Chemical formula: C₁₅H₁₃NO₃ Molecular mass: 255.269 g/mol PubChem compound: 3826
Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits analgesic activity in animal models. The mechanism of action of ketorolac, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. The biological activity of ketorolac tromethamine is associated with the S-form. Ketorolac tromethamine possesses no sedative or anxiolytic properties.
The peak analgesic effect of ketorolac tromethamine occurs within 2 to 3 hours and is not statistically significantly different over the recommended dosage range of ketorolac tromethamine. The greatest difference between large and small doses of ketorolac tromethamine is in the duration of analgesia.
Ketorolac given systemically does not cause pupil constriction. Results from clinical studies indicate that ketorolac has no significant effect on intra-ocular pressure.
Ketorolac tromethamine is a racemic mixture of []S and [+]R-enantiomeric forms, with the S-form having analgesic activity.
The pharmacokinetics of ketorolac tromethamine, following IV, IM and oral doses of ketorolac tromethamine tablets, are compared in Table 1. In adults, the extent of bioavailability following administration of the oral and IM forms of ketorolac tromethamine was equal to that following an IV bolus.
In adults, following administration of single oral, IM or IV doses of ketorolac tromethamine in the recommended dosage ranges, the clearance of the racemate does not change. This implies that the pharmacokinetics of ketorolac tromethamine in adults, following single or multiple IM, IV or recommended oral doses of ketorolac tromethamine, are linear. At the higher recommended doses, there is a proportional increase in the concentrations of free and bound racemate.
Ketorolac tromethamine is 100% absorbed after oral administration (see Table 1). Oral administration of ketorolac tromethamine after a high-fat meal resulted in decreased peak and delayed time-to-peak concentrations of ketorolac tromethamine by about one hour. Antacids did not affect the extent of absorption.
The mean apparent volume (Vβ) of ketorolac tromethamine following complete distribution was approximately 13 liters. This parameter was determined from single-dose data. The ketorolac tromethamine racemate has been shown to be highly protein bound (99%). Nevertheless, plasma concentrations as high as 10 mcg/mL will only occupy approximately 5% of the albumin binding sites. Thus, the unbound fraction for each enantiomer will be constant over the therapeutic range. A decrease in serum albumin, however, will result in increased free drug concentrations.
Ketorolac tromethamine is excreted in human milk.
Ketorolac tromethamine is largely metabolized in the liver. The metabolic products are hydroxylated and conjugated forms of the parent drug. The products of metabolism, and some unchanged drug, are excreted in the urine.
The principal route of elimination of ketorolac and its metabolites is renal. About 92% of a given dose is found in the urine, approximately 40% as metabolites and 60% as unchanged ketorolac. Approximately 6% of a dose is excreted in the feces. A single-dose study with 10 mg ketorolac tromethamine (n = 9) demonstrated that the S-enantiomer is cleared approximately 2 times faster than the R-enantiomer and that the clearance was independent of the route of administration. This means that the ratio of S/R plasma concentrations decreases with time after each dose. There is little or no inversion of the R- to S- form in humans. The clearance of the racemate in normal subjects, elderly individuals and in hepatically and renally impaired patients is outlined in Table 2.
The half-life of the ketorolac tromethamine S-enantiomer was approximately 2.5 hours (SD ± 0.4) compared with 5 hours (SD ± 1.7) for the R-enantiomer. In other studies, the half-life for the racemate has been reported to lie within the range of 5 to 6 hours.
Ketorolac tromethamine administered as an IV bolus every 6 hours for 5 days to healthy subjects (n=13), showed no significant difference in Cmax on Day 1 and Day 5. Trough levels averaged 0.29 mcg/mL (SD ± 0.13) on Day 1 and 0.55 mcg/mL (SD ± 0.23) on Day 6. Steady-state was approached after the fourth dose.
Accumulation of ketorolac tromethamine has not been studied in special populations (geriatric, pediatric, renal failure or hepatic disease patients).
Based on single-dose data only, the half-life of the ketorolac tromethamine racemate increased from 5 to 7 hours in the elderly (65 to 78 years) compared with young healthy volunteers (24 to 35 years) (see Table 2). There was little difference in the Cmax for the two groups (elderly, 2.52 mcg/mL ± 0.77; young, 2.99 mcg/mL ± 1.03).
Limited information is available regarding the pharmacokinetics of dosing of ketorolac tromethamine in the pediatric population. Following a single intravenous bolus dose of 0.5 mg/kg in 10 children 4 to 8 years old, the half-life was 5.8 ± 1.6 hours, the average clearance was 0.042 ± 0.01 L/hr/kg, the volume of distribution during the terminal phase (Vβ) was 0.34 ± 0.12 L/kg and the volume of distribution at steady state (Vss) was 0.26 ± 0.08 L/kg. The volume of distribution and clearance of ketorolac in pediatric patients was higher than those observed in adult subjects (see Table 1). There are no pharmacokinetic data available for administration of ketorolac tromethamine by the IM route in pediatric patients.
