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CLINICAL PHARMACOLOGY

Pharmacodynamics

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 TORADOL (ketorolac tromethamine) occurs within 2 to 3 hours and is not statistically significantly different over the recommended dosage range of TORADOL (ketorolac tromethamine) . The greatest difference between large and small doses of TORADOL (ketorolac tromethamine) is in the duration of analgesia.

Pharmacokinetics

Ketorolac tromethamine is a racemic mixture of [-]S- and [+]R-enantiomeric forms, with the S-form having analgesic activity.

Comparison of IV, IM and Oral Pharmacokinetics

The pharmacokinetics of ketorolac tromethamine, following IV and IM doses of ketorolac tromethamine and oral doses of TORADOL (ketorolac tromethamine) , are compared in Table 1. In adults, the extent of bioavailability following administration of the ORAL form of TORADOL and the IM form of ketorolac tromethamine was equal to that following an IV bolus.

Linear Kinetics

In adults, following administration of single ORAL doses of TORADOL or 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 or IV doses of ketorolac tromethamine or recommended oral doses of TORADOL (ketorolac tromethamine) , are linear. At the higher recommended doses, there is a proportional increase in the concentrations of free and bound racemate.

Absorption

TORADOL (ketorolac tromethamine) is 100% absorbed after oral administration (see Table 1). Oral administration of TORADOL (ketorolac tromethamine) after a high-fat meal resulted in decreased peak and delayed time-to-peak concentrations of ketorolac tromethamine by about 1 hour. Antacids did not affect the extent of absorption.

Distribution

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 μg/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 (see PRECAUTIONS: Nursing Mothers).

Metabolism

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.

Excretion

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 TORADOL (ketorolac tromethamine) (n=9) demonstrated that the S-enantiomer is cleared approximately two 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 (see CLINICAL PHARMACOLOGY: Kinetics in Special Populations).

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.

Accumulation

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 μg/mL (SD ± 0.13) on Day 1 and 0.55 μg/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).

Kinetics in Special Populations

Geriatric 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 μg/mL ± 0.77; young, 2.99 μg/mL ± 1.03) (see PRECAUTIONS: Geriatric Use).

Pediatric Patients

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.

Renal Insufficiency

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 (see WARNINGS: Renal Effects).

Hepatic Insufficiency

There was no significant difference in estimates of half-life, AUC∞ and Cmax in 7 patients with liver disease compared to healthy volunteers (see PRECAUTIONS: Hepatic Effect and Table 2).

Race

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%
Tmax1 (min) 44 ± 34 33 ± 21§ 44 ± 29 33 ± 21§ 1.1 ± 0.7§ 2.9 ± 1.8
Cmax2 (μg/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 (μg/mL) [steady state qid] 1.05 ± 0.26§ 1.56 ± 0.44§ 3.11 ± 0.87§ N/A|| 3.09 ± 1.17§ 6.85 ± 2.61
Cmin3 (μg/mL) [steady state qid] 0.29 ± 0.07§ 0.47 ± 0.13§ 0.93 ± 0.26§ N/A 0.61 ± 0.21§ 1.04 ± 0.35
Cavg4 (μg/mL) [steady state qid] 0.59 ± 0.20§ 0.94 ± 0.29§ 1.88 ± 0.59§ N/A 1.09 ± 0.30§ 2.17 ± 0.59
5 (L/kg) 0.175 ± 0.039 0.210± 0.044
% Dose metabolized = < 50
% Dose excreted in feces = 6
% Dose excreted in urine = 91
% 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
§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
|| Not applicable because 60 mg is only recommended as a single dose
1Time-to-peak plasma concentration
2Peak plasma concentration
3Trough plasma concentration
4Average plasma concentration 5Volume of distribution

Table 2 - The Influence of Age, Liver, and Kidney Function on the Clearance and Terminal Half-life of Ketorolac Tromethamine (IM1 and ORAL2) in Adult Populations

Type of Subjects Total Clearance [in L/h/kg]3 Terminal Half-life [in hours]
IM ORAL IM ORAL
Mean
(range)
Mean
(range)
Mean
(range)
Mean
(range)
Normal Subjects
IM (n=54)
mean age=32, range=18-60
Oral (n=77)
mean age=32, range=20-60
0.023
(0.010-0.046)
0.025
(0.013-0.050)
5.3
(3.5-9.2)
5.3m
(2.4-9.0)
Healthy Elderly Subjects
IM (n=13),
Oral (n=12)
mean age=72, range=65-78
0.019
(0.013-0.034)
0.024
(0.018-0.034)
7.0
(4.7-8.6)
6.1
(4.3-7.6)
Patients with Hepatic Dysfunction
IM and Oral (n=7)
mean age=51, range=43-64
0.029
(0.013-0.066)
0.033
(0.019-0.051)
5.4
(2.2-6.9)
4.5
(1.6-7.6)
Patients with Renal Impairment
IM (n=25), Oral (n=9) serum creatinine=1.9-5.0 mg/dL,
mean age (IM)=54, range=35-71
mean age (Oral)=57, range=39-70
0.015
(0.005-0.043)
0.016
(0.007-0.052)
10.3 (5.9-19.2) 10.8 (3.4-18.9)
Renal Dialysis Patients
IM and Oral (n=9) mean age=40, range=27-63
0.016
(0.003-0.036)
13.6
(8.0-39.1)
1Estimated from 30 mg single IM doses of ketorolac tromethamine
2Estimated from 10 mg single oral doses of ketorolac tromethamine
3Liters/hour/kilogram
IV Administration

In normal adult subjects (n=37), the total clearance of 30 mg IV-administered ketorolac tromethamine was 0.030 (0.017-0.051) L/h/kg. The terminal half-life was 5.6 (4.0-7.9) hours. (See Kinetics in Special Populations for use of IV dosing of ketorolac tromethamine in pediatric patients.)

Clinical studies

Adult Patients

In a postoperative study, where all patients received morphine by a PCA device, patients treated with ketorolac tromethamineIV as fixed intermittent boluses (e.g., 30 mg initial dose followed by 15 mg q3h), required significantly less morphine (26%) than the placebo group. Analgesia was significantly superior, at various postdosing pain assessment times, in the patients receiving ketorolac tromethamineIV plus PCA morphine as compared to patients receiving PCA-administered morphine alone.

Pediatric Patients

There are no data available to support the use of TORADOL (ketorolac tromethamine) ORAL in pediatric patients.

Last reviewed on RxList: 12/17/2007
This monograph has been modified to include the generic and brand name in many instances.

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