Ketorolac Tromethamine (Page 2 of 9)

Distribution

The mean apparent volume (V _ß ) 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 (≥ 65 Years of Age)).

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 (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 C _max 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

* 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 C max and T max 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
Pharmacokinetic Parameters (units)	Oral *	Intramuscular †			Intravenous Bolus ‡
	10 mg	15 mg	30 mg	60 mg	15 mg	30 mg
Bioavailability (extent)	100%
T max § (min)	44 ± 34	33 ± 21 ¶	44 ± 29	33 ± 21 ¶	1.1 ± 0.7 ¶	2.9 ± 1.8
C max # (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
C max (mcg/mL) [steady state qid]	1.05 ± 0.26 ¶	1.56 ± 0.44 ¶	3.11 ± 0.87 ¶	N/A Þ	3.09 ± 1.17 ¶	6.85 ± 2.61
C min ß (mcg/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
C avg à (mcg/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
V β è(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

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

* Estimated from 30 mg single IM doses of ketorolac tromethamine † Estimated from 10 mg single oral doses of ketorolac tromethamine ‡ Liters/hour/kilogram
	Total Clearance [in L/h/kg] ‡		Terminal Half-Life [in hours]
Type of Subjects	IM	ORAL	IM	ORAL
	Mean (range)	Mean (range)	Mean (range)	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	0.025	5.3	5.3
	(0.010 to 0.046)	(0.013 to 0.050)	(3.5 to 9.2)	(2.4 to 9)
Healthy Elderly Subjects IM (n = 13), Oral (n = 12) mean age = 72, range = 65 to 78	0.019	0.024	7	6.1
	(0.013 to 0.034)	(0.018 to 0.034)	(4.7 to 8.6)	(4.3 to 7.6)
Patients With Hepatic Dysfunction IM and Oral (n = 7) mean age = 51, range = 43 to 64	0.029	0.033	5.4	4.5
	(0.013 to 0.066)	(0.019 to 0.051)	(2.2 to 6.9)	(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	0.016	10.3	10.8
	(0.005 to 0.043)	(0.007 to 0.052)	(5.9 to 19.2)	(3.4 to 18.9)
Renal Dialysis Patients IM and Oral (n = 9) mean age = 40, range = 27 to 63	0.016	—	13.6	—
	(0.003 to 0.036)	(8 to 39.1)