptotic cells than in ketamine-treated brains. The lesions were characterized by mild, multifocal amounts of necrolytic debris, degenerated axons, and cell bodies and apoptotic nuclei in layers 1 and 2 of the cortex. The same cell types seen in the ketamine group were involved, but their numbers were significantly lower than in the ketamine group. Their incidence and severity were also less than those seen in the high-dose dexmedetomidine group. In Group 4, the high-dose dexmedetomidine group, HE, silver, TUNEL, and AC3-stained sections from the frontal cortex demonstrated fewer damaged and apoptotic cells than in ketamine-treated brains. The lesions were characterized by mild, multifocal amounts of necrolytic debris, degenerated axons, and cell bodies and apoptotic nuclei in layers 1 and 2 of the cortex. The same cell types seen in ketamine were included, although in significantly fewer numbers. The results of this study demonstrate that treatment with 20 mg / kg IM + 20–50 mg / kg / h ketamine is associated with significant neuroapoptotic and necrotic cell damage, primarily in layers I and II of the cortex. This was characterized by diffuse, homogeneous, multifocal, or diffuse lesions extending throughout the frontal cortex, including layers I–VI, primarily within layers I and II. No significant neuroapoptotic lesions were present in the untreated group. In animals receiving dexmedetomidine, neuroapoptosis was absent or minimal after either 3 μg / kg × 10 min + 3 μg / kg / h or 30 μg / kg × 30 min + 3 μg / kg / h. Lesions were less severe in lower-dose animals, suggesting a dose-response relationship, and were significantly less severe than in ketamine-treated animals. These findings suggest that dexmedetomidine is not associated with significant neuroapoptosis. Notably, these findings suggest that dexmedetomidine is not associated with significant neuroapoptosis at low doses.

[0101] Example 5: Pharmacokinetics of dexmedetomidine in pediatric patients aged 1 to 24 months This study characterizes the pharmacokinetic and pharmacodynamic profiles of dexmedetomidine administered to pediatric subjects as a continuous IV infusion after an intravenous (IV) loading dose. A 36-patient, open-label, single-center, ascending-dose study of dexmedetomidine was conducted in pediatric subjects following cardiac surgery. The study investigated the pharmacokinetics and pharmacodynamics of dexmedetomidine. Subjects were 1 to 24 months of age, were intubated or mechanically ventilated in the immediate postoperative period, and were scheduled for tracheal extubation within 24 hours after surgery. Subjects received one of the doses shown in Table 35 below. The main objectives of this study were: To determine the pharmacokinetics of ascending doses of dexmedetomidine administered as an intravenous bolus followed by continuous IV infusion (CIVI) in infants after cardiac surgery. To describe the pharmacokinetic effects of dexmedetomidine in infants (age: 1 month to 2 years) in postoperative surgical patients during the 24-hour period before and during extubation. Secondary objectives were to: To obtain correlation data on the relationship between the level of sedation and plasma concentrations of dexmedetomidine in infants after cardiac surgery; To evaluate safety in the patient population aged 1 month to 2 years.

[0102] This was a single-center, phase I, dose-escalation pharmacokinetic study of a single bolus of dexmedetomidine followed by a continuous infusion for up to 24 hours in infants immediately following cardiac surgery who required endotracheal intubation and mechanical ventilation in the postoperative period. This dose-response study of dexmedetomidine in infants consisted of two phases: a screening / registration phase and a dose-escalation phase. Patients whose parents or legal guardians provided informed consent were screened within 7 days before enrollment. A screening / enrollment phase was conducted first. Postoperative infants (aged 1 month to 2 years) were screened. Infants were eligible for the study if they had undergone cardiac surgery, required mechanical ventilation in the postoperative period, and were expected to be extubated within the first 24 hours after surgery. Enrollment criteria had to be met within 7 days before enrollment. The screening / enrollment phase was followed by a dose-escalation phase. All patients received 4 mg / kg pentobarbital orally, an intraoperative IV dose of 20 μg / kg fentanyl, an IV dose of 0.2 mg / kg pancuronium at the induction of bypass, and an additional 0.2 mg / kg pancuronium at the placement of bypass. Three bolus and infusion dose combinations of dexmedetomidine were administered as follows: each cohort of 12 patients received either low-dose dexmedetomidine (0.35 μg / kg IV bolus administered over 10 minutes, 0.25 μg / kg / hour continuous IV infusion), medium-dose dexmedetomidine (0.7 μg / kg IV bolus administered over 10 minutes, 0.5 μg / kg / hour continuous IV infusion), or high-dose dexmedetomidine (1 μg / kg IV bolus administered over 10 minutes, 0.75 μg / kg / hour continuous IV infusion). The dexmedetomidine infusion was continued during the extubation procedure, and tracheal extubation was performed when the patient met respiratory criteria. Dose escalation among patients is shown in Table 35.

[0103] TIFF0007818561000043.tif2560

[0104] Twelve patients were studied at each dose level. If more than two patients at a dose level experienced dose-limiting toxicity (DLT) possibly, probably, or definitely related to the study drug, no further patients were studied at that dose level because the maximum tolerated dose (MTD) of the drug would have been exceeded. If the MTD was exceeded at the first dose level, subsequent patient cohorts were treated with a 0.25 μg / kg loading dose and a 0.14 μg / kg / hour infusion. If the MTD was exceeded at the second or third dose level, enrollment in the protocol was halted. The decision to escalate the dose was based on safety and pharmacokinetic review of all patients in the previous cohort. If the median clearance was less than 70% of that reported in the adult population (35 L / h), escalation into the study was halted. This dose-escalation study included dose cohorts of: 1) 0.35 μg / kg bolus, 0.25 μg / kg / hour infusion; 2) 0.7 μg / kg bolus, 0.5 μg / kg / hour infusion; or 3) 1 μg / kg bolus, 0.75 μg / kg / hour infusion. This study provided pharmacokinetic data that may allow for refinement of dosing recommendations in critically ill patient populations (infants and young children undergoing cardiac surgery who required mechanical ventilation in the postoperative period). This patient population included, but was not limited to, infants diagnosed with tetralogy of Fallot, atrioventricular canal defect, ventricular septal defect, aortic coarctation, bidirectional Glenn's syndrome, hemi-Fontan, and Fontan completion. We used the Bispectral Index Scale (BIS) to measure sedation in infants after cardiac surgery and explored the utility of noninvasive measurement of sedation. This study was also designed to obtain preliminary data on the relationship between sedation levels and dexmedetomidine plasma concentrations in infants after cardiac surgery. Safety was also assessed in this study.

[0105] Patients were eligible for study participation if they met the following criteria: ≥ 1 month and ≤ 24 months of age; post-cardiac surgery with endotracheal intubation / mechanical ventilation in the immediate postoperative period; scheduled extubation within 24 hours after surgery; adequate renal function (defined as serum creatinine ≤ 0.6 mg / dL at 1 month to 12 months of age or serum creatinine ≤ 1.0 mg / dL at > 12 months to 24 months of age); adequate liver function (defined as total bilirubin ≤ 1.5 mg / dL and serum glutamic pyruvic transaminase (SGPT) ≤ 165 U / L at 1 month to 12 months of age and SGPT ≤ 90 U / L at 12 months to 24 months of age); isolated cardiac surgery; and all parents or legal guardians of the patient signed written informed consent. Patients were not eligible to participate in the study if they met any of the following criteria: had received another investigational drug within the past 30 days or had received a continuous infusion of a muscle relaxant in the postoperative setting; had a positive blood test that had not subsequently turned negative or had other evidence of an ongoing serious infection; would not, in the opinion of the investigator, comply with the safety monitoring requirements of the study; had signs or symptoms of elevated intracranial pressure (including, but not limited to, Cushing's triad) showed postoperative hypotension based on age (1-2 months: systolic ≤ 45 mmHg, diastolic ≤ 25 mmHg, or mean arterial pressure ≤ 35 mmHg; >2-6 months: systolic ≤ 55 mmHg, diastolic ≤ 35 mmHg, or mean arterial pressure ≤ 45 mmHg; and >6-24 months: systolic ≤ 65 mmHg, diastolic ≤ 45 mmHg, or mean arterial pressure ≤ 55 mmHg); or had pre-existing bradycardia based on age (1-2 months: heart rate ≤ 90 bpm; 2-12 months: heart rate ≤ 80 bpm; >12-24 months: heart rate ≤ 70 bpm); had heart block; weighed < 5 kg; or, in the opinion of the investigator, was not a suitable candidate for the investigational drug study. Patients were discontinued from the study if any of the following occurred: DLT, including bradycardia, hypotension, oversedation, or serious adverse effects; the patient's parent / guardian refused further protocol treatment; noncompliance that, in the investigator's opinion, prevented continued participation in the study; and the investigator determined that a drug break was in the patient's best interest. Patients who discontinued protocol treatment were followed until they met study discontinuation criteria, which were defined as the last dose of study drug, death, loss to follow-up, or 30 days after withdrawal of consent for any further data submission. Follow-up data were requested unless consent was withdrawn.

[0106] Eligible patients who met all inclusion criteria and no exclusion criteria received oral pentobarbital premedication at 4 mg / kg, an intraoperative dose of 20 μg / kg fentanyl, and intraoperative anesthetics at 0.2 mg / kg pancuronium at bypass induction and another 0.2 mg / kg pancuronium at bypass placement, followed by study medication: dexmedetomidine (0.35 μg / kg, 0.7 μg / kg, or 1 μg / kg) administered as an IV loading dose over 10 minutes, followed by a continuous maintenance IV infusion of 0.25 μg / kg / hour, 0.5 μg / kg / hour, or 0.75 μg / kg / hour. Patients received one of three loading / maintenance regimens of dexmedetomidine: low-dose dexmedetomidine (0.35 μg / kg bolus, 0.25 μg / kg / hour infusion), medium-dose (0.7 μg / kg bolus, 0.5 μg / kg / hour infusion), or high-dose dexmedetomidine (1 μg / kg bolus, 0.75 μg / kg / hour infusion) in 12 patients in the cohort. The dexmedetomidine infusion was continued during the extubation procedure, and tracheal extubation was performed when patients met respiratory criteria. The study medication consisted of the test drug in water (investigational drug), Precedex® (dexmedetomidine HCl injection), 118 μg dexmedetomidine and 9 μg sodium chloride, IV. The study medication was supplied as a clear, colorless, isotonic solution at pH 4.5. This solution was preservative-free and contained no additives or chemical stabilizers. It was freely soluble in water with a pKa of 7. Dexmedetomidine was obtained from a commercial supplier for this study and stored in the pharmacy at controlled room temperature between 15°C and 30°C (59°F and 86°F). Freezing was avoided. Patients who met the inclusion criteria were enrolled in the study. Thirty-eight patients were enrolled in the study. Thirty-six patients completed the study drug infusion: 12 patients in each of the low-, medium-, and high-dose cohorts. The study was not randomized; it was a dose-escalation study of a single bolus of dexmedetomidine followed by continuous IV infusion for up to 24 hours in infants immediately after surgery. Patients returning from the operating room with a tracheal intubation and scheduled for tracheal extubation within 24 hours were administered the study drug, dexmedetomidine, as a bolus dose over 10 minutes followed by a continuous IV infusion. Twelve patients were studied at each dose level. If more than two patients at a dose level experienced a DLT possibly, probably, or definitely attributable to the study drug, the MTD for that drug was considered exceeded, and no further patients were investigated at that dose level. If the MTD was exceeded at the first dose level, subsequent patient cohorts were to be treated with a 0.25 μg / kg loading dose and a 0.14 μg / kg / hour infusion. If the MTD was exceeded at the second or third dose level, enrollment in the protocol would be discontinued. Dose levels were continuously studied with pharmacokinetic analyses following completion of each dose level. Accrual into the study was discontinued if the median clearance was less than 70% of that reported in the adult population (35 L / hour). This was an open-label study. Patients were not permitted to receive continuous infusions of muscle relaxants in the postoperative setting. Patients identified as "under sedated," in clinical terms, were permitted additional sedation or analgesia in the form of fentanyl (0.25-1 μg / kg / dose), morphine (10-100 μg / kg / dose), or midazolam (10-100 μg / kg / dose). The date and time of administration of any additional sedatives were recorded. Any medications taken during the study other than the study drug were also recorded.

[0107] Dose is AUC and C max The use of power estimates and confidence intervals to detect dose proportionality, with expected proportional increases in both sedation and sedation, is statistically reliable and clinically appropriate. The University of Michigan Sedation Score (UMSS) is a validated pediatric sedation scale and will be utilized as the pharmacokinetic measure in the study in Example 5. Other pharmacokinetic, PD, and safety measures have been widely utilized in this study and are generally recognized as reliable, accurate, and appropriate for this study. Pharmacokinetic variables for evaluation included the following: maximum observed plasma concentration (C max ), time to maximum observed plasma concentration (T max ), the area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC 0-t ), the area under the plasma concentration-time curve from time zero to infinity (AUC 0-inf ), terminal elimination rate constant (λz), terminal half-life (t 1 / 2 ), end-of-infusion concentration (steady state, C ss ), plasma clearance (Cl), weight-adjusted clearance (Cl w ), distribution volume (V d ), and weight-adjusted volume of distribution (V dw The main PD variables were assessed using the Bias Index (BIS) to assess sedation level, and the University of Michigan Sedation Scale. Safety variables included study drug exposure, adverse events (adverse effects), hepatotoxicity, DLTs, laboratory results, vital signs, concomitant medication use, and 12-lead electrocardiogram. Approximately 14 mL of blood (14 samples per patient) was collected from each patient for drug concentration measurements. Blood samples (1 mL) were collected into heparinized tubes for plasma dexmedetomidine pharmacokinetic assessment. In the low-dose treatment group, blood samples were collected at time zero before the bolus dose, at the end of the bolus dose, 0.5 hours after the start of the infusion, at the end of the maintenance infusion, and at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after the end of the maintenance infusion. In the remaining cohort, blood samples were collected before the bolus dose, 0.5, 1, 2, and 4-6 hours after the start of the infusion, 15-30 minutes before the end of infusion (EOI), and 0.25, 0.5, 1, 2, 4, 8, 12, and 15-18 hours after the EOI. Samples were collected at a site separate from the infusion site. Samples were not collected from the second lumen of the multilumen catheter through which the drug was administered. The exact time the sample was taken was recorded, along with the exact time the drug was administered. Plasma was separated and stored at -80°C until assayed. The lower limit of quantitation in plasma for dexmedetomidine is ≤4.24 pg / mL. Each heparinized tube was labeled with the patient's study number, study identification number, and the date and time the sample was taken. Data was recorded in a pharmacokinetic study report and attached to the sample.