Based on single-dose data only, the mean half-life of ketorolac tromethamine in renally impaired patients is between 6 and 19 hours and is dependent on the extent of the impairment. There is poor correlation between creatinine clearance and total ketorolac tromethamine clearance in the elderly and populations with renal impairment (r=0.5).
In patients with renal disease, the AUC∞ of each enantiomer increased by approximately 100% compared with healthy volunteers. The volume of distribution doubles for the S-enantiomer and increases by 1/5th for the R-enantiomer. The increase in volume of distribution of ketorolac tromethamine implies an increase in unbound fraction.
The AUC∞-ratio of the ketorolac tromethamine enantiomers in healthy subjects and patients remained similar, indicating there was no selective excretion of either enantiomer in patients compared to healthy subjects.
There was no significant difference in estimates of half-life, AUC∞ and Cmax in seven patients with liver disease compared to healthy volunteers (see Table 2).
Pharmacokinetic differences due to race have not been identified.
Table 1. Table of Approximate Average Pharmacokinetic Parameters (Mean ± SD) Following Oral, Intramuscular and Intravenous Doses of Ketorolac Tromethamine:
| Pharmacokinetic Parameters (units) | Oral* | Intramuscular† | Intravenous Bolus‡ | |||
| 10 mg | 15 mg | 30 mg | 60 mg | 15 mg | 30 mg | |
| Bioavailability (extent) | 100% | |||||
| Tmax§ (min) | 44 ± 34 | 33 ± 21¶ | 44 ± 29 | 33 ± 21¶ | 1.1 ± 0.7¶ | 2.9 ± 1.8 |
| Cmax#(mcg/mL) [single dose] | 0.87 ± 0.22 | 1.14 ± 0.32¶ | 2.42 ± 0.68 | 4.55 ± 1.27¶ | 2.47 ± 0.51¶ | 4.65 ± 0.96 |
| Cmax (mcg/mL) [steady state q.i.d.] | 1.05 ± 0.26¶ | 1.56 ± 0.44¶ | 3.11 ± 0.87¶ | N/AÞ | 3.09 ± 1.17¶ | 6.85 ± 2.61 |
| Cminß (mcg/mL) [steady state q.i.d.] | 0.29 ± 0.07¶ | 0.47 ± 0.13¶ | 0.93 ± 0.26¶ | N/A | 0.61 ± 0.21¶ | 1.04 ± 0.35 |
| Cavgà (mcg/mL) [steady state q.i.d.] | 0.59 ± 0.20¶ | 0.94 ± 0.29¶ | 1.88 ± 0.59¶ | N/A | 1.09 ± 0.30¶ | 2.17 ± 0.59 |
| Vßè (L/kg) | 0.175 ± 0.039 | 0.210 ± 0.044 | ||||
% Dose metabolized = <50
% Dose excreted in urine = 91
% Dose excreted in feces = 6
% Plasma protein binding = 99
* Derived from PO pharmacokinetic studies in 77 normal fasted volunteers
† Derived from IM pharmacokinetic studies in 54 normal volunteers
‡ Derived from IV pharmacokinetic studies in 24 normal volunteers
§ Time-to-peak plasma concentration
¶ Mean value was simulated from observed plasma concentration data and standard deviation was simulated from percent coefficient of variation for observed Cmax and Tmax data.
