Dose-Escalation Safety and Pharmacokinetic Study of K305

Study Overview
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Brief Summary
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The purpose of this study is to determine the pharmacokinetics/pharmacodynamics and safety of a nasal spray containing the anesthetic drug tetracaine in combination with oxymetazoline

Detailed Description
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The purpose of this study was to determine the safety and pharmacokinetics of the standard dose of intranasal Kovacaine Mist of 0.6 mL (18 mg tetracaine HCl with 0.3 mg oxymetazoline HCl) and a proposed maximum recommended dental dose of 1.2 mL (36 mg tetracaine HCl with 0.6 mg oxymetazoline HCl). The primary objectives were to determine if either dose significantly changed blood pressure readings (systolic and diastolic), pulse rate, or oxygen saturation levels from baseline pretreatment values and to determine the safety profile of both doses. The secondary objectives were to establish the pharmacokinetics of oxymetazoline, tetracaine, and its major metabolite (parabutylaminobenzoic acid) following the intranasal administration of both doses. Each subject received the standard dose (3 sprays in each nostril with 4 minutes between each pair of sprays) followed 1 to 3 weeks later by the high dose (as 6 sprays in each nostril).

Official Title
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Cardiovascular Changes and Tetracaine Pharmacokinetics Following Intranasal Administration of Standard and High Doses of Kovacaine Mist (Tetracaine Hydrochloride With Oxymetazoline Hydrochloride) in Healthy Volunteers

Conditions
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Anesthesia

Intervention / Treatment
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* Drug: Tetracaine HCl 3% and Oxymetazoline HCl 0.05%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female between 18 and 65 years of age BMI between19 and 29 kg/m2 Sufficiently healthy as determined by the investigator to receive the test medications and undergo the scheduled study procedure Can breathe through both nostrils Females of child-bearing potential must have a negative urine pregnancy test and must have been using adequate means of birth control for at least one month prior to study entry and during the study Screening BP ≤ 140/90 Screening SpO2 ≥ 96 Can understand and sign the informed consent document Can communicate with the investigator Can understand and comply with the requirements of the protocol. Exclusion Criteria: A clinically relevant history or presence of respiratory, thyroid, gastrointestinal, renal, hepatic, hematological, lymphatic, cardiovascular, psychiatric, neurologic, musculoskeletal, genitourinary, infective, inflammatory, immunological, dermatological, or connective tissue disease or disorder or a clinically relevant history or presence of narrow angle glaucoma and in men benign prostatic hypertrophy, Hashimotos Thyroiditis, lymphocytic thyroiditis, or uncontrolled diabetes Clinically significant abnormalities in laboratory values Clinically relevant sinus/nasal surgical history Current condition, such as nasal congestion or sinus infection, that may influence responses to study medication History of recurrent nose bleeds History of pseudocholinesterase deficiency or previous prolonged paralysis with succinylcholine or difficulty waking up from general anesthesia Allergic to or intolerant of tetracaine, benzocaine, other ester local anesthetics, or para-aminobenzoic acid (as found in PABA-containing sunscreens) Allergic to or intolerant of oxymetazoline or preservatives found in these solutions History of alcoholism and/or drug abuse Have taken a monamine oxidase inhibitor, or vasopressor drug within the past 3 weeks Have received or taken local anesthetics within 72 hours of the first or second treatment visits Are nursing, pregnant, suspected of being pregnant, or trying to become pregnant (Females will be required to take a urine pregnancy test at each study visit to rule out pregnancy) Have used any investigational drug and/or participated in any clinical trial within 30 days of baseline

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Kovacaine Nasal Spray<br>Tetracaine HCl 3% and Oxymetazoline HCl 0.05%: 6 sprays of 0.1 mL - total of 18 mg tetracaine HCl and 0.3 mg oxymetazoline HCl followed by 12 sprays of 0.1 mL - total of 36 mg tetracaine HCl and 0.6 mg oxymetazoline HCl | Drug: Tetracaine HCl 3% and Oxymetazoline HCl 0.05%<br>* Tetracaine HCl 3% and Oxymetazoline HCl 0.05%<br>* Other names: Kovacaine Nasal Spray;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of Oxymetazoline | Extra-vascular, non-compartmental analysis is used to derive pharmacokinetic parameters; estimated from observed plasma concentration values, the dose administered, the AUCs, and the terminal elimination phase rate constant for each dose group | Baseline, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120 minutes | 
| Cmax of Tetracaine | Extra-vascular, non-compartmental analysis is used to derive pharmacokinetic parameters; estimated from observed plasma concentration values, the dose administered, the AUCs, and the terminal elimination phase rate constant for each dose group | Baseline, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120 minutes | 
| Cmax of PBBA | Extra-vascular, non-compartmental analysis is used to derive pharmacokinetic parameters; estimated from observed plasma concentration values, the dose administered, the AUCs, and the terminal elimination phase rate constant for each dose group | Baseline, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120 minutes | 
| Half Life of Oxymetazoline | Extra-vascular, non-compartmental analysis is used to derive pharmacokinetic parameters; estimated from observed plasma concentration values, the dose administered, the AUCs, and the terminal elimination phase rate constant for each dose group | Baseline, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120 minutes | 
| Half Life of Tetracaine | Extra-vascular, non-compartmental analysis is used to derive pharmacokinetic parameters; estimated from observed plasma concentration values, the dose administered, the AUCs, and the terminal elimination phase rate constant for each dose group | Baseline, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120 minutes | 
| Half Life of PBBA | Extra-vascular, non-compartmental analysis is used to derive pharmacokinetic parameters; estimated from observed plasma concentration values, the dose administered, the AUCs, and the terminal elimination phase rate constant for each dose group | Baseline, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulse Oximetry Maximum Change From Baseline |  | Baseline, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120 minutes | 
| Diastolic BP Maximum Change From Baseline |  | Baseline, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120 minutes | 
| Systolic BP Maximum Change From Baseline |  | Baseline, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120 minutes | 
| Pulse Rate Maximum Change From Baseline |  | Baseline, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120 minutes |