[0108] The primary pharmacokinetic evaluation was to characterize the pharmacokinetics of ascending doses of dexmedetomidine administered as an IV bolus followed by a continuous IV infusion to infants after cardiac surgery.Data from all fully evaluable patients (those receiving at least a 2-hour dexmedetomidine infusion) were included in the analysis. Pharmacokinetic assessments, monitored continuously hourly for up to 24 hours after discontinuation of the infusion, included heart rate, blood pressure, mean arterial pressure, cardiac rhythm, oxygen saturation, and respiratory rate. Sedation levels were assessed using the Bispectral Index Scale (BIS, Aspect Medical Systems, Natick, MA) and the University of Michigan Sedation Scale (UMSS). The bispectral index scale (BIS) integrates various electroencephalogram (EEG) descriptors into a single variable. BIS measurements are dimensionless, scaled from 100 to 0, with 100 representing awake EEG and zero representing complete electrical silence (cortical inhibition). BIS and sleep medication dose were found to correspond in a statistically significant linear monotonic manner during clinical trials, with BIS decreasing as sleep medication dose increased. A BIS monitor was attached to the patient's forehead before the bolus dose and remained in place until EOI. Clinical team members periodically checked the sensor to ensure signal quality and accurate placement / adhesion. BIS values ​​were blinded except for the signal quality index (SQI). Pre-stimulus BIS values ​​were recorded for sedation assessment (or during non-stimulation periods). Maximum BIS decoded during stimulation was also recorded. "Resting" or non-stimulation BIS values, along with stimulation-induced BIS changes, provide better data for assessing drug PD, as they are useful not only for assessing sedative effects but also for assessing the drug's analgesic properties. The investigator was blinded to the BIS measurements until after the study was completed. The maximum BIS measurements and corresponding SQI were recorded for each time the patient was on the study. After the infusion was stopped, the BIS sensor was removed from the patient's head and the patient was declared awake by the clinical care team.

[0109] The UMSS is a simple, valid, and reliable tool that facilitates rapid and frequent assessment and documentation of a child's depth of sedation. The UMSS is a simple observational tool that assesses the level of alertness based on a 1-5 point scale ranging from 1 (fully alert) to 5 (unable to be aroused by deep stimulation). The UMSS score was assessed and recorded by the clinical nurse caring for the patient every hour until the BIS sensor was removed. Adverse events were reported in a routine manner at scheduled times throughout the trial. Certain adverse events were reported in an expedited manner to allow optimal monitoring of patient safety and care. Adverse events were reviewed by the principal investigator (PI), co-PIs, and study coordinator in biweekly meetings. Events were classified as either adverse effects or serious adverse effects. An adverse effect was defined as any untoward medical occurrence during treatment or administration of a medicinal product, regardless of whether it had a causal relationship to the treatment. Treatment-emergent adverse events (treatment-emergent adverse effects) were defined as any adverse effect with onset or worsening of an effect reported by the patient from the time the first dose of study drug was administered until 24 hours after discontinuation of study drug. Treatment-emergent adverse effects were defined as any adverse effect with onset or worsening of an effect reported by the patient from the time study drug administration was initiated until the time study drug was discontinued. Post-study drug adverse events were defined as any adverse effect with onset or worsening of an effect reported by the patient at any time after discontinuation of study drug within a specified period. Adverse events were also classified by severity (mild, moderate, or severe). A serious adverse event was defined as any untoward medical occurrence at any dose that resulted in death, was life-threatening, required inpatient hospitalization or extension of existing hospitalization, or caused persistent or significant disability / incapacity, or congenital anomaly / birth defect. A MedWatch report was completed for each event. Events were classified by the treating clinician and study coordinator. Events were classified as probably not related to the study drug, probably related, or probably related, and as either previously described (expected) or undescribed (unexpected). The PI was notified of any serious adverse event by pager or telephone. All drug-related and previously undescribed toxicities were reviewed by the PI within 24 hours. Expected serious adverse events due to surgical procedures did not require immediate review and were reviewed every other week. Previously undescribed toxicities and all serious adverse events were reported to the IRB with investigator documentation within 72 hours of the event. A letter summarizing any adverse reactions or events that occurred and the event outcome was written. If one or more unexpected or previously documented serious adverse effects attributable to the study drug were observed, escalation to the protocol was withheld. An ad hoc committee including the PI, subspecialty investigators, and at least two superspecialists not participating in the trial was convened by the PI within 24 hours of the second event.An assessment of the risks to patients was conducted and a recommendation was made to the IRB for review as to whether to continue the study or terminate the trial. If the decision was made to continue the trial, amendments to the protocol, an updated assessment of risks and benefits, and a revised informed consent would be submitted to the IRB. Dose-limiting toxicity (DLT) was defined as any event that was probably, probably, or definitely attributable to dexmedetomidine and that met any of the following criteria: Age-specific bradycardia: Heart rate ≦80 bpm (1-2 months); Heart rate ≦70 bpm (>2-12 months); Heart rate ≦60 bpm (>12-24 months) Age-specific hypotension: Systolic ≦40mmHg, diastolic ≦20mmHg, or mean arterial pressure (MAP) ≦30mmHg (1 month to 2 months) Systolic ≦50mmHg, diastolic ≦30mmHg, or MAP ≦40mmHg (>2 months to 6 months) Systolic ≦60mmHg, diastolic ≦40mmHg, or MAP ≦50mmHg (>12 months to 24 months) Brachypnea: Respiratory rate ≦14 bpm in extubated patients Observations deemed clinically relevant or requiring intervention by the clinical care provider. Clinical signs included difficulty arousing with moderate stimulation, bradypnea (respiratory rate ≤ 14), bradycardia, and hypotension; and Serious adverse events.

[0110] Laboratory data were collected to review standard of care during the study, including arterial blood gases, blood lactate, basic metabolic panel, magnesium panel, phosphorus panel, coagulation panel, liver function panel, and complete blood count. Approximately 14 mL of blood was drawn from each patient for laboratory testing during the study. Further safety assessments were performed, including physical examination, 12-lead electrocardiogram, hepatotoxicity, and sedative / analgesic adjuvant titration (dose titration). Statistical analysis was performed using SAS, version 9.1. Pharmacokinetic parameters were determined by noncompartmental analysis using Pro, version 5.1. Unless otherwise specified, all statistical data were two-sided, and a p-value of ≤ 0.05 was considered statistically significant (after rounding to the fifth decimal place). Continuous variables were summarized using descriptive statistics (number of patients [N], mean, median, standard deviation (SD), minimum, and maximum). Coefficients of variation (CV) were calculated for continuous pharmacokinetic variables. max For discrete variables, N, median, minimum, and maximum were displayed. Means and medians were displayed to one decimal place rather than raw values. For categorical variables, N and percentages were shown. All percentages were reported to one decimal place. A patient list of all collected and recorded data and derived variables was presented. Changes between the protocol-defined and SAP-defined analyses included the following: There were two differences between the study and protocol. One difference related to the definition of DLT. The study defined DLT to include age-specific bradycardia and hypotension, as well as clinically relevant oversedation and serious adverse effects. The protocol included only age-specific bradycardia, age-specific hypotension, and respiratory rate-specific bradypnea. Another difference was in the perspective on ECG data collection. The protocol stated that ECGs would be obtained pre- and post-treatment and compared for evidence of new ischemia. ECG charts and QT intervals were not available, and there were no plans to analyze the ECG data. Although the protocol mentioned the collection of plasma samples for pharmacogenomic studies, no samples were collected for pharmacogenomic testing or analysis. Four patient populations were defined in this study. Enrollment population: All patients who signed the informed consent were included in the enrollment population. Intent-to-Treat (ITT) population: Patients who were treated and complied with the protocol were included in the ITT population. Safety Population: All patients who received study drug were included in the safety population. All safety analyses used this population. Pharmacokinetic population: All patients who received a dexmedetomidine infusion of at least 2 hours were included in the pharmacokinetic population.

[0111] Plasma samples were assayed for dexmedetomidine concentration. The following parameters were calculated for each patient: AUC 0-t , AUC 0-inf , C max , T max , Cl, Cl w , V d , weight-adjusted distribution volume (V dw ), λz, t 1 / 2 , and C ss Area under the plasma concentration-time curve (AUC) and C max was the main pharmacokinetic parameter. Using the independent model method by Hospira, WinNonlin, version 5.1 (Pharsight, The above pharmacokinetic parameters were determined using non-compartmental analysis (Mountain View, CA, USA). Summary statistics for these parameters were tabulated. AUC and C max The geometric mean and coefficient of variation are shown. AUC and C between dose levels administered within age groups and overall max A dose-proportionality assessment was performed using a power analysis approach and data visualization techniques. Dose proportionality was statistically assessed using a power model. The power model had the following form: parameter = a(dose) b × random error (a and b are the coefficient and exponent parts of the equation, respectively). The power model was analyzed using linear regression after logarithmic transformation using the following equation: ln(parameter) = ln(a) + b × ln(dose) + random error. Dose proportionality was concluded if the 95% confidence interval (CI) for b included 1 or if b = 0 (H0) was not rejected when fitted to the dose-normalized parameters. Data visualization techniques were used to compare weight-adjusted clearance, AUC, and C with respect to age against administered dose to determine if there were any trends in the data that indicated the need for further evaluation.max This involved plotting the An exploratory evaluation of potential pharmacokinetic / PD relationships was performed. PD parameters such as sedation level or need for rescue sedatives and pharmacokinetic parameters AUC or C max We explored the relationship between Pharmacodynamic analyses were summarized by dose level for the ITT and pharmacokinetic populations. PD parameters included sedation level and vital signs, monitored continuously hourly for up to 24 hours after discontinuation of the infusion. Parameters included heart rate, blood pressure, MAP, cardiac rhythm, oxygen saturation, and respiratory rate. Descriptive statistics (arithmetic mean, SD, median, minimum, and maximum) were calculated for the quantitative PD data as well as for the changes from baseline by dose level. Sedation level was assessed using the BIS and UMSS. UMSS scores were summarized by the number and percentage of patients at each sedation level by dose level. The number and percentage of patients using fentanyl, morphine, or midazolam during study drug administration were summarized by dose level, and treatment differences were assessed by Fisher's exact test. For each dose level, the total amount of fentanyl, morphine, and midazolam was summarized descriptively by time after the start of the infusion at each dose level. The time windows analyzed for the total amount of sedative drug after the start of the infusion were 4 hours, 4 to 8 hours, 8 to 12 hours, and 0 to 24 hours. Pharmacokinetic parameters (e.g., AUC, C max , or C ss Exploratory analyses were performed to examine the association between exposure to sedatives and sedative use (e.g., total dose).

[0112] Descriptive statistics were used to summarize vital sign measurements of heart rate, blood pressure, temperature, mean arterial pressure (MAP), respiratory rate, and peripheral oxygen saturation (SpO2) in a dose-dependent manner over time compared to baseline. Treatment differences in mean change from baseline at each time point were assessed by one-way analysis of variance (ANOVA) with treatment as a factor in the model. Patients were asked to list all safety data, including study drug exposure, adverse effects, cardiac ischemia, liver function tests, DLT assessments, clinical laboratory evaluations, physical examinations, and use of concomitant medications. Descriptive statistics (arithmetic mean, SD, median, minimum, and maximum) were calculated for quantitative safety data as well as for differences from baseline, where appropriate. Exposure to study drug was calculated according to the bolus and maintenance doses of study drug administered. The loading dose (or bolus) was summarized using the parameters total dose and duration of administration. The maintenance dose was summarized using the total dose and total duration of administration (in hours). The total dose was equal to the loading dose + CIVI rate × duration of administration. Both duration of administration and total time of administration, excluding interruptions, were calculated using the time of the last dose minus the time of the first dose. The use of patient weight was facilitated in dose calculations. Adverse effects were coded using the most recent version of the Medical Devices and Regulatory Resources Act (MedDRA, version 11.0) available, and adverse effects were summarized by dose level for the number of patients reporting an adverse effect and the number of adverse effects reported. Patient-reported adverse event data listings included the verbatim term, coded term, treatment group, severity, and relationship to the given treatment. Serious adverse events associated with death and adverse events leading to discontinuation of study drug were also summarized. A treatment-emergent adverse event was defined as any adverse event reported by a patient with onset or worsening of symptoms from the time the first dose of study drug was administered until 24 hours after discontinuation of study drug. For summarization by severity, if a patient had multiple events occurring in the same system organ class (SOC) or the same preferred term, the event with the highest severity was summarized. Any adverse event with unknown severity was summarized as serious. A similar methodology was applied to the relationship to study drug. Laboratory test results were tabulated descriptively for change from baseline with treatment. All laboratory values ​​outside the normal range were flagged in the data listing. Patients were assessed by body system and classified as normal or abnormal. ECG data were not analyzed as ECG charts and QT intervals were not available. Hepatotoxicity was summarized by number and percentage of patients by dose level at each scheduled visit. The sample size was based on the determination of the pharmacokinetic profile of dexmedetomidine. Based on an estimated interpatient variability of 50% for steady-state concentrations, a sample size of 36 evaluable patients was used to determine the AUC and C between the three dose groups. ss The study was sufficient to detect a difference of 0.05 (α 0.05, power 80%). Twelve evaluable patients were planned to be enrolled in each dose group. Based on a clinical intensive care unit (CICU) patient population survey, we estimated that 15 months would be required to achieve enrollment. Patient demographics are summarized in Table 36.

[0113] Table 36. Patient characteristics - enrolled patients JPEG0007818561000044.jpg43120 a Low-dose dexmedetomidine (0.35 μg / kg bolus, 0.25 μg / kg / hour infusion). b medium-dose dexmedetomidine (0.7 μg / kg bolus, 0.5 μg / kg / hour infusion); c High-dose dexmedetomidine (1.0 μg / kg bolus, 0.75 μg / kg / hour infusion). d Two patients in the high-dexmedetomidine dose group discontinued the study and were not included in the ITT population.

[0114] Thirty-eight patients were enrolled in the study and assigned to one of three treatment groups: low-dose dexmedetomidine (0.35 μg / kg bolus, 0.25 μg / kg / hour infusion), medium-dose dexmedetomidine (0.7 μg / kg bolus, 0.5 μg / kg / hour infusion), or high-dose dexmedetomidine (1.0 μg / kg bolus, 0.75 μg / kg / hour infusion). Of the 38 enrolled patients, three (7.9%) discontinued the study prematurely. One patient in the low-dose dexmedetomidine treatment group discontinued the study after completing the study drug infusion. Two patients in the high-dose dexmedetomidine treatment group discontinued the study prematurely; these patients were not included in the pharmacokinetic population. Thirty-six (94.7%) of the 38 enrolled patients completed treatment. All 38 patients enrolled in the study received at least one dose of study drug and were included in the safety population. Thirty-six patients received at least a 2-hour dexmedetomidine infusion and had sufficient concentration data to calculate the primary pharmacokinetic parameters; these patients were included in the pharmacokinetic population. Thirty-six patients in the intention-to-treat population completed treatment. Patients who discontinued treatment prematurely were recorded. Protocol deviations were also recorded. Demographics of the patient population were collected along with medical and reproductive history. Prior and concomitant medications were also recorded. Summary statistics for dexmedetomidine loading dose and maintenance infusion dose are shown in Table 37 below.

