Study to Determine the Tolerability, Safety and Pharmacokinetics of Ketorolac Tromethamine by Intranasal Administration in Healthy Volunteers

Conditions

Healthy Volunteers

Brief summary

This was a phase 1, open label, multiple dose study in healthy male and female volunteers. Subjects received intranasal ketorolac tromethamine (30 mg) three times daily (t.i.d.) for three days (seven doses in total). Doses were administered every eight hours. The objective of this study in healthy volunteers was to determine the safety, tolerability, and pharmacokinetics of multiple doses of intranasal ketorolac tromethamine.

Related papers

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Interventions

DRUGKetorolac tromethamine

Subjects received intranasal ketorolac tromethamine (30 mg) three times daily (t.i.d.) for three days (seven doses in total). Doses were administered every eight hours.

Study design

Allocation

NA

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 60 Years

Healthy volunteers

Yes

Inclusion criteria

* Male or female volunteers, aged 18 to 60 years inclusive * Female subjects of child bearing potential were to have 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 using 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 ranges 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 of at least 60 kg

Exclusion criteria

* Subject had a clinically significant illness in the four weeks prior to screening * Use of prescribed medications in the three weeks prior to dosing or over-the-counter preparations for seven days prior to dosing, except paracetamol which was allowed up to 48 hours prior to dosing. 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 * Subjects with a history of alcohol abuse or those currently drinking more than 28 units per week (males) or 21 units per week (females) * Current tobacco use or a history of smoking within the past five 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 three 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 who had a serious adverse reaction or significant hypersensitivity to any drug * Subjects having donated 500 mL or more of blood within the three 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 may have interfered with the absorption of the nasal spray or with the assessment of adverse events (AEs) * Any suspicion of rhinitis medicamentosa (chronic daily use of topical decongestants) * Use of a monoamine oxidase inhibitor (MAOI) 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

Design outcomes

Primary

Measure	Time frame	Description
Cmax (the Maximum Observed Plasma Concentration)	Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 1 (morning doses)	PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.
Tmax (the Time to Maximum Concentration)	Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 1 (morning doses)	PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.
AUC 0-8h (the Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose)	Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 1 (morning doses)	PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.
Cmax,ss (the Maximum Observed Plasma Concentration at Steady State)	Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 3 (morning doses)	PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.
Tmax,ss (the Time to Maximum Concentration at Steady State)	Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 3 (morning doses)	PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.
Cmin,ss (the Minimum Observed Plasma Concentration at Steady State)	Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 3 (morning doses)	PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.
Tmin,ss (the Time to Minimum Concentration at Steady State)	Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 3 (morning doses)	PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.
AUCτ (the Area Under the Plasma Concentration-time Curve Over the Dosing Interval at Steady-state)	Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 3 (morning doses)	PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.
MRT (the Mean Residence Time	Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 3 (morning doses)	PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.

Countries

United Kingdom

Participant flow

Recruitment details

January 9, 2006 - February 27, 2006; Clinical Unit

Pre-assignment details

After subjects had given their informed consent, subjects were required to pass a screening visit within 3 weeks prior to study drug administration.

Participants by arm

Arm	Count
Ketorolac Tromethamine Ketorolac tromethamine : Subjects received intranasal ketorolac tromethamine (30 mg) three times daily (t.i.d.) for three days (seven doses in total). Doses were administered every eight hours.	15
Total	15

Baseline characteristics

Characteristic	Ketorolac Tromethamine
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	0 Participants
Age, Categorical Between 18 and 65 years	15 Participants
Age, Continuous	31.7 years STANDARD_DEVIATION 10.4
Region of Enrollment United Kingdom	15 participants
Sex: Female, Male Female	5 Participants
Sex: Female, Male Male	10 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	14 / 15
serious Total, serious adverse events	0 / 15

Outcome results

Primary

AUC 0-8h (the Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose)

PK analysis by standard model independent methods was performed by a pharmacokineticist using WinNonlin Professional. Actual blood sampling times were converted to a time from dosing (elapsed time). Elapsed times were listed by subject for each treatment, together with the individual plasma concentrations of ketorolac.

Time frame: Blood samples for determination of plasma concentration of ketorolac were taken immediately prior to each dose and every hour for 8 hours post-dose on Day 1 (morning doses)