In vitro anti-LPS dose determination of ketorolac tromethamine and in vivo safety of repeated dosing in healthy horses.

Flunixin meglumine (FM) is a commonly used Nonsteroidal anti-inflammatory drug (NSAID) in horses, but clinical efficacy is often unsatisfactory. Ketorolac tromethamine (KT) demonstrates superior efficacy compared to other NSAIDs in humans, but its anti-inflammatory effects have not been investigated in the horse. Safety of repeated dosing of KT has not been evaluated. The first objective was to conduct a dose determination study to verify that a previously described dosage of KT would inhibit Lipopolysaccharide (LPS)-induced eicosanoid production in vitro, and to compare KT effects of this inhibition to those of FM. Then, a randomized crossover study was performed using nine healthy horses to evaluate plasma concentrations of KT and FM following IV administration. Administered dosages of KT and FM were 0.5 mg/kg and 1.1 mg/kg, respectively. Safety following six repeated doses of KT was assessed. Ketorolac tromethamine and FM suppressed LPS-induced Thromboxane B2 (TXB2 ) and Prostaglandin E2 (PGE2 ) production in vitro for up to 12 hr. Intravenous administration produced plasma concentrations of KT and FM similar to previous reports. No adverse effects were observed. A KT dosage of 0.5 mg/kg IV inhibited LPS-induced eicosanoids in vitro, and repeated dosing for up to 3 days appears safe in healthy horses. Investigation of in vivo anti-inflammatory and analgesic effects of KT is warranted.

Body weight, gender and pregnancy affect enantiomer-specific ketorolac pharmacokinetics.

AIMS: Although ketorolac analgesia is linked only to the S-enantiomer, there is limited information on the stereo-selective pharmacokinetics of this agent. We studied the stereo-selective pharmacokinetics of ketorolac in a pooled dataset of two studies, with women at delivery and 4-5 months postpartum, and males and nonpregnant females. METHODS: Nonlinear mixed-effect modelling was used to evaluate the stereo-selective pharmacokinetics of ketorolac tromethamine after a single intravenous injection immediately after delivery (n = 41), 4-5 months postpartum (n = 8, paired), and in male (n = 12) and nonpregnant female (n = 14) subjects. All of the males and six of the nonpregnant females were recruited from another study, in which they were undergoing blood sampling for 24 h. All remaining cases underwent blood sampling for 8 h. RESULTS: For both the R- and S-enantiomers, body weight affected ketorolac clearance. In addition, clearance for both enantiomers was 36% [95% confidence interval (CI) 15%, 58%] higher in male than in female subjects of the same body weight, and 55% (95% CI 33%, 78%) higher in women at delivery than in nonpregnant women of the same body weight. Women at delivery also had a 27% (95% CI 8%, 46%) higher distribution volume than nonpregnant women. The proportional effects of the covariates were not significantly different for the two ketorolac enantiomers. CONCLUSIONS: Besides the anticipated impact of body weight on clearance, R- and S-ketorolac clearance is increased in male subjects and in women at delivery. To reach an exposure equivalent to that in nonpregnant women, males should receive a 36% increased ketorolac dose and pregnant women a 55% increased dose, in addition to a dose adjustment by body weight.

Enantiomer-specific ketorolac pharmacokinetics in young women, including pregnancy and postpartum period.

Racemic ketorolac clearance (CL) is significantly higher at delivery, but S-ketorolac disposition determines the analgesic effects. The aim of this study was to investigate the effect of pregnancy and postpartum period on enantiomer-specific (S and R) intravenous (IV) ketorolac pharmacokinetics (PKs). Data in women shortly following cesarean delivery (n=39) were pooled with data in a subgroup of these women that was reevaluated in the later postpartum period (postpartum group, n=8/39) and with eight healthy female volunteers. All women received single IV bolus of 30 mg ketorolac tromethamine. Five plasma samples were collected at 1, 2, 4, 6, and 8 hours and plasma concentrations were determined using high performance liquid chromatography. Enantiomer-specific PKs were calculated using PKSolver. Unpaired analysis showed that distribution volume at steady state (Vss, L/kg) for S- and R-ketorolac was significantly higher in women shortly following cesarean delivery (n=31) compared to postpartum group (n=8) or to healthy female volunteers (n=8). CL, CL to body weight, and CL to body surface area (CL/BSA) for S- and R-ketorolac were also significantly higher in women following delivery. In addition, S/R-ketorolac CL/BSA ratio was significantly higher at delivery. Paired PK analysis in eight women shortly following delivery and in postpartum group showed the same pattern. Finally, the simultaneous increase in CL and Vss resulted in similar estimates for elimination half-life in both unpaired and paired analysis. In conclusion, pregnancy affects S-, R-, and S/R-ketorolac disposition. This is of clinical relevance since S-ketorolac (analgesia) CL is even more increased compared to R-ketorolac CL, and S/R-ketorolac CL ratio is higher following delivery compared to postpartum period or to healthy female volunteers.

Comparison of intranasal ketorolac tromethamine pharmacokinetics in younger and older adults.

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(½ß)) 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.

Pharmacokinetics of intravenous ketorolac following caesarean delivery.