[0115] Table 37. Summary statistics for dose-related data JPEG0007818561000045.jpg156110

[0116] Two patients were excluded from the pharmacokinetic analysis. Both patients were in the high-dexmedetomidine dose group. Thirty-six patients had sufficient concentration data to calculate pharmacokinetic parameters and were included in the pharmacokinetic analysis set. Patients who received treatment and complied with the protocol were included in the ITT population. The pharmacokinetic and ITT populations included the same patients; therefore, the analysis of baseline characteristics was identical to the ITT and pharmacokinetic profile analyses. The safety profile was analyzed for the safety population; 38 patients received at least one dose of study drug and were included in the safety population. The pharmacokinetic profile demonstrated linearity and dose proportionality between the 0.25, 0.50, and 0.75 μg / kg / hr dose levels; AUC and C max The mean doses were given as 20.5, 40.4, and 65.1 μg for the 0.25, 0.50, and 0.75 μg / kg / hr dose levels, respectively, with corresponding increases in exposure as shown. 0-inf , AUC 0-t and C max The apparent t of dexmedetomidine was positively linear between the dose levels of 0.25, 0.50, and 0.75 μg / kg / hour. 1 / 2 were 2.33 hours, 2.12 hours, and 3.05 hours for the low, medium, and high doses, respectively. The geometric mean slopes and 95% confidence intervals between the three dose levels were AUC 0-inf 1.263(0.820,1.706) for C max The mean values ​​for α and β were 0.898 (0.652, 1.143). Similar positive linear trends were observed among the three age groups: 1 to <6 months, 6 to <12 months, and 12 to 24 months. The statistical analysis to assess the dose proportionality of the three doses of dexmedetomidine is presented below in Table 38. Given the AUC 0-t , AUC 0-inf , and C max Dose proportionality could be calculated for , and the 95% CI of the slope included one of these parameters.

[0117] JPEG0007818561000046.jpg99122 a Low-dose dexmedetomidine: 0.35 μg / kg bolus, 0.25 μg / kg / hour infusion. b Medium-dose dexmedetomidine: 0.7 μg / kg bolus, 0.5 μg / kg / hour infusion. c High-dose dexmedetomidine: 1.0 μg / kg bolus, 0.75 μg / kg / hour infusion. d Estimated slopes were calculated computer-generated from linear regression of log(PK parameter) versus log(dose) over the dose range. CI = confidence interval

[0118] AUC generated using a power-law fitting model 0-inf , AUC 0-t , and C max The predicted mean curves are shown in Figures 34A to 34C. A linear plot illustrating the mean dexmedetomidine concentration over time is shown in Figure 35. As shown in Figure 35, the mean dexmedetomidine concentration profiles (over time) for the three treatment groups were similar. The mean dexmedetomidine plasma concentrations tended to increase with increasing dose of dexmedetomidine. The highest mean plasma concentrations were observed in the high-dose dexmedetomidine treatment group. The AUC and C max values ​​increased. Half-life values ​​were independent of dose level. Mean half-life values ​​for the low-, medium-, and high-dose combinations were 2.33, 2.12, and 3.05 hours, respectively. The pharmacokinetic parameters of dexmedetomidine are summarized using descriptive statistics and presented in Table 39.

[0119] JPEG0007818561000047.jpg181122 JPEG0007818561000048.jpg37122 a Low-dose dexmedetomidine: (0.35 mcg / kg bolus, 0.25 mcg / kg / hour infusion). bMedium-dose dexmedetomidine: (0.7 mcg / kg bolus, 0.5 mcg / kg / hour infusion). c High-dose dexmedetomidine: (1.0 mcg / kg bolus, 0.75 mcg / kg / hour infusion). d T max are shown only as median values ​​(min, max). CV = coefficient of variation, ITT = intention to treat, max = maximum, min = minimum, N, n = number of patients, SD = standard deviation

[0120] Clearance and body weight-adjusted clearance with respect to age are shown in Figure 36. No significant increase or decrease in clearance or body weight-adjusted clearance was observed with increasing age. No further regression analysis was performed between age and pharmacokinetic parameters. Table 40 summarizes the sedation levels measured using the UMSS at each time point during the treatment period for the enrolled population. At all dose levels, patients experienced deep sedation (UMSS 3-4) from pre-dose through 2 hours post-infusion and maintained moderate levels of sedation (UMSS 1-3) from the 4-hour infusion through the end of the infusion. There was a correlation between plasma concentrations and UMSS 30 minutes after the start of the infusion for the low dose, 8 hours after the end of the infusion for the medium dose, and 30-15 minutes before the end of the infusion and 60 minutes after the end of the infusion for the high dose. According to the UMSS, fewer patients were classified as "unawakenable" 1 hour after the infusion compared with pre-bolus / baseline for all three dexmedetomidine dose groups. Sedation levels decreased 1 hour after dexmedetomidine infusion in all dose groups. Patients experienced a decrease in sedation from the time of infusion through 6 hours post-infusion. This was evident for all three doses of dexmedetomidine; the incidence of patients who were "unawakenable" pre-bolus / baseline was 91.7%, 91.7%, and 83.3% for the low-, medium-, and high-dose dexmedetomidine groups, respectively. At 6 hours post-infusion, the incidence of patients who were "moderately sedated / somnolence" was 58.3%, 41.7%, and 50.0% for each of the dexmedetomidine dose groups.

[0121] Table 40. Summary of sedation levels (UMSS) at the time of sedation during treatment - ITT population JPEG0007818561000049.jpg149121 JPEG0007818561000050.jpg93120 a Low-dose dexmedetomidine: (0.35 mcg / kg bolus, 0.25 mcg / kg / hour infusion). b Medium-dose dexmedetomidine: (0.7 mcg / kg bolus, 0.5 mcg / kg / hour infusion). c High-dose dexmedetomidine: (1.0 mcg / kg bolus, 0.75 mcg / kg / hour infusion). d P values ​​are from the Cochran-Mantel-Haenszel test. Note: UMSS score was not applicable for patient 33 due to continuous infusion of neuromuscular blockade. ITT = Intent-to-Treat, -- = Not Applicable, N = Number of Patients, UMSS = University of Michigan Sedation Scale

[0122] Summary sedation levels (BIS scores) at each time point during the treatment period were reviewed for the ITT population. Patients experienced a decrease in sedation from the time of infusion to 6 hours post-infusion. This was more evident with the low and medium doses of dexmedetomidine; the pre-infusion mean change from baseline maximum BIS values ​​was -1.0 ± 9.72 and -5.8 ± 13.22 for patients in the low- and medium-dose groups, respectively. At 6 hours post-infusion, the mean change from baseline maximum BIS values ​​was 12.7 ± 28.52 and 14.2 ± 12.21 for patients in the low- and medium-dose groups, respectively. Patients receiving the highest dose of dexmedetomidine also became increasingly alert over time, but the mean change from baseline to 6 hours post-infusion was less than that observed with the lower doses; the pre-infusion mean change from baseline maximum BIS score was -8.2 ± 13.43 and 2.3 ± 14.86 at 6 hours post-infusion. SQI was summarized at each time point during the treatment period for the ITT population. SQI values ​​were similar among the three dexmedetomidine dose groups post-bolus / pre-infusion and remained stable up to 16 hours post-infusion; there was greater variability after 16 hours post-infusion of dexmedetomidine. The correlation analysis between UMSS scores and dexmedetomidine plasma concentrations is shown in Table 41. Pearson correlation was used to test the zero-point correction of plasma dexmedetomidine and UMSS scores, and significant correlations were observed at the following time points: 30 minutes after the start of infusion for low-dose dexmedetomidine (p=0.0266), 8 hours after EOI for medium-dose dexmedetomidine (p=0.0423), and 30-15 minutes before EOI (p=0.0255) and 60 minutes after EOI (p=0.0502) for high-dose dexmedetomidine. Except for these time points, dexmedetomidine plasma concentrations did not correlate with UMSS sedation scores.

[0123] JPEG0007818561000051.jpg165122 JPEG0007818561000052.jpg165122 JPEG0007818561000053.jpg171122 Note: Correlation p-values ​​assessed within treatment groups (Pearson product moments) product moment)). a Low-dose dexmedetomidine (0.35 μg / kg bolus, 0.25 μg / kg / hour infusion). b medium-dose dexmedetomidine (0.7 μg / kg bolus, 0.5 μg / kg / hour infusion); c High-dose dexmedetomidine (1.0 μg / kg bolus, 0.75 μg / kg / hour infusion). DEX = dexmedetomidine, ITT = intention to treat, max = maximum, min = minimum, N, n = number of patients, SD = standard deviation. UMSS = University of Michigan Sedation Scale

[0124] UMSS score and dexmedetomidine plasma AUC 0-t A correlation analysis was performed between the data presented and clinically meaningful. UMSS score and dexmedetomidine plasma Cl w A correlation analysis was performed between the UMSS score and dexmedetomidine clearance. The strongest correlation was observed with the low dose; significant correlations were observed before infusion (p=0.0015), 1 hour after infusion (p=0.0191), and 12 hours after infusion (p=0.0385). A significant correlation was also observed for the high-dose dexmedetomidine when the infusion was discontinued (p=0.0295). A correlation analysis was performed between the UMSS score and dexmedetomidine clearance. A significant correlation between the UMSS score and dexmedetomidine clearance was observed before infusion and 12 hours after infusion for the low-dose dexmedetomidine (p=0.0371 and p=0.0470, respectively). Only patients with sufficient pharmacokinetic data to calculate the primary pharmacokinetic parameters were included in the pharmacokinetic analysis population. In general, missing data were not imputed. Pharmacokinetic sample collection times and observed values ​​for dexmedetomidine were examined separately for patients receiving low-dose dexmedetomidine (0.25 μg / kg / h), medium-dose dexmedetomidine (0.5 μg / kg / h), and high-dose dexmedetomidine (0.75 μg / kg / h). Pharmacokinetic parameters were examined as natural log-transformed values ​​for dexmedetomidine. Pharmacokinetic parameters expressed as observed values ​​for dexmedetomidine were also examined. Analysis of the correlation between UMSS score and dexmedetomidine plasma concentration is shown in Table 41. No data provided any association with response. Significant correlations between UMSS score and dexmedetomidine plasma concentration were observed at the following time points: 30 minutes after the start of the low-dose dexmedetomidine infusion (p=0.0266), 30-15 minutes before the end of the high-dose dexmedetomidine infusion (p=0.0255), and 8 hours after the end of the medium-dose dexmedetomidine infusion (p=0.0423). The pharmacokinetic profile demonstrated linearity and dose proportionality between the 0.25, 0.50, and 0.75 μg / kg / hr dose levels; AUC and C max The AUC of dexmedetomidine increased proportionally. The dose levels of 0.25, 0.50, and 0.75 μg / kg / hour were given with mean doses of 20.5, 40.4, and 65.1 μg, respectively, to represent dose escalation. 0-inf and C max The apparent t of dexmedetomidine was dose-proportional at dose levels of 0.25 to 0.75 μg / kg / hour. 1 / 2 were 2.33 hours, 2.12 hours, and 3.05 hours at the low, medium, and high dose levels, respectively. The geometric mean slopes and 95% confidence intervals between the three dose levels were AUC 0-inf About 1.263(0.820,1.706), C max The mean plasma concentrations and AUC 0-t , and AUC 0-inf A dose-dependent increase in AUC was observed for dexmedetomidine.0-t , AUC 0-inf , and C max Dose proportionality was concluded. No notable differences were observed in weight-adjusted clearance versus age for any of the dose groups. Patients experienced deep sedation (UMSS 3-4) from pre-dose through 2 hours post-infusion at all dose levels and maintained moderate sedation levels (UMSS 1-3) from 4 hours post-infusion through the end of the infusion. There was a correlation between plasma concentrations and UMSS 30 minutes after the start of the infusion for the low dose, 8 hours after the end of the infusion for the medium dose, and 30-15 minutes before the end of the infusion and 60 minutes after the end of the infusion for the high dose. Thirty-eight patients received at least one dose of dexmedetomidine and were included in the safety analysis set. Two patients (assigned to the high-dose dexmedetomidine treatment group) did not complete study treatment; these patients were not included in the ITT or pharmacokinetic analyses. Twelve patients within each treatment group (36 patients total) completed the study drug infusion. Study drug exposure is summarized in Table 42. The mean doses given to the 36 ITT patients were 20.5, 40.4, and 65.1 μg for the 0.25, 0.50, and 0.75 μg / kg / hour dose levels, respectively, with corresponding dose escalation. The mean duration of the infusion dose was approximately 9.1, 10.0, and 11.2 hours for the low, mid, and high dose levels, respectively.

[0125] Table 42. Summary of Exposure to Dexmedetomidine (Total Dose) - ITT Population JPEG0007818561000054.jpg34121 a Low-dose dexmedetomidine: (0.35 mcg / kg bolus, 0.25 mcg / kg / hour infusion). b Medium-dose dexmedetomidine: (0.7 mcg / kg bolus, 0.5 mcg / kg / hour infusion). c High-dose dexmedetomidine: (1.0 mcg / kg bolus, 0.75 mcg / kg / hour infusion). d The total dose is equal to the sum of the loading dose and the maintenance dose. e The total dose duration is the sum of the loading dose and maintenance dose durations. ITT=inclusive analysis, max=maximum, min=minimum, N=number of patients, SD=standard deviation

[0126] All 38 patients in the safety population and 36 ITT patients experienced at least one treatment-emergent adverse effect between the time of administration of the first dose of dexmedetomidine and 24 hours after discontinuation of study drug. Thirty-three patients experienced a treatment-emergent adverse effect considered to be treatment-related. SOCs with the highest incidence of treatment-emergent adverse effects included vascular disorders SOC (10 patients [83.3%] receiving low-dose dexmedetomidine, 10 patients [83.3%] receiving medium-dose dexmedetomidine, and 14 patients [100.0%] receiving high-dose dexmedetomidine) and metabolism and nutrition disorders SOC (10 patients [83.3%] receiving low-dose dexmedetomidine, 10 patients [83.3%] receiving medium-dose dexmedetomidine, and 14 patients [100.0%] receiving high-dose dexmedetomidine). %] while receiving medium-dose dexmedetomidine, 12 patients [100.0%] while receiving medium-dose dexmedetomidine, and 7 patients [50.0%] while receiving high-dose dexmedetomidine); and cardiac disorder SOC (3 patients [25.0%] while receiving low-dose dexmedetomidine, 4 patients [33.3%] while receiving medium-dose dexmedetomidine, and 4 patients [28.6%] while receiving high-dose dexmedetomidine). The majority of treatment-emergent adverse events were considered mild in intensity (9 patients [75.0%] with low-dose dexmedetomidine, 9 patients [75.0%] with medium-dose dexmedetomidine, and 7 patients [50.0%] with high-dose dexmedetomidine). A small proportion of treatment-emergent adverse events were considered moderate in intensity (2 patients [16.7%] with low-dose dexmedetomidine, 3 patients [25.0%] with medium-dose dexmedetomidine, and 7 patients [50.0%] with high-dose dexmedetomidine). One patient in the low-dose dexmedetomidine treatment group experienced a treatment-emergent adverse event considered serious. The majority of treatment-emergent adverse effects were considered drug-related: low-dose dexmedetomidine (11 patients, 91.7%); medium-dose dexmedetomidine (11 patients, 91.7%); and high-dose dexmedetomidine (11 patients, 78.6%). One hundred seventy-one treatment-emergent adverse events were reported by 38 patients in the safety population. Four patients (three in the high-dose group and one in the medium-dose group) experienced treatment-emergent adverse events leading to discontinuation of study drug. No patients discontinued study drug as a result of death. The most commonly reported treatment-emergent adverse events were hyperglycemia and hypertension. The incidence of hyperglycemia was higher with medium-dose dexmedetomidine compared with low-dose and high-dose dexmedetomidine (low-dose dexmedetomidine, 83.3%; medium-dose dexmedetomidine, 100.0%; high-dose dexmedetomidine, 50.0%). The incidence of hypertension was similar across all three dexmedetomidine dose groups (low-dose dexmedetomidine, 66.7%; medium-dose dexmedetomidine, 58.3%; high-dose dexmedetomidine, 71.4%).

