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Pharmacokinetics and Safety of Ketorolac Following Single Intranasal and Intramuscular Administration in Healthy Volunteers

From Medeval Limited, a Division of ICON plc, Skelton House, Manchester Science Park, Lloyd Street North, Manchester, United Kingdom.

Address for reprints: Oneeb Majid, ICON Development Solutions, Medeval Limited, Skelton House, Lloyd Street North, Manchester M15 6SH, UK.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Ketorolac was administered to 15 healthy volunteers in a phase 1, single-dose, crossover, randomized study. Subjects received open-label randomized 15- and 30-mg intramuscular (IM) ketorolac and blinded randomized 15- and 30- mg intranasal (IN) ketorolac. The IN ketorolac was well tolerated; the only nasal symptoms were some instances of mild irritation. The IN ketorolac was rapidly and well absorbed (median t_max, 0.50-0.75 hours), and the half-life was approximately 5 to 6 hours, values that were similar to those following IM administration. Relative bioavailability of IN compared to IM administration at the same doses was approximately 67% to 75%. Dose proportionality was noted between the 15- and 30-mg IN and IM dose levels. Thus, IN ketorolac offers a therapeutic alternative to IM administration and may provide benefits in the clinical setting.

Key Words: Ketorolac • intranasal • intramuscular • pharmacokinetics • volunteers

The nasal route of administration provides such an alternative to parenteral injections, and a formulation for ketorolac has been developed. The physiochemical properties of ketorolac, principally solubility, are such that it may be the only NSAID that can be delivered in an amount suitable for intranasal (IN) administration (100 µL) and still achieve therapeutic plasma concentrations.

In humans, ketorolac is well and rapidly absorbed following IM administration, with an absolute bioavailability of 100%^2,3 and peak concentrations occurring within 30 to 60 minutes of administration.^4,5 Ketorolac is highly protein bound (>99%),³ with a correspondingly small volume of distribution (0.1 L/kg).⁵ It is metabolized in the liver via glucuronidation and parahydroxylation, with most of the drug recovered in the urine as conjugates.^3,6 None of the metabolites have any significant analgesic activity. The terminal half-life ranges from 4 to 6 hours.^3-5 No genderrelated differences in pharmacokinetics have been reported.^2,4

We report here pharmacokinetic data from a study of healthy volunteers performed during the development of an IN formulation of racemic ketorolac tromethamine. The primary objectives of this study were to compare the safety, tolerability, and pharmacokinetics of IN compared to IM administration of ketorolac, at single doses of 15 mg and 30 mg. Although an additional IN dose of 45 mg was administered in this study, it is not included in the comparative data reported here because the same dose was not given by the IM route.

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Study Design
This was a phase 1, single-dose, 5-way crossover, randomized study conducted at Medeval Limited, Manchester, United Kingdom. The main part of the study consisted of 5 periods of identical design, differing only in the allocated treatment and examination of the nares. In periods 1 and 5, all subjects received, in random order, single, open-label, 15-mg and 30-mg IM injections of ketorolac. In periods 2, 3, and 4, subjects received at weekly intervals (range, 5-10 days), in random order, 3 single, blinded, 15-, 30-, and 45-mg IN doses of ketorolac. In all periods, serial blood samples were taken up to 24 hours postdose. Prior to and at periodic intervals following each IN treatment, or at any time a subject complained of intolerable local burning or itching, nasal irritation was assessed by an ear, nose, and throat surgeon.

All subjects gave their written informed consent prior to undertaking any study procedures. The protocols and consent forms were reviewed and approved prior to study commencement by the Medeval Independent Ethics Committee in Manchester. The study was performed in compliance with the guidelines of the Declaration of Helsinki and the Data Protection Act 1998 and in accordance with the International Conference on Harmonisation guidelines for good clinical practice: CPMP/ICH/135/95, January 1997.

Subject Population
Eligible subjects were healthy men and nonpregnant women between 18 and 60 years of age. All subjects had to be in good health as assessed by physical examination, medical history, 12-lead electrocardiogram, and clinical laboratory evaluations (hematology, biochemistry, urinalysis, drugs of abuse screen, alcohol breath test). Subjects had to be without any known allergy or sensitivity to ketorolac or formulation ingredients (ethylene diamine tetra-acetic acid [EDTA]), without an allergic reaction to aspirin or other NSAIDs, have no current upper respiratory tract infection or other respiratory tract condition that could interfere with the absorption of the nasal spray, be without a history of chronic rhinitis and/or rhinorrhea, and had refrained from using any systemic drug with analgesic (except acetaminophen), decongestant, antiinflammatory, or antihistaminic activity and had not used an IN product within 72 hours prior to study entry.

