BACKGROUND: The nonsteroidal anti-inflammatory drug (NSAID) ketorolac tromethamine shows higher plasma concentrations and a longer plasma half-life in adults ≥65 years of age than in subjects aged <65 years, after intramuscular administration. An intranasal formulation of ketorolac tromethamine is approved for short-term treatment of moderate to moderately severe pain requiring analgesia at the opioid level. OBJECTIVE: The objective of this study was to compare the pharmacokinetics of a single intranasal dose of ketorolac tromethamine 31.5 mg (15.75 mg per nostril) in adults aged ≥65 and <65 years. METHODS: Healthy adults with body mass indices of 15-30 kg/m(2) were eligible for the study. Following intranasal ketorolac tromethamine dosing, blood samples (approximately 7 mL per sample) for pharmacokinetic assessment were obtained at 15, 30 and 45 min and 1, 1.5, 2, 4, 6, 8, 12, 15 and 24 h after dosing. Plasma ketorolac concentration versus time data were analysed to determine maximum (peak) ketorolac concentration (C(max)) and time to reach C(max) (t(max)) and estimate pharmacokinetic parameters. RESULTS: Thirty healthy subjects were enrolled in and completed the study. For analysis, data were stratified by participant age into two groups, consisting of younger adult subjects (<65 years of age) and older adult subjects (≥65 years of age). Mean (±SD) age was 44 ± 10 and 72 ± 6 years in the younger and older groups, respectively. Mean (±SD) plasma ketorolac C(max) was 10 % higher (2,028.8 ± 1,069.5 and 1,840.1 ± 995.9 ng/mL) and mean (±SD) terminal elimination half-life (t(½β)) was 37 % longer (4.52 ± 1.14 and 3.31 ± 0.96 h) in the ≥65-years age group than in the <65-years group, respectively. Mean (±SD) plasma ketorolac area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) was 28 % higher in older subjects than in younger subjects (8,794.8 ± 4,129.4 and 6,890.8 ± 3,448.5 ng · h/mL, respectively). Differences were not statistically significant, but did not demonstrate formal equivalence. Mean (±SD) residence time was 36 % higher in the ≥65-years age group than in the <65-years group (6.02 ± 1.50 and 4.44 ± 1.06 h, respectively) (p = 0.003). There were no serious adverse events during the study. Two mild events of headache and eyelid infection occurred. There were no clinically relevant changes or an apparent difference between age groups in laboratory or physical assessments. CONCLUSION: The increased systemic exposure to ketorolac following intranasal administration in adults ≥65 years of age warrants reduction of the intranasal ketorolac tromethamine dose, and halving the dose to 15.75 mg (one spray to one nostril) in this patient population is recommended based on similar dosing adjustments made for intramuscular ketorolac tromethamine.
BACKGROUND: The nonsteroidal anti-inflammatory drug (NSAID) ketorolac tromethamine shows higher plasma concentrations and a longer plasma half-life in adults ≥65 years of age than in subjects aged <65 years, after intramuscular administration. An intranasal formulation of ketorolac tromethamine is approved for short-term treatment of moderate to moderately severe pain requiring analgesia at the opioid level. OBJECTIVE: The objective of this study was to compare the pharmacokinetics of a single intranasal dose of ketorolac tromethamine 31.5 mg (15.75 mg per nostril) in adults aged ≥65 and <65 years. METHODS: Healthy adults with body mass indices of 15-30 kg/m(2) were eligible for the study. Following intranasal ketorolac tromethamine dosing, blood samples (approximately 7 mL per sample) for pharmacokinetic assessment were obtained at 15, 30 and 45 min and 1, 1.5, 2, 4, 6, 8, 12, 15 and 24 h after dosing. Plasma ketorolac concentration versus time data were analysed to determine maximum (peak) ketorolac concentration (C(max)) and time to reach C(max) (t(max)) and estimate pharmacokinetic parameters. RESULTS: Thirty healthy subjects were enrolled in and completed the study. For analysis, data were stratified by participant age into two groups, consisting of younger adult subjects (<65 years of age) and older adult subjects (≥65 years of age). Mean (±SD) age was 44 ± 10 and 72 ± 6 years in the younger and older groups, respectively. Mean (±SD) plasma ketorolac C(max) was 10 % higher (2,028.8 ± 1,069.5 and 1,840.1 ± 995.9 ng/mL) and mean (±SD) terminal elimination half-life (t(½β)) was 37 % longer (4.52 ± 1.14 and 3.31 ± 0.96 h) in the ≥65-years age group than in the <65-years group, respectively. Mean (±SD) plasma ketorolac area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) was 28 % higher in older subjects than in younger subjects (8,794.8 ± 4,129.4 and 6,890.8 ± 3,448.5 ng · h/mL, respectively). Differences were not statistically significant, but did not demonstrate formal equivalence. Mean (±SD) residence time was 36 % higher in the ≥65-years age group than in the <65-years group (6.02 ± 1.50 and 4.44 ± 1.06 h, respectively) (p = 0.003). There were no serious adverse events during the study. Two mild events of headache and eyelid infection occurred. There were no clinically relevant changes or an apparent difference between age groups in laboratory or physical assessments. CONCLUSION: The increased systemic exposure to ketorolac following intranasal administration in adults ≥65 years of age warrants reduction of the intranasal ketorolac tromethamine dose, and halving the dose to 15.75 mg (one spray to one nostril) in this patient population is recommended based on similar dosing adjustments made for intramuscular ketorolac tromethamine.