[0127] The study drug-related treatment-emergent adverse effect of hypertension occurred at the highest incidence (low-dose dexmedetomidine, 66.7%; medium-dose dexmedetomidine, 58.3%; high-dose dexmedetomidine, 50.0%). The incidence of drug-related treatment-emergent adverse effects was similar across all three dexmedetomidine dose groups. The majority of treatment-emergent adverse effects experienced by patients in the low-dose and medium-dose groups were mild in intensity (low-dose 9 patients, 75.0%; medium-dose 9 patients, 75.0%). In the low-dexmedetomidine and medium-dose groups, a smaller percentage of patients experienced treatment-emergent adverse effects that were moderate in intensity (2 patients, 16.7% in the low-dose group; 3 patients, 25.0% in the medium-dose group). In the high-dexmedetomidine treatment group, a smaller percentage of patients experienced both mild and moderate treatment-emergent adverse effects; 7 patients, 50.0%, experienced mild treatment-emergent adverse effects, and 7 patients, 50.0%, experienced moderate treatment-emergent adverse effects. Only one severe treatment-emergent adverse effect was reported in the low-dexmedetomidine group. Twenty-five patients experienced at least one treatment-emergent adverse effect during the study that the investigator considered to be mild. Twelve patients experienced at least one treatment-emergent adverse effect that was considered to be moderate in intensity, and one patient experienced at least one treatment-emergent adverse effect that was considered to be severe in intensity. One death was reported during the study. Four patients experienced treatment-emergent adverse effects that led to discontinuation of the therapeutic drug.

[0128] There were no meaningful differences in clinical laboratory results, selected vital signs (systolic blood pressure, diastolic blood pressure, mean arterial pressure, temperature, respiratory rate), or physical examination findings between the three dexmedetomidine dose levels. Clinically significant hematological abnormalities were observed in one patient (8.3%) in each of the low-dose and medium-dose dexmedetomidine groups (anemia) and in two patients (16.7%) in the low-dose dexmedetomidine group (thrombocytopenia). With the exception of one patient in the low-dose dexmedetomidine group who had thrombocytopenia, none of these reported adverse effects emerged under treatment. Greater mean changes in heart rate were observed at all time points for patients in the high-dose dexmedetomidine treatment group compared with the other treatment groups. The following clinically significant abnormalities considered adverse events were observed in the chemistry laboratory data: hyperkalemia (1 patient in each dose group), hypernatremia (1 patient in the low-dose group), hypocalcemia (1 patient each in the low- and medium-dose groups), hypoglycemia (1 patient each in the low- and medium-dose groups), and hypokalemia (1 patient each in the low- and medium-dose groups). Treatment-emergent adverse effects associated with vascular disorders included hypertension (8 patients, low dose; 7 patients, medium dose; and 10 patients, high dose) and hypotension (5 patients, low dose; 5 patients, medium dose; and 10 patients, high dose). Statistically significant treatment differences in the change from baseline in heart rate were observed up to and including 5 hours post-infusion. Treatment-emergent adverse effects associated with heart rate included tachycardia in 3 patients receiving low-dose dexmedetomidine, 1 patient receiving medium-dose dexmedetomidine, and 3 patients receiving high-dose dexmedetomidine. A statistically significant treatment difference in change from baseline in temperature was observed 28 hours postinfusion; temperature changes from baseline were -1.43 ± 1.559°C, 0.30 ± 0.265°C, and 1.46 ± 1.041°C for low-, medium-, and high-dose dexmedetomidine, respectively (p = 0.008); no significant differences were observed at any other time point. Treatment-emergent adverse effects related to temperature included hypothermia (1 patient, low dose and 2 patients, medium dose) and hyperthermia (1 patient, low dose and 1 patient, high dose). No clinically meaningful changes in respiratory rate were observed, and no related adverse effects were reported. Physical examination findings were not considered clinically significant and were not reported as adverse effects. ECG results were reported as adverse effects in seven patients. ECG-related adverse effects included ischemia (two patients, both in the low-dose group), ECG negative T waves (one patient in the low-dose group), ST-segment elevation (one patient in the low-dose group), bradycardia (one patient in the medium-dose group), ECG changes (one patient in the high-dose group), and sinus bradycardia complete heart block (one patient in the high-dose group). Hepatotoxicity as defined by SAP was reported in one patient (8.3%) in the low-dose group (within 24 hours of infusion interruption), one patient (8.3%) in the medium-dose group (2-4 weeks after infusion or at the next follow-up visit), and two patients (14.3%) in the high-dose group (within 24 hours of infusion interruption); no adverse effects related to hepatotoxicity were reported. No patients in this study reported DLT.

[0129] Patients receiving each dexmedetomidine dose level received fentanyl as an additional intraoperative sedative. The amount of fentanyl administered was less in patients receiving the medium (69.32 μg) and high (80.20 μg) doses of dexmedetomidine compared with patients receiving the low dose (99.32 μg). Postoperatively, patients received fentanyl, midazolam, and morphine sulfate. No treatment differences were observed regarding the amount of additional sedatives received. At most observed time points postinfusion, a higher proportion of patients receiving the medium dose of dexmedetomidine received additional sedative or analgesic medications compared with patients receiving the low dose of dexmedetomidine. At most time points postinfusion, a lower proportion of patients receiving the high dose of dexmedetomidine received additional sedative or analgesic medications compared with the low dose. There was no apparent relationship between dexmedetomidine dose level and the amount of fentanyl, midazolam, and morphine sulfate administered to patients at any of the observed post-infusion time points. This was a single-center, Phase I, dose-escalation, pharmacodynamic study of dexmedetomidine administered as a single bolus dose followed by a continuous infusion for up to 24 hours in infants who had recently undergone cardiac surgery and required endotracheal intubation and mechanical ventilation in the postoperative period. Dexmedetomidine is a highly selective α2 agonist with hypnotic and anxiolytic properties attributed to α2A-adrenergic receptors in the locus coeruleus. Dexmedetomidine was first approved in 1999 for sedation of intubated and mechanically ventilated patients for up to 24 hours in the intensive care setting. Recently, dexmedetomidine has been approved as a short-term (<24 hours) sedative for use in non-intubated adult patients requiring sedation before and during surgery and other procedures. Thirty-eight infants in the postcardiac surgery state were assigned to three treatment groups: low-dose dexmedetomidine (12 patients), medium-dose dexmedetomidine (12 patients), and high-dose dexmedetomidine (14 patients). Thirty-six patients completed the dexmedetomidine infusion, 12 in each dose group. Patients were primarily Caucasian (61.1%) with a mean age of 8.3 months. Patients in the low-dose dexmedetomidine group received a 0.35 μg / kg bolus and a 0.25 μg / kg / hour infusion; patients in the medium-dose dexmedetomidine group received a 0.7 μg / kg bolus and a 0.5 μg / kg / hour infusion; and patients in the high-dose dexmedetomidine group received a 1 μg / kg bolus and a 0.75 μg / kg / hour infusion. Pharmacokinetic samples were collected from before the bolus dose until 18 hours after the end-of-life (EOI) time point for measurement of dexmedetomidine pharmacokinetic parameters. Thirty-six patients were in the pharmacokinetic population; 36 patients completed treatment. Periodic checks of the BIS monitor allowed assessment of the drug's sedative and analgesic properties after the infusion was discontinued and until the clinical care team deemed the patient awake. Hourly UMSS scores were also assessed until BIS sensor removal.

[0130] The primary variable observed for the pharmacokinetic evaluation of dexmedetomidine was the maximum plasma concentration (C max ), the area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC 0-t ), the area under the plasma concentration-time curve from time zero to infinity (AUC 0-inf ), the time at which the maximum plasma concentration was observed (Tmax ), terminal elimination rate constant (λz), terminal half-life (t 1 / 2 ), end-of-infusion concentration (steady-state C ss ), plasma clearance (Cl), and volume of distribution (V d ) was. C max , AUC 0-t , and AUC 0-inf Mean values ​​were analyzed to demonstrate dose proportionality. There were no apparent changes in clearance and weight-adjusted clearance across the age range in this study. Pharmacodynamic assessments were continuously monitored hourly for up to 24 hours after discontinuation of the infusion. Pharmacodynamic assessments included heart rate, blood pressure, mean arterial pressure, cardiac rhythm, oxygen saturation, and respiratory rate. BIS and UMSS were used to assess sedation levels. There were no significant differences in systolic blood pressure, diastolic blood pressure, mean arterial pressure, body temperature, respiratory rate, or physical examination findings among the three dexmedetomidine dose levels. Administration of higher bolus doses resulted in deeper sedation levels (BIS); changes from baseline were smaller in patients receiving the higher-dose dexmedetomidine than in patients receiving the lower-dose dexmedetomidine up to 6 hours after infusion. Of the 38 patients in the safety population, all experienced at least one adverse effect considered treatment-emergent. Thirty-three patients experienced at least one adverse effect considered related to treatment. SOCs with the highest incidence of treatment-emergent adverse effects included the vascular disorders SOC (10 patients [83.3%] receiving low-dose dexmedetomidine, 10 patients [83.3%] receiving medium-dose dexmedetomidine, and 14 patients [100.0%] receiving high-dose dexmedetomidine) and the metabolic and nutritional disorders SOC (10 patients [83.3%] receiving low-dose dexmedetomidine, 12 patients [100.0%] receiving medium-dose dexmedetomidine, and 7 patients [50.0%] receiving high-dose dexmedetomidine). No patients experienced DLTs in this study.

[0131] In this study, the main objective of the study was to evaluate the pharmacokinetics (mean plasma concentration, AUC 0-t , and AUC 0-inf) and demonstrated a dose-dependent increase in sedation levels. At most time points investigated, there was a significant difference in sedation levels, serum plasma concentrations, AUC 0-t , or AUC 0-inf There was no significant correlation between UMSS score and dexmedetomidine clearance (weight-adjusted and unadjusted) at the majority of time points tested. Dexmedetomidine was generally well tolerated in infant postoperative cardiac patients. The following conclusions were drawn regarding the administration of dexmedetomidine to infants after cardiac surgery: The pharmacokinetic profile demonstrated linearity and dose proportionality between the 0.25, 0.50, and 0.75 μg / kg / hr dose levels; AUC and C max increased proportionally. Patients had deep sedation (UMSS 3-4) from pre-dose through 2 hours post-infusion for all dose levels, and moderate sedation (UMSS 3-4) from 4 hours post-infusion through the end of the infusion. 1~3) were maintained. There was a correlation between plasma concentrations and UMSS 30 minutes after the start of infusion at the low dose, 8 hours after the end of infusion at the medium dose, and 30 to 15 minutes before the end of infusion and 60 minutes after the end of infusion at the high dose. There was no apparent change in clearance or weight-adjusted clearance over the age range examined in this study. At the majority of time points, no correlation was observed between serum plasma concentrations of dexmedetomidine and levels of sedation or clearance of dexmedetomidine. A greater mean change in heart rate was observed in patients treated with high-dose dexmedetomidine compared with other treatment groups. Dexmedetomidine at the dose administered in this study was generally well tolerated. No clinically meaningful differences in the safety profile were observed among the three dose groups.

[0132] Example 6: Pooled Pharmacokinetic Data of Dexmedetomidine in Pediatric Patients Pharmacokinetic data from the studies in Example 1, Example 3, and Example 5 were combined. Data from patients treated with dexmedetomidine and with at least one measurable plasma concentration with associated dosing and sample timing information were included. In Example 1, only subjects from the original 30 patient population study were included. In Example 5, only data from patients receiving at least two hours of dexmedetomidine maintenance infusion and with at least one measurable plasma concentration with associated dosing and sample timing information were included. A population pharmacokinetic analysis of dexmedetomidine with covariate evaluation was performed on these data. Full-profile pharmacokinetic sampling was performed on all subjects in the studies in Example 5 and Example 3. In the study in Example 1, blood was drawn six or seven times as specified by the protocol based on the subject's age and weight. In the study in Example 1, blood samples (0.15 mL) for pharmacokinetic analysis were collected via a central or peripheral venous or arterial line unless inaccessible. If inaccessible, samples were collected via capillary draw (heel stick). When appropriate, blood samples were drawn at a site opposite the infusion site. Subjects in Group I weighing less than 2 kg had blood drawn at the end of the loading dose, 10 to 14 hours after the start of the maintenance infusion, at the end of the maintenance infusion, 10 to 30 minutes after maintenance, and 3 to 4 hours and 6 to 10 hours after maintenance. Subjects in Group I weighing at least 2 kg had blood drawn at the end of the loading dose, 4 to 8 hours and 10 to 14 hours after the start of the maintenance infusion, at the end of the maintenance infusion, and 10 to 30 minutes, 1 to 2 hours, and 6 to 10 hours after maintenance. Subjects in Group II had blood drawn at the end of the loading dose, 4 to 8 hours after the start of the maintenance infusion, at the end of the maintenance infusion, 10 to 30 minutes, and 1 to 2, 3 to 4, and 6 to 10 hours after maintenance.