A total of 15 healthy volunteers participated (6 men, 9 women; 13 Caucasian, 1 Afro-Caribbean, and 1 Afro-Caucasian) who were 19 to 45 years of age and 49 to 92 kg in weight.

Ketorolac Dosing
Ketorolac nasal solutions were supplied by West Pharmaceutical Services (Albert Einstein Centre, Nottingham, UK) in Pfeiffer unit-dose nasal devices. Three strengths were supplied filled with 123 µL of ketorolac tromethamine solution (7.5%, 15%, and 22.5% w/w). Each solution also contained 0.02% EDTA and water for injection. Commercial supplies (Toradol; Roche Laboratories Ltd, Nutley, NJ) of ketorolac trometamol (tromethamine) ampoules (30 mg in 1.0 mL) were used for the IM doses.

In each period, subjects were admitted to the Clinical Unit the evening before dosing and remained resident until 24 hours postdose. Prior to the IN administration, all subjects blew their noses. IN doses were administered as 1 spray (100 µL) into each nostril with the subject in a normal, upright position. Subjects were instructed to refrain from nose blowing and, if possible, sneezing for 30 minutes after dosing. IM doses were injected deep in the upper outer quadrant of the buttocks. The IN doses were chosen based on a previous pilot study and were expected to yield pharmacokinetic parameters similar to those achieved with clinically relevant IM injections of 15 and 30 mg.

Pharmacokinetic Sampling
Blood samples (5.5 mL) were collected in each study period for the quantification of ketorolac in plasma, from a suitable arm vein via a cannula or by direct venipuncture predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, 15, and 24 hours postdose. For each sample taken via the cannula, there was a 1-mL discard, and cannulae were flushed with heparinized saline. The blood samples were drawn into Vacutainers containing sodium heparin. Plasma was obtained after centrifugation of the blood samples (3000 rpm for 10 minutes at room temperature) and transferred to appropriately labeled polypropylene tubes, which were stored at -20°C until analysis.

Assay Methodology
Plasma concentrations of ketorolac were determined using a validated high-performance liquid chromatography (HPLC) assay with ultraviolet detection at 312 nm. The lower limit of quantification (LLOQ) was 10.05 ng/mL. Appropriate volumes of standard solutions of internal standard (naproxen), methanol (210 µL), and 200 µL of 0.05 M ammonium acetate buffer (pH 3.7) were added to 1-mL plasma samples. Ten milliliters of hexane/ethyl acetate (70/30 v/v) was added, and samples were shaken for 10 minutes and centrifuged (3000 rpm for 10 minutes) before freezing at -80°C ± 10°C for 30 minutes. The organic layer was transferred into test tubes, blown down to dryness, and reconstituted in 50 µl of mobile phase. Samples were transferred to tapered vials and centrifuged (6000 rpm for 5 minutes) prior to injection onto the HPLC system. Samples (15 µl) were separated on a Hypersil Hypurity Advance C18 5 µ column maintained at 40°C, using a mobile phase of 0.4% acetic acid/acetonitrile (550/450 v/v)/1 mL triethylamine at a flow rate of 0.4 mL/min. Approximate retention times were 6.4 minutes for ketorolac and 3.5 minutes for internal standard.

Interassay precision ranged from 9.48% to 12.26%, and interassay bias ranged from 1.00% to 4.66%. At the LLOQ, the precision of the quality control standards was 8.38% and the bias was -0.305%. There were no significant interfering peaks at the retention times of ketorolac or internal standard in blank human plasma.

Pharmacokinetic Parameters and Analyses
Pharmacokinetic analysis by standard model independent methods, as implemented in WinNonlin Professional, was performed using actual blood sampling times. Parameters determined included maximum observed plasma concentration (C_max) and the corresponding time of the C_max (t_max), area under the curve from time 0 to the last quantifiable time point postdose (AUC_0-t), area under the curve from time 0 to infinity (AUC_0-), elimination rate constant (_z), apparent terminal half-life (t), and the mean residence time (MRT). C_max and t_max were identified by examination of the plasma profiles for each subject: the values were taken as the coordinates of the data point with the highest concentration. AUC_0-t was calculated using linear trapezoids from the time point preceding the first quantifiable concentration to the last observed quantifiable plasma time concentration (C_last). AUC_0- was obtained through summation of AUC_0-t and the extrapolated area, estimated by taking the ratio of C_last and _z. _z was determined by linear regression of the logarithm of plasma concentration on time over the terminal elimination phase. Start points of the terminal elimination phase were determined by examination of the profiles of the logarithmic plasma concentrations. A minimum of 3 data points were used. The of ketorolac was calculated as the ratio of the natural log of 2 with _z. MRT was calculated as the ratio of the area under the first moment curve (AUMC_0-) to that of AUC_0-.