# Peak plasma concentration
Þ Not Applicable because 60 mg is only recommended as a single-dose
ß Trough plasma concentration
à Average plasma concentration
è Volume of Distribution
Table 2. The Influence of Age, Liver and Kidney Function on the Clearance and Terminal Half-life of Ketorolac Tromethamine (IM* and Oral†) in Adult Populations:
| Types of Subjects | Total Clearance [in L/h/kg]‡ | Terminal Half-Life [in hours] | ||
| IM Mean (range) | ORAL Mean (range) | IM Mean (range) | ORAL Mean (range) | |
| Normal Subjects IM (n = 54) mean age = 32, range = 18 to 60 Oral (n = 77) mean age = 32, range = 20 to 60 | 0.023 (0.010 to 0.046) | 0.025 (0.013 to 0.050) | 5.3 (3.5 to 9.2) | 5.3 (2.4 to 9) |
| Healthy Elderly Subjects IM (n = 13), Oral (n = 12) mean age = 72, range = 65 to 78 | 0.019 (0.013 to 0.034) | 0.024 (0.018 to 0.034) | 7 (4.7 to 8.6) | 6.1 (4.3 to 7.6) |
| Patients with Hepatic Dysfunction IM and Oral (n = 7) mean age = 51, range = 43 to 64 | 0.029 (0.013 to 0.066) | 0.033 (0.019 to 0.051) | 5.4 (2.2 to 6.9) | 4.5 (1.6 to 7.6) |
| Patients with Renal Impairment IM (n = 25), Oral (n = 9) serum creatinine = 1.9 to 5 mg/dL mean age (IM) = 54, range 35 to 71 mean age (oral) = 57, range = 39 to 70 | 0.015 (0.005 to 0.043) | 0.016 (0.007 to 0.052) | 10.3 (5.9 to 19.2) | 10.8 (3.4 to 18.9) |
| Renal Dialysis Patients IM and Oral (n = 9), mean age = 40, range = 27 to 63 | 0.016 (0.003 to 0.036) | ―― | 13.6 (8 to 39.1) | ―― |
* Estimated from 30 mg single IM doses of ketorolac tromethamine
† Estimated from 10 mg single oral doses of ketorolac tromethamine
‡ Liters/hour/kilogram
In normal adult subjects (n = 37), the total clearance of 30 mg IV administered ketorolac tromethamine was 0.030 (0.017 to 0.051) L/h/kg. The terminal half-life was 5.6 (4 to 7.9) hours.
IM: Following intramuscular administration, ketorolac trometamol was rapidly and completely absorbed, a mean peak plasma concentration of 2.2 mcg/ml occurring an average of 50 minutes after a single 30 mg dose. The influences of age, kidney and liver function on terminal plasma half-life and mean total clearance are outlined in the table below (estimated from a single 30 mg IM dose of ketorolac).
| Type of subjects | Total clearance (l/hr/kg) mean (range) | Terminal half-life (hrs) mean (range) |
| Normal subjects (n 4) | 0.023 (0.010 - 0.046) | 5.3 (3.5 - 9.2) |
| Patients with hepatic dysfunction (n=7) | 0.029 (0.013 - 0.066) | 5.4 (2.2 - 6.9) |
| Patients with renal impairment (n=25) (serum creatinine 160 - 430 micromol/l) | 0.016 (0.005 - 0.043) | 10.3 (5.9 - 19.2) |
| Renal dialysis patients (n=9) | 0.016 (0.003 - 0.036) | 13.6 (8.0 - 39.1) |
| Healthy elderly subjects (n=13) (mean age 72) | 0.019 (0.013 - 0.034) | 7.0 (4.7 - 8.6) |
IV: Intravenous administration of a single 10 mg dose of ketorolac trometamol resulted in a mean peak plasma concentration of 2.4 mcg/ml occurring an average of 5.4 minutes after dosing, with a terminal plasma elimination half-life of 5.1 hours, an average volume of distribution of 0.15 l/kg, and a total plasma clearance of 0.35 ml/min/kg.
The pharmacokinetics of ketorolac in man following single or multiple doses are linear. Steady-state plasma levels are achieved after dosing every 6 hours for one day. No changes in clearance occurred with chronic dosing. The primary route of excretion of ketorolac and its metabolites is renal: 91.4% (mean) of a given dose being found in the urine and 6.1% (mean) in the faeces.
More than 99% of the ketorolac in plasma is protein-bound over a wide concentration range.
Rabbit aqueous humor bioavailability:
| Mean concentration of total radioactivity | 0.856 µg-equiv./ml @ 0.5 hr |
| 1.607 µg-equiv./ml @ 2 hr | |
| Tmax | 3.38 hr |
| Cmax | 1.905 µg-equiv./ml |
| AUC(0-8 hr) | 9.39 µg-equiv. hr/ml |
| Total AUC | 13.53 µg-equiv. hr/ml |
| Half-life | 3.77 hr |
| Absolute ocular bioavailability | 3.7% |
After topical ocular doses in the rabbit the half life of total radioactivity in aqueous humor was longer than after intracameral injection. This suggests that topical dosing may lead to a "reservoir" effect in the corneal epithelium and continued flux of drug from the reservoir into the aqueous humor.
After ophthalmic doses were administered to rabbits, peak concentrations of radioactivity were achieved within 1 hour in the ocular tissues and were highest in the cornea (6.06 mcg-eq/ml). At 1 hour, the majority of the radioactivity (0.9% of administered dose) was recovered from the sclera (0.58%) and cornea (0.24%), and smaller amounts were recovered from the aqueous humor (0.026%), vitreous humor (0.023%), retina-choroid (0.018%), iris-ciliary body (0.007%) and lens (0.002%).
Relative to plasma AUC values, the AUC's in rabbits were higher for cornea (104 fold), sclera (27 fold), iris-ciliary body (5.8 fold), retina-choroid (5.6 fold), aqueous humor (3.3 fold) and approximately one-half in the vitreous humor and lens. After ophthalmic administration, concentrations of drug-related radioactivity were higher in the ocular tissues and lower in plasma compared with those after IV dosing.