[0133] In the study of Example 5, blood samples (1 mL) for pharmacokinetic measurements were collected at a site remote from the infusion site according to the following schedule: before the loading dose, 0.5, 1, 2, and 4-6 hours after the start of the maintenance infusion, 30-15 minutes before the end of the maintenance infusion, and 0.25, 0.5, 1, 2, 4, 8, 12, and 15-18 hours after the end of the maintenance infusion. In Study Example 3, venous blood samples (1 mL) for pharmacokinetic measurements were collected at the site opposite the infusion site according to the following schedule: ≤30 minutes before the loading dose, within 5 minutes before the end of the loading dose, 0.5, 1, 2, and 4-6 hours after the start of the maintenance infusion, within 30 minutes before the end of the maintenance infusion, and 10 minutes, 0.5, 1, 2, 4, and 10 hours after the end of the maintenance infusion. Blood samples were collected in labeled tubes containing heparin as the anticoagulant. A validated high-performance liquid chromatography-tandem mass spectrometry method was utilized to quantify dexmedetomidine in human plasma. The lower limit of quantification (LLOQ) was 4.24 pg / mL for the Example 5 study, 30.24 pg / mL for the Example 3 study, and 29.97 pg / mL for the Example 1 study. For the Examples 3 and 1 studies, administration information, pharmacokinetic sampling information, dexmedetomidine concentration, and covariate data, as appropriate, were integrated to construct an analysis-ready dataset of the chronological sequence of relevant events for each subject from the start of the first dose to the time of the last blood sample. The analysis-ready datasets for the Examples 3 and 1 studies were compiled along with a supplemental analysis-ready dataset for the Example 5 study. Potential covariates selected to explain variability in the pharmacokinetic parameters of dexmedetomidine were explored. The following time-invariant (stationary) demographic and clinical covariates were determined at the screening visit and were assumed to remain constant for the duration of the trial: Weight, kg Age, years Alanine aminotransferase, U / L Total bilirubin, mg / dL Ethnicity: 1=Caucasian, 2=Black, 3=Asian, 4=Native American, 5=Hispanic, 6=Other ·Gender: 0=male, 1=female Cardiac physiology: 0 = biventricular, 1 = univentricular Concomitant use of glucuronidation pathway inhibitors within 24 hours before surgery or during surgery or treatment: 0 = no, 1 = yes Intravenous albumin infusion: 0=no, 1=yes Cardiopulmonary bypass use: 0=no, 1=yes Gestational age: 1 = preterm (≥28 to <36 weeks), 0 = full term (≥36 to ≤44 weeks) Sampling site: 0 = venous, 1 = arterial, 2 = capillary (heel stick).

[0134] Only the study in Example 1 recorded the sampling site; studies that did not record this information assumed it was venous. The effect of concomitant metabolic inducers could not be explored due to the limited time frame for past medication history collection, as specified in the study in Example 5 (i.e., 24 hours before surgery). As aspartate aminotransferase and serum albumin data were not available from the study in Example 5, they were not considered as possible covariates. Although dexmedetomidine is a substrate of CYP2A6, a comprehensive literature review on CYP2A6 inhibition identified a very limited number of marketed drugs known to inhibit this CYP enzyme. Given the potential use of these medications in the pediatric population, further covariate evaluation of this factor was deemed unnecessary. SAS version 9.1 or later was used for data preparation, summary statistics, and illustrations. Summary statistics were computed to describe independent and independent variables, including means, medians, standard deviations, and other measures, as appropriate. Population pharmacokinetic modeling was performed using the computer program NONMEM®, version VI, level 2.0. Intel® 8000 Series, running the OpenSUSE 10.2 distribution of Linux, was used. The NONMEM analysis was performed on an x86 computer. The Fortran compiler used was the GNU Fortran compiler, part of the GCC version 3.3.5 compiler.

[0135] For each analysis, NONMEM computes the minimum of the objective function (MVOF), a statistic proportional to minus two times the log-likelihood of the data. For hierarchical models, the change in MVOF caused by the inclusion of a parameter is asymptotically chi-squared distributed with a number of degrees of freedom equal to the number of parameters added to or removed from the model. First-order conditional estimation (FOCE) methods, taking interactions into account, were used at all stages of the model development process. Various graphs and tables were generated from the analysis dataset to understand the information content of the data relative to the predictive model, to search for extreme values ​​and / or potential outliers, to assess possible trends in the data, and to determine whether any errors occurred in data manipulation and generation of the analysis dataset. Exploratory analyses were also used to validate the tested model and to test model assumptions. Data visualization techniques were used to search for patterns and extreme values ​​that may have introduced significant bias during the analysis. Outliers were defined as unusual observations that deviated significantly from the rest of the measured observations for a particular subject. The general steps followed to develop the pharmacokinetic model of dexmedetomidine are outlined below. 1. Exploratory data analysis. 2. Refinement of the dexmedetomidine population pharmacokinetic model originally developed in Example 5 using the combined Study data from Example 5 and Study Example 3 to include covariate analysis. 3. Further refinement of the dexmedetomidine population pharmacokinetic model after data from the study in Example 1 became available and were integrated with previous data. The effects of covariates on the pharmacokinetic parameters were reassessed. 4. Prediction Correction Visual Prediction Check Final model evaluation was performed using a variable predictive check (VPC) procedure. Correlations between covariates were examined to avoid possible multicollinearity or confounding of covariate submodel effects. Pairwise scatterplots of all continuous covariates and boxplots of continuous covariates versus categorical variables were generated. In no case were two highly correlated covariates included in the same parameter-covariate model, except for weight and age, which were expected to be correlated in this population.

[0136] A linear open two-compartment model of dexmedetomidine was initially tested as a possible basic structural model. To determine the appropriate characterization of random effects, this model was refined based on the dexmedetomidine concentration data from the studies in Examples 5 and 3. This model included the effects of weight, age, time on CPB, and cardiac physiology (univentricular or biventricular) on dispositional parameters; however, the basic structural model initially evaluated for this analysis did not include covariate effects unless such effects were necessary to achieve model stability. The effects of weight and age were assumed to be part of the basic structural model given the characterization of this patient population and their potential impact on pharmacokinetics. When data from the study in Example 1 became available, a population pharmacokinetic model was fitted to the combined dataset and refined. The impact of covariates on pharmacokinetic parameters was reassessed. Covariate analysis was performed to explore measurable sources of dexmedetomidine variability and estimated interindividual variability (IIV) in the pharmacokinetic model parameters. Table 43 lists the parameters that considered the covariate effects.

[0137] JPEG0007818561000055.jpg63106

[0138] Graphical and statistical approaches were used to develop covariate models and evaluate the mathematical relationships and their statistical significance. After development of the basic structural pharmacokinetic model, the influence of covariates on selected pharmacokinetic parameters for dexmedetomidine was assessed univariately. Diagnostic plots showing the association between unknown IIV and covariates in CL and Vc were examined for possible trends and appropriate functional forms (e.g., linear, power, or exponential) to test for parameter-covariate associations. Covariates contributing at least a 3.84 change in MVOF (α = 0.05, 1 degree of freedom for a chi-squared distribution) and a 5% reduction in IIV in the parameters of interest were included in the model, and this process was repeated. After completion of forward selection, the error model for IIV in the full multivariate model was re-evaluated. Univariate backward elimination, which proceeded after all adjustments, was performed on the error model. Covariates were considered significant and retained in the model if they contributed at least 10.83 changes in MVOF when removed from the model (α = 0.001, 1 degree of freedom for a chi-squared distribution). The reduced multivariate model with all significant covariates was assessed for residual bias in both the IIV and residual variance (RV) error models. Diagnostic plots of parameter-missing IIV versus all covariates were evaluated to detect any shortcomings or biases in the covariate model and to ensure that no trends remained that could indicate that potential associations were not fully explained by the model. Models were checked for possible simplifications of the covariate function, such as a power function that could be transformed into a linear function (with power terms approximately 1.0) or significant discrete group covariates that could be redefined using fewer groups or parameters. Goodness-of-fit diagnostic plots were examined for model misfit. The validity of the final model was assessed using a simulation-based predictive correction VPC method. The final model was used to simulate the analysis dataset 1,000 times in NONMEM. Statistics of interest were calculated from the simulated and observed data for comparison; for example, the 5th, 50th (median), and 95th percentiles of the distribution of dexmedetomidine concentrations within discrete bins (ranges) of time, treatment group, and age were calculated. These simulated concentration percentiles were then plotted against time since the end of the maintenance infusion. Percentiles based on the initial observation dataset and / or the observed data were overlaid to visually assess the agreement between the model-based simulated data and the observed data. Due to the wide range of doses used in these studies and the spectrum of subjects with respect to age (and weight), Bergstrand, We utilized predictively corrected VPC with bins defined by time, treatment group, and age, as suggested by et al. (AAPS J. 2011;13(2):143-151). This technique can improve the ability to diagnose possible model misformulation by removing the variability introduced into the typical VPC when binning across potentially large variations in dose or other influential covariates. A total of 1448 dexmedetomidine concentration records were received from 131 subjects and three studies. After exclusions, 1279 dexmedetomidine concentrations collected from 120 subjects in these studies were available for analysis (Table 44).

[0139] Table 44. Data characteristics of each study included in the population pharmacokinetic analysis JPEG0007818561000056.jpg156111 JPEG0007818561000057.jpg85111

[0140] Table 45 summarizes the number of subjects and dexmedetomidine concentrations included in the analysis by study and randomized treatment group.

[0141] Table 45. Summary of Number of Subjects and Dexmedetomidine Concentrations by Study and Dexmedetomidine Treatment Group JPEG0007818561000058.jpg63106

[0142] The demographic characteristics of subjects overall and by study are shown in Table 46.

[0143] Table 46. Summary of Subject Demographic Characteristics by Study JPEG0007818561000059.jpg82107

[0144] Overall, slightly more than half of the subjects were male (55%), the median age was 1.56 years (range 0.01-16.97 years), and the median weight was 10.35 kg (range 1.12-99 kg). The majority of subjects were Caucasian (55%). For the most part, the age and weight ranges presented in the three studies encompass a range of maturity and size, from very small infants to near-adults, with little or no overlap in these characteristics between studies. As shown in Table 47, the median alanine aminotransferase level was 21.0 U / L across subjects, with the median for subjects in Example 5 (24.0 U / L) being slightly higher than the median for subjects in Example 3 (19.0 U / L) and Example 1 (19.5 U / L). The median total bilirubin for all groups was 0.5 mg / dL, although the total bilirubin levels of subjects in Example 1 were significantly higher (median total bilirubin level 4.65 mg / dL). mg / dL).

[0145] Table 47. Summary of Laboratory Test Values ​​by Study JPEG0007818561000060.jpg63107

[0146] Table 48 shows summary statistics for subject cardiac status (cardiopulmonary bypass and ventricular physiology), administration of albumin infusion or drugs known to be glucuronidation pathway inhibitors, and blood collection site for pharmacokinetic analysis of dexmedetomidine concentrations.

[0147] Table 48. Summary of Cardiac Conditions, Concomitant Medications, and Pharmacokinetic Sampling Sites JPEG0007818561000061.jpg6387

[0148] All subjects in Example 5 and most subjects (70.7%) in Example 3 underwent cardiopulmonary bypass surgery, whereas relatively few subjects (19.2%) underwent this procedure in the study of Example 1. Subjects with single ventricle physiology were present only in the study of Example 5 (52.8%). Overall, most subjects (84.2%) did not receive albumin infusion, and 89.2% of subjects received concomitant medications known to be glucuronidation pathway inhibitors within 24 hours before surgery, during surgery, or during dexmedetomidine treatment. Plasma samples for dexmedetomidine concentration determination were collected according to a predefined schedule for the studies in Examples 1, 3, and 5, before and after the loading dose, near the start of and during the maintenance infusion, and after discontinuation of the maintenance infusion. The number of plasma dexmedetomidine concentrations contributed by each individual subject ranged from 1 to 13 throughout the study, with Example 5 contributing the most samples per subject (10-13, median 13), Example 3 contributing a similar amount per subject (1-12, median 12), and, as expected, Example 1 contributing the fewest (5-7, median 7 samples per subject). The overall range of dexmedetomidine doses for both the loading dose and the maintenance infusion was large (56 ng-140,000 ng and 357 ng-828,800 ng, respectively). Summary statistics for dexmedetomidine loading and maintenance infusion doses are shown in Tables 5A, 27A, and 37. Across all treatment groups, the median total dexmedetomidine dose was 2184 ng, 36,011 ng, and 120,550 ng, respectively, for the studies in Examples 1, 3, and 5. The loading dose infusion duration (median 0.167 hours across almost all treatment groups) and maintenance dose infusion duration (median ranging from approximately 6 to 9 hours across almost all treatment groups) were quite consistent throughout the studies.

[0149] Figures 16A-C show line graphs of plasma dexmedetomidine concentrations versus time since the start of the loading dose infusion for each treatment group in the three studies. Figures 17A-C show line graphs of dexmedetomidine concentrations versus time since the end of the maintenance infusion for each treatment group. Based on concentrations measured after the end of the infusion, these plots suggest that a two-compartment model is likely adequate to represent these data. While this finding is consistent with previous reports describing the population pharmacokinetics of dexmedetomidine in infants, other types of models were further investigated. 18A-B show semi-log scatterplots of dose-normalized dexmedetomidine plasma concentrations versus time since the end of maintenance infusion stratified by study, demonstrating that dexmedetomidine pharmacokinetics were generally similar across the treatment groups in the Example 3 and Example 5 studies. Smoothing splines are used on these plots to illustrate trends over time within each treatment group. There appears to be a trend toward higher dose-normalized dexmedetomidine concentrations in the lowest dose group (0.05 mg / kg + 0.05 mg / kg / hr) in the Example 1 study, but the pattern is less evident in the 0.10 mg / kg + 0.10 mg / kg / hr and 0.20 mg / hr + 0.20 mg / kg / hr dose groups. While the percentage of BLQ samples within the studies of Example 5 and Example 3 is quite similar (slightly less than 10% in each study, 3% and 5% overall, respectively), the study of Example 1 has a much higher percentage of samples that are BLQ (40% in this study, 5% overall). The BLQ samples remained in the database and were set at half the LLOQ of the assay used to determine dexmedetomidine concentrations in the respective studies. For model development, we first used the combined data from the studies in Examples 3 and 5. Based on previous modeling efforts and exploratory analysis results (particularly the scatter plots of dexmedetomidine concentration versus time), a two-compartment model, as well as one- and three-compartment linear models, were fitted to the data (Su A mammillary two-cone compartment model best described the data, and an exponential error model was used to estimate IIV for CL, Vc, Q, and Vp volumes. Residual variance was estimated for each study separately using a mixed additive and constant coefficient of variance error model. Based on literature recommendations, fixed non-proportional exponents for body weight scaling were included for clearance and volume parameters (0.75 for CL and Q, 1.0 for Vc and Vp). These standard exponents predict a less-than-proportional increase in CL and Q with increasing body weight and a proportional increase in Vc and Vp with increasing body weight. The basic structural pharmacokinetic model that explains the data from these two studies also included a negative linear relationship between age and Vp, as well as a negative power function relating age and Q. Pharmacokinetic parameter estimates and standard deviations of the estimates for fits of a two-compartment model to these data are shown in Table 49.

[0150] Table 49. Parameter estimates and standard deviations from the dexmedetomidine pharmacokinetic model developed using only data from Examples 5 and 3. JPEG0007818561000062.jpg67100 Abbreviations: CL, elimination clearance; IIV, interindividual variability; NA, not applicable; %CV, coefficient of variation expressed as a percentage; %SEM, standard error of the mean expressed as a percentage; Q, intercompartmental clearance; RV, residual variability; Vc, volume of the central compartment; Vp, volume of the peripheral compartment; WTKG, body weight in kg.