Statistical Analyses
The statistical evaluation included all subjects who completed the study as per protocol. Prior to statistical analysis, method assumptions (homogeneity of variance) were checked. Dose-route comparisons for log-transformed AUC_0- were performed by analysis of variance (ANOVA) using PROC GLM in SAS with the factors subject, period, treatment, and first-order carryover in the model statement. First-order carryover was not statistically significant and was dropped from the model. As the study design was not based on a balanced Latin square, least squares means (LSmeans) could not be calculated, and dose-route comparisons were based on arithmetic means. Ninety percent confidence intervals (CIs) were obtained for treatment differences, and an adjustment for multiple comparisons was applied according to Tukey. The difference between the means and the associated 90% CIs were back transformed to give the point estimate and conventional CI. Dose-route comparisons for C_max (which did not show homogeneity of variance) and t_max were made between pairs of treatments using the Wilcoxon matched pairs signed rank test. Ninety percent CIs were obtained for the median differences based on the Hodges-Lehmann estimator.⁷

A dose-proportionality assessment for AUC_0- was carried out on the IN doses based on the superposition principle, with AUC_0- dose-normalized prior to analysis. Pharmacokinetic parameters were log transformed and analyzed by ANOVA, with subject, treatment, period, and first-order carryover in the model statement. First-order carryover was not found to be statistically significant, so it was removed from the model. LSmeans and associated 90% CIs were obtained for treatment differences, which were back transformed to give the point estimate and conventional CI.

An indication of dose proportionality was also assessed for the IM doses. AUC_0- was dose normalized prior to analysis. Pharmacokinetic parameters were log transformed and analyzed using ANOVA, with subject, treatment, period, and subject within sequence in the model statement. A sequence effect, which should have provided an indication of carryover, could not be estimated as the design was not balanced. It was also not possible to obtain LSmeans. The dose comparison was therefore based on the difference between the arithmetic means and the associated 90% CIs, which were back transformed to give the point estimate and conventional CI.

Dose proportionality for C_max for both the IN and the IM treatments were assessed using the nonparametric Wilcoxon matched pairs signed rank test. Ninety percent CIs were obtained for the median differences based on the Hodges-Lehmann estimator. t_max was analyzed in a similar manner.

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
All 15 subjects completed the study according to the protocol. Arithmetic mean (±SE) plasma linear concentration-time profiles are given in Figure 1 (15- and 30-mg IN and IM treatments). Pharmacokinetic parameters are summarized in Table I. Following single-dose IN administration, absorption of ketorolac started immediately, and median t_max ranged from 0.50 to 0.75 hours postdose, irrespective of dose. Mean values of MRT were approximately 6 to 7 hours. Following C_max, there was a steady decline in ketorolac concentrations, with an apparent terminal phase half-life of approximately 5 to 6 hours. Very similar profiles were observed for the IM doses. Relative bioavailability of IN compared to IM dosing was 75% and 67% at the 15- and 30-mg dose levels, respectively.

View larger version (12K): [in this window] [in a new window]   Figure 1. Mean ± SE plasma ketorolac concentrations following single administration of intranasal and intramuscular ketorolac 15 mg and 30 mg (n = 15).

Statistical comparisons of IN and IM administration show that neither of the 2 IN doses gave equivalent AUC_0- or C_max values to the IM doses (Tables II and III). AUC_0- values following 15- and 30-mg IN treatments were 75% and 63%, respectively, of the corresponding IM doses. The 90% CIs for all AUC_0- comparisons did not include 1, indicating nonequivalence. C_max values were lower following IN compared to the same dose IM, differences that were statistically significant. The t_max values did not in general show any statistically significant differences between dose routes.

Dose proportionality was established for AUC_0- between the 15-mg and 30-mg IM and IN doses, with the 90% CIs within the range of 0.8 to 1.25 (Table IV). For C_max, dose proportionality was also shown between 15- and 30-mg doses for both the IN and IM routes (Table V). The only difference in t_max was observed between the 15- and 30-mg IN doses (P = .0144).

View this table: [in this window] [in a new window]   Table IV Statistical Summary of Dose Proportionality for AUC0-: ANOVA Analysis

There were no adverse events of severe intensity, and the most common treatment-emergent adverse event reported following IN treatments during the study was nasal passage irritation. Most occurrences of nasal passage irritation were of short duration and mild in severity, and all resolved without any intervention. There were no incidences of edema or ulceration or any adverse events of gastrointestinal origin following IN administration. Following IM dosing, there was a lower incidence of adverse events compared to IN dosing, including 1 incidence of dyspepsia and 1 incidence of injection site pain.