After ophthalmic doses in the rabbit, ketorolac was absorbed rapidly into the systemic circulation (Tmax, 15 min). Plasma half-lives after ophthalmic doses (6.6-6.9 hr) were longer than those after IV administration (1.1 hr), suggesting that removal of drug from eye into the venous circulation may be rate-limiting. By comparison of drug levels in aqueous humor after intracameral injection vs. plasma levels after IV administration, ketorolac was shown to clear more rapidly from plasma (6 ml/min) than from the anterior chamber (11 mcl/min).
In the cynomolgus monkey, peak plasma levels of ketorolac occurred at 1.1 hr after the ophthalmic dose. The plasma half-life of ketorolac was similar after ophthalmic (1.8 hr) and IV doses (1.6 hr).
The majority of the ophthalmic dose was excreted in urine (66% in rabbit and 75% in monkey) and a small amount in faeces (11% in rabbit and 2% in monkey). The extent of systemic absorption after ophthalmic dosing averaged 73% in the rabbit and 76% in the cynomolgus monkey.
After ophthalmic administration in rabbits, ketorolac represented the major component (more than 90%) of radioactivity in aqueous humor and plasma and the p-hydroxy metabolite accounted for 5% of radioactivity in plasma. Ketorolac was also the major component (96%) of plasma radioactivity after ophthalmic dosing in monkeys.
After ophthalmic dosing in the rabbit, 72%, 17% and 6% of the total radioactivity in urine was comprised of intact ketorolac, p-hydroxy ketorolac and other polar metabolites, respectively. After IV dosing, the relative proportions of total radioactivity in urine averaged 6% as intact ketorolac, 68% as p-hydroxy ketorolac and 22% as polar metabolites.
In the monkey, intact ketorolac and its polar metabolite accounted for 32% and 65% of the total radioactivity in urine, respectively, after ophthalmic dosing, and 50% and 49% of the radioactivity in urine, respectively, after IV dosing. Thus, the metabolism of ketorolac was qualitatively similar after ophthalmic and IV administration in the monkey and rabbit.
Ketorolac solutions (0.1% or 0.5%) or vehicle were instilled into the eyes of patients approximately 12 hours and 1 hour prior to surgery. Concentrations of ketorolac in aqueous humor sampled at the time of surgery were at the lower limit of detection (40 ng/ml) in 1 patient and below the quantitation limit in 7 patients dosed with 0.1% ketorolac. The average aqueous humor level of ketorolac in patients treated with 0.5% ketorolac was 95 ng/ml. Concentrations of PGE2 in aqueous humor were 80 pg/ml, 40 pg/ml and 28 pg/ml in patients treated with vehicle, 0.1% ketorolac and 0.5% ketorolac, respectively.
In the 21-day multiple dose (TID) tolerance study in healthy subjects, only 1 of 13 subjects had a detectable plasma level pre-dose (0.021 μg/ml). In another group of 13 subjects, only 4 subjects showed very low plasma levels of ketorolac (0.011 to 0.023 μg/ml) 15 minutes after the ocular dose.
Thus, higher levels of ketorolac in the aqueous humor and very low or no detectable plasma levels after ophthalmic doses, suggest that the use of ketorolac by the ophthalmic route in treatment of ocular disorders results in quite low systemic absorption in patients.
An 18-month study in mice with oral doses of ketorolac trometamol at 2 mg/kg/day (0.9 times human systemic exposure at the recommended IM or IV dose of 30 mg qid, based on area-under-the-plasma-concentration curve [AUC]), and a 24-month study in rats at 5 mg/kg/day (0.5 times the human AUC), showed no evidence of tumorigenicity.
Ketorolac trometamol was not mutagenic in the Ames test, unscheduled DNA synthesis and repair, and in forward mutation assays. Ketorolac trometamol did not cause chromosome breakage in the in vivo mouse micronucleus assay. At 1590 mcg/ml and at higher concentrations, ketorolac trometamol increased the incidence of chromosomal aberrations in Chinese hamster ovarian cells.
Impairment of fertility did not occur in male or female rats at oral doses of 9 mg/kg (0.9 times the human AUC) and 16 mg/kg (1.6 times the human AUC) of ketorolac trometamol, respectively.
In addition, octoxinol 40 was separately evaluated for its ocular safety. Ketorolac was found to be non-irritating, it did not demonstrate a local anaesthetic effect, it did not influence the healing of experimental corneal wounds in rabbits, it did not enhance the spread of experimental ocular infections of Candida albicans, Herpes simplex virus type one, or Pseudomonas aeruginosa in rabbits, and it did not increase the ocular pressure of normal rabbit eyes.
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