[0151]

number

[0152] e Residual variability estimates are expressed as variance. The %CVs corresponding to the RVs in Example 5 range from 108%CV at 2.12 ng / L (half the lower assay limit) to 19%CV at 700 ng / L. f Residual variation estimates are expressed as variances. The %CVs corresponding to the RVs in Example 3 range from 79%CV at 15.12 ng / L (half the lower limit of the assay) to 27%CV at 2000 ng / L.

[0153] Most parameters were estimated with reasonable precision (standard error of the mean [%SEM] < 34% expressed as a percentage) except for the IIV of Vp, which was assessed with slightly lower precision (%SEM = 56.7%). The diagnostic plots showed a good fit to the data without obvious bias, but were slightly less predictive of concentrations measured >10 h after the end of the infusion. This reduced prediction may be due to prediction of late samples at levels below the assay's limit of quantitation (in this case, the observed data were clamped to half the assay limit). Model development continued by adding the data from Example 1 to the combined data set from Examples 3 and 5. When the model developed using the data from Examples 5 and 3 was fitted to the combined data set including Example 1, initially high correlations were observed between many parameters. Due to differences in weight and age of the subjects in Example 1 compared to the older subjects in the other two studies, a model including only a non-proportional function of weight was next evaluated, eliminating the additive effect of age included in the previous model. After first refining this model with the combined data set, the effect of maturation on various pharmacokinetic parameters was then addressed. In assessing maturational effects on dexmedetomidine pharmacokinetics, allometric exponential shifts were examined for preterm subjects (i.e., subjects with a gestational age of ≤28 weeks in Example 1) and neonates (i.e., subjects under 1 month of age, regardless of gestational age) compared with all other subjects. Allometric exponential shifts for neonatal CL and Vc were associated with the greatest decrease in MVOF (approximately 48 points) and good prediction of parameter estimates, and were therefore retained in the model. Furthermore, both Q and Vp were found to be statistically significantly associated with age. A power function was used to describe the negative association between these parameters and age (i.e., both parameters decrease with increasing age). The final backbone pharmacokinetic model for the combined data set of Examples 1, 3, and 5 was a two-compartment model with an exponential error model, separate additive and constant coefficients for the variable RV model for each study, fixed non-proportional exponents for the clearance and volume parameters (as described above) (with additive shifts in the CL and Vc exponents for neonates), the effect of age on Q and Vp described by a power function (both decreasing with increasing age), and IIV estimated for CL, Q, Vc, and Vp using covariate parameters for IIV related to CL and Vp, and IIV related to Q and Vc. The final backbone pharmacokinetic model and standard errors are shown in Table 50.

[0154] Table 50. Parameter estimates and standard errors from the dexmedetomidine basic structure model JPEG0007818561000064.jpg105106Abbreviations: CL, elimination clearance; IIV, interindividual variability; NA, not applicable; NEO, neonatal continuous variate; %CV, coefficient of variation expressed as a percentage; %SEM, standard error of the mean expressed as a percentage; Q, intercompartmental clearance; RV, residual variability; Vc, volume of the central compartment; Vp, volume of the peripheral compartment; WTKG, body weight in kg.

[0155]

number

[0156] e Residual variability estimates are expressed as variance. The %CVs corresponding to the RVs in Example 1 range from 51%CV at 14.97 ng / L (half the lower assay limit) to 44%CV at 200 ng / L. f Residual variability estimates are expressed as variance. The %CVs corresponding to the RVs in Example 5 range from 112%CV at 2.12 ng / L (half the lower assay limit) to 19%CV at 700 ng / L. gResidual variability estimates are expressed as variance. The %CVs corresponding to the RVs in Example 3 range from 75%CV at 15.12 ng / L (half the lower limit of the assay) to 26%CV at 3000 ng / L.

[0157] With the exception of the parameter for the proportional shift of the non-proportional exponential part of neonatal Vc (%SEM of 56.7%), all other fixed and random effects model parameters were estimated with reasonable precision (most %SEM < 40%). Goodness-of-fit plots for the basic structural model of the pooled data sets of Examples 1, 3, and 5 are shown in Figures 19A-B. Diagnostic plots indicate a good fit to the pooled data and no substantial bias. The following covariates were examined for CL and Vc: sex, ethnicity, cardiopulmonary bypass use, albumin infusion (present), and sampling site (arterial vs. venous vs. capillary). The following covariates were examined for CL only: alanine aminotransferase, total bilirubin, glucuronidation pathway inhibitors (present), and cardiac physiology (univentricular vs. biventricular). The effect of ethnicity was modeled as Caucasian vs. Hispanic vs. all "other" racial groups (Asian, Black) (combined due to small sample size). Linear and power models were used in NONMEM to test each continuous covariate. Categorical covariates were tested using additive shift. Delta-parameter plots were generated to illustrate possible associations between the remaining unknown IIV and covariates of interest on CL or Vc. No clear trends were observed indicating likely parameter-covariate associations. Furthermore, the lack of trends in the plots for age and weight suggests that these factors were adequately taken into account in the basic structural model, which included non-proportional weight associations and the additive effects of maturation. Although the effects of several covariates (total bilirubin, albumin infusion, and alanine aminotransferase on CL) were statistically significant (P value < 0.05 based on the reduction in MVOF after their inclusion in the model), none of these covariate effects was associated with a ≥ 5% reduction in IIV of CL.

[0158] As a result of the univariate forward selection results, no additional covariates were added to the base model. Therefore, a backward elimination step was not performed; this base model was then evaluated for further refinement and simplification. The base structural model after forward selection was then examined for possible simplifications in an effort to identify the most appropriate and parsimonious model that adequately characterized these data. Removal of the non-proportional exponential shift to neonatal Vc resulted in a statistically insignificant increase in MVOF of 1.991 (P-value > 0.05) and was therefore removed from the model. A further simplification of the RV model from Example 1 to a constant coefficient for the variable error model was also performed; this simplification was also performed because it was accompanied by a statistically insignificant increase in MVOF of 1.331 (P-value > 0.05). Goodness-of-fit diagnostic plots were examined for model misfit. Several alternative methods for handling BLQ samples were also evaluated, including Beals M3 and excluding BLQ samples after the first in the series; however, these attempts were only minimally successful or did not result in model improvement. Further evaluation of the model, including all outliers, resulted in unsuccessful minimization; therefore, observations identified as outliers during model development were permanently excluded. Simulation-based predictive correction VPC was performed, simulating the analysis dataset 1,000 times using the final pharmacokinetic model. This VPC method was utilized to improve the ability to diagnose possible model misspecification by removing variability due to a wide range of doses and subject age / weight. Therefore, for the purposes of predictive correction, distinct bins were defined based on time since end of infusion, dexmedetomidine treatment group, and age. Figure 20 shows the 90% prediction intervals derived from 1000 simulated data points overlaid on the observed dexmedetomidine concentrations versus time since the end of the maintenance infusion. Concentrations measured before the end of the maintenance infusion are plotted as negative values ​​relative to the time since the end of the maintenance infusion. The majority of the observed data fall within the prediction interval. The percentage of observed concentrations below the 5th percentile was 6.3%, and the percentage of observed concentrations above the 95th percentile was 4.7%. VPC demonstrates no obvious bias in the overall model fit by comparing the simulated data (based on the model) to the raw data. Figure 21 shows a comparison of the 5th, 50th, and 95th percentiles of the observed predicted-corrected data with the model-based simulated data. This plot also confirms the high degree of reliability between the simulation-based data and the observed data, with the 50th percentiles of the observed and simulated data tracking very closely over the entire time range. For VPC purposes, simulated concentrations were treated in the same manner as observed concentrations, thereby setting values ​​below the assay limit of the study to one-half the appropriate limit. The final population pharmacokinetic model was a two-compartment model with an exponential error model, fixed non-proportional exponents for the clearance (0.75 for CL and Q) and volume of distribution (1.0 for Vc and Vp) parameters (with additive shifts in the CL and Vc exponents for neonates), age effects on Q and Vp described by power functions (both decreasing with increasing age), covariance terms for IIVs related to CL and Vp and to Q and Vc, separate additive plus constant coefficients for the variability error models of Studies Example 3 and Example 5, and IIVs estimated for CL, Q, Vc, and Vp using constant coefficients for the variability error model of Study Example 1. The final population pharmacokinetic model parameter estimates for dexmedetomidine are provided in Table 51.

[0159] Table 51. Parameter estimates and standard errors from the final population pharmacokinetic model of dexmedetomidine JPEG0007818561000066.jpg108119Abbreviations: CL, elimination clearance; IIV, interindividual variability; NA, not applicable; NEO, neonatal continuous variate; %CV, coefficient of variation expressed as a percentage; %SEM, standard error of the mean expressed as a percentage; Q, intercompartmental clearance; RV, residual variability; Vc, volume of the central compartment; Vp, volume of the peripheral compartment; WTKG, body weight in kg.

[0160]

number

[0161] e Residual variability estimates are expressed as variance. The %CV corresponding to the RV in Example 1 is 46%CV. f Residual variability estimates are expressed as variance. The %CVs corresponding to the RVs in Example 5 range from 111%CV at 2.12 ng / L (half the lower assay limit) to 19%CV at 700 ng / L. g Residual variability estimates are expressed as variance. The %CVs corresponding to the RVs in Example 3 range from 75%CV at 15.12 ng / L (half the lower limit of the assay) to 26%CV at 3000 ng / L.

[0162] All fixed-effect parameters were estimated with good precision (%SEM < 20%), with parameters related to Q being slightly less precise (%SEM of approximately 40%). Random effects were also estimated with good precision (many %SEM < 25%, excluding the IIV for Q, where %SEM = 37%). Inter-individual variability for CL, Vc, and Vp was moderate, ranging from 35%CV to 55%CV. The unknown IIV for Q was very high at 163%CV. Overall, RVs were lowest for the data in Example 5 (approximately 19%CV) and slightly higher for the data in Example 3 (26%CV). In both studies, the variability in the lower part of the RV model was found to be significant and adequately explained the data in Example 1, with a relatively high estimated 46%CV, regardless of concentration level. Equations showing the relationship between typical dexmedetomidine parameter values ​​and the factors of interest included in the model are provided in Equation 1, Equation 2, Equation 3, and Equation 4.

[0163]

number

[0164] During the ceremony: CL j is the typical value predicted by the model for dexmedetomidine clearance for the jth subject, Vc j is the typical value predicted by the model for the central intercompartmental dexmedetomidine volume for the jth subject, Q j is the typical value predicted by the model for the dexmedetomidine intercompartmental clearance of the jth subject, Vp j is the typical value predicted by the model for the dexmedetomidine volume in the peripheral compartment of the jth subject, age j is the age of the jth subject in the year, WTKG j is the weight of the jth subject in kg, and NEO j is a continuous variable that takes the value 1 for newborn subjects and 0 otherwise. Goodness-of-fit plots for this model are provided for the entire population in Figures 22A-22D. At the overall dataset level, these diagnostic plots demonstrate a reasonably unbiased fit of the model to the dataset, with slightly underpredicted samples collected 10 hours or later after the end of the infusion. This is evident in the grouping of points associated with positive weighted residuals after 10 hours in the plot of weighted residuals versus time since the end of the infusion. Furthermore, these plots provide support for the model selected for the RV based on the lack of trends or patterns in the plots of individual weighted residuals versus individual predicted concentrations. To further demonstrate the validity of the model across the treatment and age range of subjects, additional goodness-of-fit plots stratified by treatment and age group were generated. Although some treatment and age groups have very small sample sizes, these plots did not demonstrate any substantial persistent trends of misfit or bias across the range of dose or age levels. Empirical Bayes shrinkage calculations of the distributions of the estimates suggest that there is no concern about excessive shrinkage for any of the pharmacokinetic parameters, as the estimates all show low shrinkage (i.e., 3.5% for CL, 13.7% for Vc, 13.7% for Q, and 12.6% for Vp). Pairwise scatter plots of these terms are given in Figure 25. These plots demonstrate the modeled correlations between CL and the IIV of Vp and between Q and the IIV of Vc, as well as virtually no correlation between the other pairs of terms.

[0165] The final basic structure pharmacokinetic model of dexmedetomidine using the combined data from the three studies was a two-compartment model with fixed non-proportional exponents for clearance and volume parameters, additive shifts for the CL and Vc exponents for neonates, and age effects on Q and Vp. The non-proportional weight adjustment, using fixed coefficients of 0.75 for CL and 1 for the volume term, is based on a well-described scientific framework that can relate to underlying physiology and is frequently used in pediatric pharmacokinetic analyses. Because the non-proportional coefficients were fixed, age-based maturation could be accounted for through size effects. When data from the study in Example 1 were included in the analysis, shifts for CL and Vc were included in the neonatal group to correct for maturation in only the youngest subjects. Additionally, age effects (decreasing with age) on Q and Vp were included in the model for all subjects. This is consistent with known age-dependent changes in the proportions of body water and fat that affect drug distribution. Overall, this covariate approach avoided problems with collinearity between size and age by first fixing size as a fixed non-proportional exponent and then using age to delineate maturation, as previously suggested in the literature. Additional covariate effects were tested for dexmedetomidine CL and Vc based on clinical interest and physiological plausibility, but no effects met the prespecified criteria for inclusion in the model. In a previously developed two-compartment population pharmacokinetic model of infants (1-24 months of age) after open cardiac surgery, significant covariate effects included total bypass time on CL and Vc and ventricular physiology (mono- or bi-ventricular) on CL, in addition to the fixed nonproportional effects of body weight on CL, Q, Vc, and Vp. Several factors may contribute to the differences in findings between these two analyses. While Su et al. used a full-model approach for covariate selection, the present analysis utilized stepwise hypothesis testing with fairly strict criteria requiring the achievement of both statistical significance and a 5% reduction in IIV (see Anesth Analg. 2010;110(5):1383-1392). The data available for covariate assessment were also comparable to those of Su et al. Unlike Su et al., who determined that total bypass time was an important covariate as a continuous variable, the current analysis was limited to assessing CPB use as a dichotomous variable, including presence or absence.