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The aims of the study reported here were to compare the safety, tolerability, and pharmacokinetics of single 15- and 30-mg IN doses of ketorolac with those achieved with single 15- and 30-mg IM doses of ketorolac. We have shown that IN ketorolac was well tolerated, with only some mild, short-lasting adverse events of nasal irritation. There were no adverse events of gastrointestinal etiology following IN ketorolac. Further studies are ongoing to ascertain whether the IN route of administration decreases gastrointestinal events as compared with historical rates seen with other routes of administration. The incidence of adverse events was less following IM compared to IN administration, but 1 subject did complain of dyspepsia after IM dosing, which was considered to be possibly related to ketorolac. The increased incidence of adverse events with the IN treatment was mainly due to local nasal passage irritation. (Another unpublished trial has shown that 5 days of IN dosing showed mild, reversible nasal irritation, but no subjects withdrew because of these effects [data on file].) The subjects were able to administer the nasal spray appropriately, although within a few minutes of IN dosing, there were some incidences of sneezing and nasal drip.

The pharmacokinetic profiles were well characterized. Plasma ketorolac concentrations were quantifiable out to 24 hours postdose, and parameters of AUC_0- and t were well estimated. The data show that ketorolac was rapidly absorbed following IN administration, with median t_max values ranging from 0.50 to 0.75 hours postdose, similar to that observed following IM administration. The MRT and terminal half-life values were similar by both routes, with mean values of approximately 5 to 7 hours and 5 hours, respectively. These values are in good agreement with previously published data.^2,3,5 Systemic exposure to ketorolac was lower by the IN route compared to the same dose IM, with a relative bioavailability of approximately 67% to 75%. Thus, the IN dose of 30 mg produces a plasma level roughly equivalent to 20 mg IM, well within the optimal therapeutic window. It is known that the maximum efficacy of ketorolac lies between 15 and 30 mg IM, and higher doses are associated with increased adverse events. The 30-mg IN dose should be both efficacious and have a good adverse event profile in acute, moderate to severe pain settings when administered up to 4 times per day for 5 days, as is the case with the IM formulation.

Evidence from the literature indicates that the pharmacokinetics of ketorolac are linear within the reference range of therapeutic doses.³ The data from this study have indicated that this is true of both the IM and IN treatments at 15 and 30 mg.

This study has shown that ketorolac is rapidly and well absorbed via the IN route, with a slightly reduced bioavailability compared to the IM route. The IN administration was well tolerated. The time course of the exposure to ketorolac was similar to that following IM administration. IN administration, therefore, offers a therapeutic alternative to IM administration and may provide benefits in the clinical setting.

	ACKNOWLEDGEMENTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Financial disclosure: This study was conducted on behalf of ROXRO PHARMA, Menlo Park, California. The authors wish to thank all the clinical staff at Medeval Limited involved in the conduct of the study and Roger Whiting of ROXRO PHARMA and Lincoln Bynum of ICON Clinical Research for their comments on the article.

	REFERENCES

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

1. Yee JP, Koshiver JE, Allbon CA, Brown CR. Comparison of intramuscular ketorolac tromethamine and morphine sulfate for analgesia of pain after major surgery. Pharmacotherapy. 1986;6: 253-261.[Web of Science][Medline] [Order article via Infotrieve]

2. Brocks DR, Jamali F. Clinical pharmacokinetics of ketorolac tromethamine. Clin Pharmacokinet. 1992;23: 415-427.[Web of Science][Medline] [Order article via Infotrieve]

3. Mroszczak EJ, Lee FW, Combs D, et al. Ketorolac tromethamine absorption, distribution, metabolism, excretion, and pharmacokinetics in animals and humans. Drug Metab Dispos. 1987;15: 618-626.[Abstract]

4. Gillis JC, Brogden RN. Ketorolac: a reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use in pain management. Drugs. 1997;53: 139-188.[Web of Science][Medline] [Order article via Infotrieve]

5. Jung D, Mroszczak E, Bynum L. Pharmacokinetics of ketorolac tromethamine in humans after intravenous, intramuscular and oral administration. Eur J Clin Pharmacol. 1988;35: 423-425.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

6. electronic Medicines Compendium. Summary of product characteristics. Roche Products Limited. Available at: emc.medicines.org.uk

7. Hollander H, Wolfe DA. Nonparametric Statistical Methods. New York, NY: Wiley; 1973.
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