Tolerability, Safety and Pharmacokinetics of Four Formulations of Ketorolac Tromethamine in Healthy Volunteers

Study Overview
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Brief Summary
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This was a phase 1, double-blind, 4-way crossover study in healthy male and female volunteers. Subjects received 4 formulations of intranasal ketorolac tromethamine 30 mg. There was a wash-out period of 3-7 days between each dose. On Day 1 of each period subjects were randomised to receive either a single intranasal dose of 30 mg ketorolac tromethamine alone or single intranasal dose of 30 mg ketorolac tromethamine with 4%, 5% or 6% lidocaine hydrochloride. At the end of the study each subject had received all 4 treatments. The primary objective of this study in healthy volunteers was to compare the safety, tolerability, and pharmacokinetics of 4 formulations of ketorolac tromethamine. A secondary objective was to monitor lidocaine hydrochloride plasma levels.

Official Title
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A Phase 1, Double-blind, 4-way Crossover Study of the Tolerability, Safety and Pharmacokinetics of 4 Formulations of Ketorolac Tromethamine by Intranasal Administration in Healthy Volunteers

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Ketorolac Tromethamine
* Drug: Ketorolac Tromethamine with 4% Lidocaine hydrochloride (HCl)
* Drug: Ketorolac Tromethamine with 5% Lidocaine HCl
* Drug: 30 mg Ketorolac Tromethamine with 6% Lidocaine HCl


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female volunteers, aged 18 to 60 years inclusive Female subjects of child bearing potential must have had a negative urine pregnancy test prior to entry into the study and must not have been breast feeding All female subjects of child bearing potential and all male subjects with female partners of child bearing potential must have consented to use a medically acceptable method of contraception (oral or implanted contraceptive hormones, condom or diaphragm with spermicidal agent, intrauterine device or surgical sterilisation) throughout the study period Subject had given signed informed consent Subject was within 20% of normal weight for his/her height and body build according to the table of Desirable Weights for Men and Women (Metropolitan Life Insurance Co. 1999) Subject's medical history was considered normal, with no clinically significant abnormalities Subject was considered to be in good health in the opinion of the Investigator as determined by a pre-study physical examination with no clinically significant abnormalities, vital signs within normal range and an ECG with no clinically significant abnormalities Subject's pre-study clinical laboratory findings were within normal range or, if outside of the normal range, not deemed clinically significant in the opinion of the Investigator Subject had bilateral patent nasal airways at screening as assessed by the Investigator Body weight was at least 70 kg Exclusion Criteria: Subject had a clinically significant illness in the 4 weeks before screening Use of prescribed medications in the 3 weeks prior to dosing or over-the-counter preparations for 7 days prior to dosing, except paracetamol which was allowed up to 48 hours prior to dosing. However, use of multivitamins and oral contraceptives were permitted Subject had a significant history of drug/solvent abuse, or a positive drugs of abuse test at screening Subject had history of alcohol abuse or drank in excess of 28 units per week (males) or 21 units per week (females) Current tobacco use or a history of smoking within the past 5 years Subject was, in the opinion of the Investigator, not suitable to participate in the study Subjects who had participated in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing Subjects who had a positive result of HIV screen, Hepatitis B screen or Hepatitis C screen Subjects with a serious adverse reaction or significant hypersensitivity to any drug Subjects who has donated 500 mL or more of blood within the 3 months prior to screening Any history of co-existing nasal polyps, NSAID sensitivity and asthma Allergic reaction to aspirin or other NSAIDs Current upper respiratory tract infection or other respiratory tract condition that could have interfered with the absorption of the nasal spray or with the assessment of AEs Any suspicion of rhinitis medicamentosa (chronic daily use of topical decongestants) Use of a monoamine oxidase inhibitor in the 14 days prior to study entry Active peptic ulcer disease, gastrointestinal bleeding or perforation, or a history of peptic ulcer disease or gastrointestinal bleeding Anemia due to unexplained or known gastrointestinal bleeding History of asthma or any other chronic pulmonary disorder Renal impairment or a risk of renal failure due to volume depletion Known sensitivity to lidocaine hydrochloride

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketorolac Tromethamine<br> | Drug: Ketorolac Tromethamine<br>* 30 mg Ketorolac Tromethamine intranasal (IN)<br>|
| Experimental: Ketorolac Tromethamine with 4% Lidocaine hydrochloride (HCl)<br> | Drug: Ketorolac Tromethamine with 4% Lidocaine hydrochloride (HCl)<br>* 30 mg Ketorolac Tromethamine with 4% Lidocaine HCl IN<br>|
| Experimental: Ketorolac Tromethamine with 5% Lidocaine HCl<br> | Drug: Ketorolac Tromethamine with 5% Lidocaine HCl<br>* 30 mg Ketorolac Tromethamine with 5% Lidocaine HCl IN<br>|
| Experimental: Ketorolac Tromethamine with 6% Lidocaine HCl<br> | Drug: 30 mg Ketorolac Tromethamine with 6% Lidocaine HCl<br>* 30 mg Ketorolac Tromethamine with 6% Lidocaine HCl IN<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) |  | Anytime at pre-dose, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours (ketorolac tromethamine only), and 24 hours (ketorolac tromethamine only) post-dose | 
| Area Under the Plasma Concentration-time Profile From Time Zero to the Last Quantifiable Post-dose (AUC 0-t) |  | Anytime at pre-dose, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours (ketorolac tromethamine only), and 24 hours (ketorolac tromethamine only) post-dose | 
| Area Under the Plasma Concentration-time Profile From Time Zero to Infinity (AUC 0-∞) |  | Anytime at pre-dose, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours (ketorolac tromethamine only), and 24 hours (ketorolac tromethamine only) post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Reach Maximum Plasma Concentration (Tmax) |  | Anytime at pre-dose, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 15 hours (ketorolac tromethamine only), and 24 hours (ketorolac tromethamine only) post-dose |