[0166] Because no significant additional covariates were found, the final pharmacokinetic model was structurally similar to the basic model, except for two model improvements: the removal of the non-proportional exponential component to Vc in neonates and the simplification of the RV model for the Example 1 study to a constant coefficient variable error model. The extent of RV was relatively high in the Example 1 study data (46% CV) compared with the Example 3 data (26% CV) and the Example 5 data (19% CV). Different levels of enzyme maturation in the subjects of the Example 1 study are factors that may contribute to increased variability. Furthermore, the Example 1 study collected a relatively large amount of data after a low dexmedetomidine dose, resulting in an increased frequency of plasma concentrations in the low range of the assay, which tends to be more variable. Overall, all fixed effect parameters were accurately estimated except for that related to Q (%SEM approximately 40%). Compared to the initial model based on data from Studies Example 3 and Example 5 only (Q = 35.9 L / h, IIV of Q = 117% CV), the estimate of Q was significantly higher (70.5 L / h) and the unknown IIV of Q was also very high (163% CV). This finding may be related to the sparse nature of the additional data from Example 1; as a result, plasma sampling for dexmedetomidine concentrations was less informative for the two-compartment model parameters in neonates. The final pharmacokinetic model for dexmedetomidine was a two-compartment model, as previously described in other pediatric clinical trials. Given the slight remaining bias toward underprediction of concentrations obtained at later sampling times after the end of the maintenance infusion seen in the goodness-of-fit plots ( Figures 22A-D ), a three-compartment model was also evaluated using the concentration data from Studies Example 3 and Example 5. However, the three-compartment model fit was essentially identical to the two-compartment model and did not correct for the underprediction bias ( Figure 18 ). Because the sparse data from neonates would be even less informative at later sampling times, a three-compartment model was not attempted with the addition of the study data from Example 1.

[0167] Comparison of fixed-effect parameters with median total bypass time (57 minutes) from the two-compartment model published by Su et al. (based on only 35 subjects from the study in Example 5, ranging in age from 1 to 24 months) for 7.7 months of age and 7 kg body weight with the corresponding data from the final pharmacokinetic model developed here (based on 115 subjects, ranging in age from less than 1 week to 17 years) revealed fairly similar estimates, except for Q. The CL, Vc, Q, and Vp values ​​for the model by [End Page 110] were 7.26 L / h, 8.4 L, 24.1 L / h, and 10.2 L, compared with 8.5 L / h, 6.22 L, 68.21 L / h, and 13.21 L in the current analysis. The estimated initial distribution (α) and terminal elimination (β) half-lives in the current analysis were 3.2 minutes and 1.6 hours, respectively, in pediatric subjects with a median age and weight of 1.56 years and 10.35 kg, and 7.5 minutes and 1.8 hours in subjects aged 17 years and 70 kg. These results are generally similar to the range of initial distribution half-life (4.08 min to 9 min) and terminal elimination half-life (1.6 h to 2.65 h) previously reported for dexmedetomidine given as a 5- or 10-minute infusion of 1 μg / kg or as a 0.2 μg / kg / hour to 0.7 μg / kg / hour infusion (Diaz et al., Pediatr Crit Care Med. 2007;8:419-424; Petroz et al., Anesthesiology. 2006;105:1098-1110; and Vilo et al., Br J Anaesthesia. 2008;100:697-700). It is also of interest to compare the CL and volume of distribution (Vc + Vp) across the age ranges of the six pediatric age groups represented in the three dexmedetomidine studies that contributed to the pharmacokinetic model (28 weeks to <1 month, 1 month to <6 months, 6 months to <12 months, 12 months to <24 months, 2 years <6 years, and 6 years to <17 years). Figures 23 and 24 (top panels) provide the geometric means and 95% confidence intervals of the individual Bayesian estimates of dexmedetomidine CL and volume of distribution plotted at the midpoint of each age group, and the corresponding weight-adjusted estimates of the pharmacokinetic parameters are also depicted in the bottom panels (Figure 23 (continued) and Figure 24 (continued)). A line representing the population-based typical value versus age for each parameter is superimposed on each plot. Tables 52 and 53 provide age-specific summary statistics for the individual Bayesian parameter estimates and model-predicted typical value estimates for dexmedetomidine CL, weight-adjusted CL, volume of distribution, and weight-adjusted volume of distribution, respectively.

[0168] Table 52. Summary statistics of individual Bayesian estimates and model-predicted typical values ​​of dexmedetomidine clearance and weight-adjusted clearance CL by age JPEG0007818561000069.jpg102102

[0169] Table 53. Summary statistics of individual Bayesian estimates and model-predicted typical values ​​of dexmedetomidine volume of distribution and weight-adjusted volume of distribution by age JPEG0007818561000070.jpg102106

[0170] In Figure 23 (top panel), it is clear that the steep slope of the profile shown at the youngest level is due to additional maturational covariate effects on the CL index for newborns, and that the increase in CL with increasing age beyond 1 year is shallower. The weight-adjusted CL shown in the bottom panel of Figure 23 (Figure 23 (continued)) also increases between the two youngest age groups but continues to decrease across the remaining groups. The overall slope of the profile shown for volume of distribution in the top panel of Figure 24 indicates the net effect of increasing Vc and Vp with increasing weight and decreasing Vp with increasing age. Similarly, the apparent decrease in weight-adjusted volume of distribution with increasing age in the youngest age group (Figure 24 (continued), bottom panel) is likely due to the negative effect of age on Vp (a power function), while Vc remains constant with increasing age. For comparison with typical pharmacokinetic parameter values ​​obtained from a previously developed adult population pharmacokinetic model of dexmedetomidine, this pediatric pharmacokinetic model can be further used to extrapolate pediatric pharmacokinetic parameter values ​​to those expected for a normal adult age and weight. Based on a hypothetical pediatric subject at the upper end of the age and weight range (i.e., 17 years and 70 kg), the CL and volume of distribution of dexmedetomidine are predicted to be 47.8 L / hr and 114.6 L, compared to the corresponding values ​​of 39 L / hr (the mean weight associated with this CL was 72 kg) and 118 L reported in the Precedex product label. Similarly, a typical subject from an adult population pharmacokinetic analysis of chronic (>24 hours) dexmedetomidine use had a dexmedetomidine CL and volume of distribution of 35.8 L / h and 112.7 L, respectively, and a noncompartmental analysis of this data yielded values ​​of 39.4 L / h and 152 L, respectively. These extrapolated results based on a 70 kg subject are also consistent with estimates of CL and volume of distribution normalized to a 70 kg adult of 42.1 L / h and 125.3 L from a population pharmacokinetic analysis of pooled data from four studies of dexmedetomidine in pediatric intensive care (infusions of 1 μg / kg / h to 6 μg / kg / h given to subjects aged 1 week to 14 years). Overall, this model provides a robust characterization of dexmedetomidine pharmacokinetics in children. Model evaluation provides evidence that the model is highly predictive over the full range of dexmedetomidine concentrations occurring not only during maintenance infusion but also after discontinuation. Furthermore, this population model is based on the largest population of pediatric subjects reported to date and the widest range of ages (neonates to 17 years), maintenance doses, and infusion durations.

[0171] The conclusions of this analysis are as follows: A linear two-compartment model was found to best characterize the integrated dexmedetomidine concentration data collected from pediatric subjects enrolled in three studies after receiving a series of dexmedetomidine doses administered as a short intravenous infusion followed by a maintenance infusion of variable duration. A fixed non-proportional function was used to account for the effect of body weight on all pharmacokinetic parameters in this pediatric population. An additional non-proportional exponential part in dexmedetomidine clearance was adjusted for neonatal subjects. For dexmedetomidine, inter-compartmental clearance and the volume of the peripheral compartment, both described by age, were found to be related to maturation according to a power-law function (both decrease with increasing age). Ethnicity, sex, alanine aminotransferase, total bilirubin, cardiac physiology (univentricular vs. biventricular), concomitant use of glucuronidation pathway inhibitors, albumin infusion, use of cardiopulmonary bypass, and the effect of sampling site were not identified as statistically significant predictors of dexmedetomidine pharmacokinetic variability. Clearance estimates from this model increase with increasing age, and weight-adjusted clearance estimates decrease with increasing age, approaching values ​​expected in adults. Distribution volume estimates from this model increase with increasing age, and weight-adjusted distribution volumes decrease with increasing age, approaching values ​​expected in adults. Model evaluation supports the robustness of the model, as it predicts well across the entire concentration range.

[0172] Example 7: Pharmacokinetics of dexmedetomidine in pediatric patients aged 12 to 24 months A five-subject, randomized, open-label, single-center study of dexmedetomidine was conducted in subjects aged 12 to <24 months. The study population consisted of initially intubated, mechanically ventilated pediatric subjects who required sedation within an intensive care setting for a minimum of 6 hours but less than 24 hours. Subjects were randomized to one of two dose levels: dose level 1 consisted of a 0.7 μg / kg loading dose followed immediately by a 0.5 μg / kg / hour maintenance infusion; dose level 2 consisted of a 1 μg / kg loading dose followed immediately by a 0.75 μg / kg / hour maintenance infusion. All five subjects were randomized at a single site in the United States. Two subjects were randomized to dose level 1 and three subjects to dose level 2. All five subjects enrolled in the trial received dexmedetomidine and completed treatment. No subjects discontinued the study prematurely. Dose levels are outlined in Table 54 below.

[0173] TIFF0007818561000071.tif21104

[0174] Dexmedetomidine was administered as a continuous fixed maintenance infusion of dexmedetomidine immediately followed by a 10-minute loading dose of dexmedetomidine at both dose levels, with the duration of the infusion ranging from a minimum of 6 hours to 24 hours (combined loading dose + maintenance dose) after surgery. Dexmedetomidine was administered at the insertion site of the IV catheter to avoid drug flushing. No other drugs were administered through the IV line designated for dexmedetomidine. a . The dexmedetomidine administered was Precedex® (dexmedetomidine hydrochloride injection, 100 μg / mL, base). The dexmedetomidine solution was diluted to 4 μg / mL with 0.9% sodium chloride or 5% dextrose in water. The dexmedetomidine solution should not be refrigerated. After dexmedetomidine administration was initiated, subjects could be extubated at any time. Dexmedetomidine was infused using a controlled infusion device. Manually controlled microdrippers, macrodrippers, or other non-automated infusion devices were not permitted. Dexmedetomidine could not be given as a bolus. To ensure accurate infusion, dexmedetomidine was not administered directly into the pulmonary artery. Sedation levels were assessed using the University of Michigan Sedation Scale. Pain was assessed using the Face, Legs, Activity, Crying, and Mood (FLACC) scale. After completion of screening procedures, dexmedetomidine infusions were initiated after discontinuation of all other sedatives and after the subject achieved a UMSS of ≤ 4. The subject's most recently measured body weight (considered the baseline weight) was used to calculate sedative doses. Subjects who remained intubated or were reintubated during the post-infusion period or required sedation for other reasons during the post-infusion period were treated with the study site's standard of care. However, this did not include dexmedetomidine until all post-infusion pharmacokinetic samples were obtained. If applicable, open-label dexmedetomidine could be resumed 24 hours after study drug discontinuation. For subjects to be considered evaluable, they must have received at least 5 hours of continuous dexmedetomidine infusion. The dexmedetomidine infusion could not extend beyond 24 hours. Once dexmedetomidine was discontinued (dexmedetomidine withdrawal was not permitted), post-infusion procedures were initiated and continued for 24 hours. The dexmedetomidine infusion rate could not be adjusted during the dexmedetomidine administration period. The overall study design is provided in Table 55 below.

[0175] Table 55. Research overview JPEG0007818561000072.jpg67112

[0176] The UMSS was used to assess the adequacy of sedation throughout the study, with a target level of sedation of 2 to 4. A baseline score was obtained using the UMSS before the start of the dexmedetomidine infusion. UMSS scores were measured according to the following schedule: immediately before the loading dose, then 5 and 10 minutes during the loading dose; at the start of the maintenance infusion and 5, 10, 30, and 60 minutes during the first hour; then every 4 hours during the remainder of the maintenance infusion; and within 5 minutes of each pharmacokinetic sample. If the subject was not at the desired target level of sedation (i.e., UMSS < 2), a rescue medication could be administered for sedation. The rescue medication was midazolam. Repeated rescue doses of midazolam (0.05-0.1 mg / kg) could be given at a recommended frequency of every 2-3 minutes per dose or at a frequency based on the investigator's discretion until the subject reached the desired level of sedation. Along with the administered dose of rescue midazolam, the UMSS was obtained within 5 minutes before and 5 minutes after the administration of rescue midazolam. Pain was assessed using the FLACC scale. Rescue opiate analgesia consisting of IV fentanyl was administered based on the investigator's judgment or when the FLACC score was >4. Fentanyl was administered as an intermittent bolus or as a continuous IV infusion. When fentanyl was given as a bolus, FLACC scores were recorded within 5 minutes before and 5 minutes after the fentanyl bolus, along with the dose of rescue fentanyl administered. When fentanyl was given as a continuous infusion, FLACC scores were obtained every 4 hours, along with scheduled vital signs. Pain assessments were collected within 5 minutes before and 5 minutes after each infusion dose adjustment. The recommended dosage for fentanyl administration was a 1-4 μg / kg / dose IV bolus and a 1-3 μg / kg / hour continuous IV infusion every 2-4 hours as needed. After discontinuation of dexmedetomidine, further sedative and analgesic medications were allowed to be administered according to standard of care, but dexmedetomidine could not be restarted until after completion of the 24-hour post-dexmedetomidine observation period.

[0177] Midazolam or fentanyl was used when severe anxiety / agitation or pain was anticipated (e.g., before painful procedures such as suctioning or chest tube removal). The date, time, and type of any painful procedure (e.g., suctioning or chest tube removal) were recorded. In addition, the date and time of any non-pharmacological measures (e.g., swaddling, holding, and rocking) were noted, and UMSS and / or FLACC scores were recorded within 5 minutes before and 5 minutes after the procedure. At any time clinically indicated (e.g., subject discomfort despite maximum rescue dose) or at the investigator's discretion, substitution to alternative sedative or analgesic regimens not permitted within this protocol was possible. This did not occur in this study. For pharmacokinetic analysis, 13 1-mL venous blood samples (approximately 2.5 tsp) were collected in heparinized vacuum tubes via a peripheral, central, or peripherally-to-central catheter line at the following time points: less than 30 minutes before the start of the loading dose; within 5 minutes before the end of the loading dose; 30 minutes, 1, 2, and 4 to 6 hours after the start of the maintenance infusion; within 30 minutes before the end of the maintenance infusion (which must be within 24 hours of the start of the maintenance infusion); 10 minutes after the end of the maintenance infusion; and 30 minutes, 1, 2, 4, and 10 hours after the end of the maintenance infusion. For pharmacokinetic analysis, venous blood samples (1 mL) were collected into heparinized tubes at the site opposite the infusion site (e.g., left arm vs. right arm). Samples were not drawn from the second lumen of the multilumen catheter (through which dexmedetomidine was administered). Pharmacodynamic measurements were performed within 5 minutes before the scheduled blood draw and included sedation scores from the UMSS, pain scores from the FLACC, rescue medication (midazolam or fentanyl) use, and vital signs: HR, SBP, DBP, mean arterial pressure, respiratory rate, and oxygen saturation by pulse oximetry. An adverse event was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it is considered to be drug-related. Thus, an adverse event could be any untoward and unintended sign (e.g., abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not the event is considered to be causally related to the use of the product. The events could result from the use of the drug as specified in the protocol or labeling, any use of the drug (e.g., off-label, in combination with another drug) and any route of administration, formulation, or dose, as well as accidental or intentional overdose, drug abuse, or withdrawal. Any worsening of a pre-existing condition or disease was considered an adverse event. Clinically significant abnormalities should have progressed to resolution (i.e., stabilized, returned to normal, returned to baseline, or become explainable). Laboratory abnormalities and changes in vital signs were considered adverse events only if they led to study discontinuation, required therapeutic intervention, met protocol-specific criteria, and / or were deemed to be adverse events by the investigator.

