Ketorolac Tromethamine (Page 2 of 9)

Linear Kinetics

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.

Distribution

The mean apparent volume (V β ) 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 (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 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 C max 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).

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 C max for the two groups (elderly, 2.52 mcg/mL±0.77; young, 2.99 mcg/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 (V β ) was 0.34±0.12 L/kg and the volume of distribution at steady state (V ss ) 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 C max in 7 patients with liver disease compared to healthy volunteers (see PRECAUTIONS, Hepatic Effects and Table 2).

Race

Pharmacokinetic differences due to race have not been identified.

Table 2 The Influence of Age, Liver and Kidney Function, on the Clearance and Terminal Half-life of Ketorolac Tromethamine (IM 1 and ORAL 2) in Adult Populations

1 Estimated from 30 mg single IM doses of ketorolac tromethamine

2 Estimated from 10 mg single oral doses of ketorolac tromethamine

3 Liters/hours/kilogram

Total Clearance [in L/h/kg] 3 Terminal Half-life [in hours]
Type of Subjects IM Mean (range) ORAL Mean (range) IM Mean (range) ORAL 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) 5.3 (2.4-9)
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 (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)

IV-Administration: 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 (4.0 to 7.9) hours (see Kinetics in Special Populations for use of IV dosing of ketorolac tromethamine in pediatric patients).

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