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

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: 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

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Manchester, United Kingdom
    • Medeval Ltd

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketorolac Tromethamine	Drug: Ketorolac Tromethamine; 30 mg Ketorolac Tromethamine intranasal (IN)
Experimental: Ketorolac Tromethamine with 4% Lidocaine hydrochloride (HCl)	Drug: Ketorolac Tromethamine with 4% Lidocaine hydrochloride (HCl); 30 mg Ketorolac Tromethamine with 4% Lidocaine HCl IN
Experimental: Ketorolac Tromethamine with 5% Lidocaine HCl	Drug: Ketorolac Tromethamine with 5% Lidocaine HCl; 30 mg Ketorolac Tromethamine with 5% Lidocaine HCl IN
Experimental: Ketorolac Tromethamine with 6% Lidocaine HCl	Drug: 30 mg Ketorolac Tromethamine with 6% Lidocaine HCl; 30 mg Ketorolac Tromethamine with 6% Lidocaine HCl IN

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Egalet Ltd

Study record dates

Study Major Dates

• Study Start: August 1, 2005
• Primary Completion (Actual): September 1, 2005
• Study Completion (Actual): March 1, 2006

Study Registration Dates

• First Submitted: May 16, 2011
• First Submitted That Met QC Criteria: May 17, 2011
• First Posted (Estimate): May 18, 2011

Study Record Updates

• Last Update Posted (Actual): March 16, 2017
• Last Update Submitted That Met QC Criteria: February 7, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anesthetics; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Membrane Transport Modulators; Anesthetics, Local; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Lidocaine; Ketorolac; Ketorolac Tromethamine
• Other Study ID Numbers: ROX 2005-02