[0178] Elective surgery / procedures scheduled to occur during the study were not considered adverse events, even if the surgery / procedure was performed for a pre-existing condition and the surgery / procedure was planned before study entry. However, if a pre-existing condition unexpectedly worsened during the study (i.e., surgery was performed earlier than planned), the worsening of the condition for which the elective surgery / procedure was being performed was considered an adverse event. Common postoperative sequelae specifically related to surgery were not reported as adverse events. The following sequelae at the surgical wound site were considered common surgery-related events and were not reported as adverse events: bleeding, bruising, itching, redness, swelling, numbness, tingling, burning, pain, infection, and wound opening. Subjects were followed for the occurrence of adverse events in the period immediately following discontinuation of dexmedetomidine and up to 7 days after initiation of dexmedetomidine or at discharge (whichever occurred first). Particular attention was paid to adverse events including, but not limited to, rebound tachycardia or hypertension, withdrawal symptoms, agitation / agitation, and pulmonary complications (i.e., acute respiratory distress syndrome). The occurrence of preterm infant comorbidities, such as intraventricular hemorrhage, necrotizing enterocolitis, sepsis, and persistent ductus arteriosus, was also assessed. No serious adverse events occurred during this study. All subject-induced or spontaneously reported non-serious adverse events occurring from the start of dexmedetomidine treatment through 7 days after initiation of dexmedetomidine were collected. In addition, serious adverse events were collected from the time the subject's legal representative signed the study-specific informed consent form through 7 days after initiation of dexmedetomidine treatment. Laboratory evaluations were performed at three time points: pre-dose; 4-6 hours after the start of the maintenance infusion; and 10 minutes after the end of the maintenance infusion. All blood samples were collected in appropriately labeled tubes and sent for analysis. Whenever possible, laboratory blood samples were collected at the same time as one of the scheduled pharmacokinetic samples to avoid redundant blood collection. Clinical tests performed are given in Table 56 below.

[0179] Table 56. Laboratory tests JPEG0007818561000073.jpg77103

[0180] Core body temperature (i.e., tympanic, rectal, or via an indwelling device) was monitored. Abnormal body temperatures were to be recorded as adverse events according to the investigator's clinical judgment. Subjects with temperature fluctuations below 35.6°C (96°F) or above 38.6°C (101.5°F) were evaluated for the presence of adverse events. Physical examinations were performed during the screening period and as close to 24 hours after discontinuation of the dexmedetomidine infusion as possible or on the day of discharge, whichever occurred first, to establish baseline values ​​for evaluation. All input and output fluid volumes were recorded during the dexmedetomidine infusion period. Electrocardiograms were obtained at the following times: predose; 4-6 hours after the start of the maintenance infusion; and 10 hours after the end of the maintenance infusion. Clinically significant abnormalities were grounds for excluding subjects from study entry. All subjects underwent continuous cardiac monitoring throughout the dexmedetomidine infusion period. The investigator or physician recorded ECG interpretation as normal, clinically insignificant abnormality, or clinically significant abnormality. Pharmacokinetic assessments of clearance, exposure, distribution, and elimination were appropriate for this study. Pharmacodynamic assessments utilizing the UMSS (sedation) and FLACC (pain) have been proven valid and reliable. Safety measures used in this study were considered standard and appropriate. The primary assessment was the assessment of dexmedetomidine pharmacokinetics. Data from all fully evaluable subjects (i.e., subjects who received at least a 5-hour dexmedetomidine infusion) were included in the analysis. Pharmacodynamic measurements were performed within 5 minutes before the scheduled blood draw. Standard pharmacokinetic parameters were estimated by non-compartmental and / or population pharmacokinetic methods. Calculated dexmedetomidine parameters included: area under the concentration-time curve; maximum observed plasma concentration; steady-state concentration; plasma clearance; terminal elimination rate constant; observed time to maximum plasma concentration (in hours); terminal elimination half-life; volume of distribution; and steady-state volume of distribution. Additional parameters may be determined as appropriate, including pharmacokinetic parameters adjusted for body weight and / or dose (e.g., body weight-adjusted plasma clearance [CLw]). Pharmacodynamic variables included: UMSS sedation score; FLACC pain score; rescue medication (midazolam or fentanyl) use; and vital signs, i.e., SBP, DBP, MAP, HR, RR, SpO2.

[0181] Analysis of safety variables was based on the incidence of adverse events, clinical laboratory tests, clinical / change from baseline in vital signs, ECG, and input / output fluid balance. The following variables were also evaluated: use of a rescue plan to support vital signs, use of concomitant medications, and incidence of withdrawal signs (changes in blood pressure or HR) after discontinuation of dexmedetomidine infusion. Statistical analyses were performed using SAS, version 9.1. For continuous variables, N, mean, median, standard deviation (SD), minimum, Q1, Q3, and maximum are presented. Mean and median values ​​are shown to one decimal place rather than the raw value. SD is shown to two decimal places rather than the raw value. For categorical variables, N and percentages are presented. All percentages are reported to one decimal place. Pharmacokinetic parameters were summarized for each dose group and, where pharmacokinetically appropriate, across all dose groups using descriptive statistics (N, mean, SD, median, min, Q1, Q3, max, and CV [%]). Standard pharmacokinetic parameters were estimated by noncompartmental and / or population pharmacokinetic methods. Parameters were normalized based on the administered dose, where appropriate. The following pharmacodynamic variables were evaluated: percentage of subjects who required rescue medication for sedation during dexmedetomidine infusion; incidence of rescue medication use for analgesia during dexmedetomidine infusion; (a) total and (b) weight-adjusted total amount (per kg) of rescue medication midazolam or fentanyl given for sedation or analgesia during dexmedetomidine infusion; time to first dose of rescue medication for sedation and analgesia was summarized using Kaplan-Meier estimates; absolute time and percentage of time for dexmedetomidine infusion that subjects had a UMSS of 2 to 4 and a UMSS < 2 were summarized by descriptive statistics for each dose level; descriptive statistics for FLACC scores were summarized using all FLACC scores for subjects during the study; and time to successful extubation of subjects was summarized using Kaplan-Meier estimates. Time on dexmedetomidine was summarized descriptively for each dose level, and the number and percentage of subjects exposed to dexmedetomidine during the treatment period were also summarized by exposure time for the following time periods (<6 hours, <12 hours, <24 hours) and by dose level for the following time periods (>0 to <6 hours, ≥6 to <12 hours, ≥12 to <24 hours, and ≥24 hours). Loading doses were summarized using the parameters total dose and duration of administration. Maintenance doses were summarized for each dose level and age group for total dose infused (μg / kg), mean dose (μg / kg / hour), and duration of administration. Total dose infused was equal to the infusion rate (μg / kg / hour) × duration of infusion (hours). Total dose of dexmedetomidine infused (μg / kg), total dose (μg), and length of infusion (hours) were summarized descriptively by dose level. Prior and concomitant medications were summarized according to the WHO Drug Dictionary. The number and percentage of subjects using prior medications (preferred terms) were tabulated for each dose level. The number and percentage of subjects using concomitant medications were also tabulated. Only treatment-emergent adverse events were analyzed. The number and percentage of subjects with treatment-emergent adverse events were calculated using the Medical Dictionary for Regulatory Affairs. Adverse events were summarized for each dose level by MedDRA System Organ Class (SOC) and preferred term. Adverse event severity categories and categories of the adverse event's relationship to dexmedetomidine were similarly summarized. For each subject with multiple adverse events, only the most severe category and closest relationship to dexmedetomidine were counted once. In addition, separate tables were prepared for treatment-emergent serious adverse events, treatment-emergent adverse events leading to discontinuation, treatment-emergent adverse events associated with dexmedetomidine, and treatment-emergent adverse events by severity. For summaries by severity, if a subject had multiple events within the same SOC or preferred term, the event with the highest severity was summarized. Any adverse events lacking severity were summarized as serious. The relationship to dexmedetomidine was summarized as related (including definitely related, almost certainly related, and probably related) or not related (including almost certainly not related and not related).

[0182] All laboratory values ​​outside the normal range were flagged in the data listing, and clinically significant abnormal laboratory values ​​were recorded. The number and percentage of subjects with clinically significant abnormal laboratory values ​​at baseline, during the dexmedetomidine infusion, and during the post-dexmedetomidine period were summarized for each age group overall and by dose level. Descriptive statistics of laboratory tests and changes from baseline were summarized. The mean, minimum, and maximum post-baseline vital signs of HR, SBP, DBP, MAP, RR, and SpO2 measured during the dexmedetomidine infusion and 24-hour follow-up were determined for each subject. Absolute values ​​and changes from baseline were summarized descriptively by dose level for mean, minimum, and maximum values, respectively. The incidence of abnormal ECG findings during baseline, dexmedetomidine infusion, and post-dexmedetomidine periods was tabulated by dose level. The total input (mL) and total output (mL) measured during and after dexmedetomidine infusion were calculated for each subject and summarized descriptively by dose level. Two subjects received sedatives or analgesics during the dexmedetomidine infusion, which was a protocol violation. These were two dose level 2 subjects, one of whom received morphine and sufentanil for pain, and the other who received propofol for tracheostomy tube placement. These deviations were not considered to affect the safety of the subjects. The most common medical history in all five subjects was cardiovascular and respiratory disease. Four of the five subjects had gastrointestinal disease. All subjects were postoperative. All five subjects received prior medications before entering the study and concomitant medications during the study. The most common prior or concomitant medication categories were classified as blood and blood-forming organs (especially IV fluids and blood products) or nervous system medications. All subjects received at least one dexmedetomidine infusion post-medication; the most common medications were nervous system medications. The mean plasma pharmacokinetic parameters of dexmedetomidine after the loading dose and maintenance dose are provided in Table 57 below.

[0183] Table 57. Mean plasma pharmacokinetic parameters JPEG0007818561000074.jpg90107

[0184] T max The T was generally 0.08 hours before the end of the loading dose and was fairly consistent across all subjects and both dose levels. One exception (subject 01-0007, dose level 2) was a T of 0.68 hours after the start of the maintenance infusion. max had. C max Exposure to dexmedetomidine, measured as C or AUC, was highly variable but appeared to be dose-related. max increased from 4500 pg / mL at dose level 1 to 11737 pg / mL at dose level 2, but dose adjustment C max The dose-adjusted AUC(0-infinity) remained fairly constant. Similarly, the AUC(0-infinity) increased from 4639 (pg / mL) h at dose level 1 to 14204 (pg / mL) h at dose level 2, but the dose-adjusted AUC(0-infinity) remained fairly constant. This high variability in exposure was primarily due to one outlier (subject 01-0003, dose level 1). Also, because dose levels 1 and 2 included two and three subjects, respectively, the pharmacokinetic data should be interpreted with caution, especially when outliers are possible. The dexmedetomidine half-life was approximately 2 hours in all subjects and was dose-independent. With the exception of one outlier (subject 01-0003, dose level 1), CL and CL w Both were fairly consistent across both dose levels. Clearance was approximately 5.7 L / hr (2.5-8.2 L / hr), and the weight-adjusted CL was approximately 0.6 L / hr / kg (0.2-0.9 L / hr / kg). d was also fairly consistent across both dose levels. Again, with the exception of one outlier (subject 01-0003, dose level 1), V d The volume is approximately 16.2L (13.4-19.9L) and is adjusted for weight. d was approximately 1.6 L / kg (0.99-2.23 L / kg). The mean total amount of midazolam received was 0.50 mg (0.06 mg / kg) for subject 01-0003 (dose level 1) and 3.70 mg (0.42 mg / kg) for subject 01-0001 (dose level 2) who required rescue midazolam. The mean total amount of rescue fentanyl received was 60 μg (6.62 μg / kg) for one subject (subject 01-0003) at dose level 1 and 49.56 μg (5.50 μg / kg) for two subjects (subjects 01-0001 and 01-0004) at dose level 2. The mean total amount of midazolam received was 0.50 mg (0.06 mg / kg) for subject 01-0003 (dose level 1) and 3.70 mg (0.42 mg / kg) for subject 01-0001 (dose level 2) who required rescue midazolam. The mean total amount of rescue fentanyl received was 60 μg (6.62 μg / kg) for one subject (subject 01-0003) at dose level 1 and 49.56 μg (5.50 μg / kg) for two subjects (subjects 01-0001 and 01-0004) at dose level 2.

[0185] At dose level 1, subject 01-0003 required rescue midazolam and fentanyl. This subject required multiple IV boluses of fentanyl for pain beginning 1.43 hours after the start of the dexmedetomidine infusion. This subject also required one dose of rescue midazolam 5.27 hours after the start of the dexmedetomidine infusion for agitation / procedure-related pain. Relevant ongoing medical history included hypoplastic left heart syndrome, postoperative (cardiac catheterization, left pulmonary artery stenosis with balloon dilation, and aortopulmonary artery collateral requiring coil embolizati...

Claims

1. 1. A pharmaceutical composition for sedation in a pediatric patient, comprising: the pharmaceutical composition comprises dexmedetomidine; The pharmaceutical composition is used in a method for sedating a pediatric patient in need of sedation, the method comprises administering dexmedetomidine to the pediatric patient; administering the dexmedetomidine at a concentration of about 0.05 to about 0.25 μg / kg / hour; the pediatric patient is about 17 years of age or younger; The pediatric patient's gestational age is between 36 weeks and 44 weeks; and 10. A pharmaceutical composition, wherein the dexmedetomidine is administered as a continuous infusion for a period of less than about 36 hours.

2. 10. The pharmaceutical composition of claim 1, wherein the pediatric patient is a premature newborn.

3. 10. The pharmaceutical composition of claim 1, wherein the pediatric patient is intubated before, during, or after administration of dexmedetomidine.

4. 10. The pharmaceutical composition of claim 1, wherein the dexmedetomidine is administered parenterally.

5. 10. The pharmaceutical composition of claim 1, wherein the dexmedetomidine is administered by intravenous infusion.

6. 10. The pharmaceutical composition of claim 1, wherein the dexmedetomidine is administered before surgery.

7. 10. The pharmaceutical composition of claim 1, wherein the dexmedetomidine is administered after surgery.

8. 8. The pharmaceutical composition of claim 7, wherein the dexmedetomidine is administered after cardiopulmonary bypass surgery.

9. 10. The pharmaceutical composition of claim 1, wherein administration of dexmedetomidine reduces the need for rescue medication.

10. 10. The pharmaceutical composition of claim 9, wherein the rescue drug is a sedative.

11. 10. The pharmaceutical composition of claim 9, wherein the rescue drug is an analgesic.

12. 7. The pharmaceutical composition of claim 6, wherein the pediatric patient has an age selected from the group consisting of about 12 to about 17 years old and about 2 years old or younger.

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