BACKGROUND: Drug disposition is altered by pregnancy and the peripartum period but data on intravenous ketorolac pharmacokinetics following caesarean delivery have not been previously reported. METHODS: At the end of caesarean delivery, women received an intravenous bolus of ketorolac tromethamine 30 mg (immediate postpartum, Group IP). Plasma samples were collected at 1, 2, 4, 6 and 8h. A similar pharmacokinetic study was repeated in a subgroup of these women 4-5 months after delivery (late postpartum, Group LP) and in a group of unrelated, healthy non-pregnant female volunteers (controls, Group C). A non-compartmental linear disposition model was applied to analyse individual ketorolac time-concentration profiles. Results at delivery were compared with controls using unpaired or paired statistics as appropriate. Covariates of pharmacokinetic estimates at delivery were examined. RESULTS: Thirty-nine women were studied at caesarean delivery, of whom eight were re-evaluated 4-5 months later. In addition, eight volunteers were studied. Clearance in Group IP was higher compared to Groups LP and C (2.11 vs. 1.43 and 1.07 L/h·m(2) respectively, P<0.05). Volume of distribution was also increased in Group IP compared to Groups LP and C (0.24 vs. 0.16 and 0.17 L/kg respectively, P<0.05). No significant covariates of pharmacokinetic estimates, including gestational age, preterm vs. term, twin vs. singleton and maternal co-morbidity, were seen in Group IP. CONCLUSIONS: Ketorolac clearance and distribution volume are significantly increased following caesarean delivery. These data provide pharmacokinetic estimates on which to base studies on post caesarean analgesia.

The pharmacokinetics of ketorolac after single postoperative intranasal administration in adolescent patients.

BACKGROUND: Ketorolac tromethamine (ketorolac) administration reduces postoperative opioid requirements. The pharmacokinetic characteristics of intranasal ketorolac tromethamine in children have not been characterized. Our objective of this study was to determine the pharmacokinetics of a single intranasal dose of ketorolac in adolescent patients. METHODS: Twenty surgical patients, ages 12 to 17 years, were enrolled. After surgery, subjects received intranasal ketorolac 15 mg (weight ≤50 kg) or 30 mg (weight >50 kg) using a proprietary administration system. Blood samples were obtained for ketorolac assay at baseline (within 15 minutes before the dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after the dose. A population analysis was undertaken using nonlinear mixed-effects models. Parameter estimates were standardized to a 70-kg person. RESULTS: The intranasal dosing in adolescents was well tolerated with minimal adverse effects. A 1-compartment model with first-order absorption and elimination was satisfactory to describe time-concentration profiles. Population parameter estimates (between subject variability) were clearance (CL/F) 2.05 L/h (60.5%), volume of distribution (V/F) 15.2 L (32.4%), absorption half-life (t(1/2)abs) 0.173 hour (25.0%). Time to peak concentration (Tmax) was 52 minutes (SD 6 minutes). CONCLUSION: Administration of ketorolac by the intranasal route resulted in a rapid increase in plasma concentration and may be a useful therapeutic alternative to IV injection in adolescents because plasma concentrations attained with the device are likely to be analgesic (investigational new drug no. 62,829).

A novel formulation of ketorolac tromethamine for intranasal administration: preclinical safety evaluation.

Ketorolac tromethamine is a potent analgesic and moderately effective anti-inflammatory drug approved for treatment of moderately severe acute pain as an intravenous/intramuscular injectable solution and an oral tablet. ROXRO PHARMA, Inc has developed an intranasal formulation, SPRIX, that delivers the drug with a similar pharmacokinetic profile to that obtained with intramuscular administration. Local tolerance and systemic toxicology studies were performed in rats and rabbits and showed that intranasal administration of SPRIX exhibits toxicity similar to that of other routes of administration and does not result in any adverse effects on the nasal passage and upper and lower respiratory system.

Ketorolac tromethamine transdermal gel: development, in vitro and in vivo evaluation.

The authors developed and evaluated a transdermal gel formulation of ketorolac tromethamine (ketorolac) for the treatment of nociceptive somatic pain. The formulation was optimized for skin permeation enhancers, pH of the system, and dosage strength using in vitro and in vivo techniques. Of the various permeation enhancers evaluated, dimethyl sulfoxide (DMSO) and oleic acid were found to significantly increase skin permeation flux of ketorolac. The concentration of DMSO affected the rate as well as extent of transdermal absorption. Use of citric acid further improved the skin penetration of ketorolac. In vitro diffusion results indicated significant increase in drug permeation with increasing drug concentration. However, the same did not translate into higher skin permeation during in vivo study. Although the area under concentration time curve (AUC(0-t)) increased significantly with increasing dose, the effect on maximum serum concentration (C(max)) was insignificant. The formulation can be used for inflammatory pain management while avoiding gastric adverse events associated with oral ketorolac.

Development and validation of a high-performance thin-layer chromatographic method, with densitometry, for quantitative analysis of ketorolac tromethamine in human plasma.

Ketorolac tromethamine is a potent nonsteroidal anti-inflammatory drug that is widely used in the treatment of moderate to severe pain. A new method was developed and validated for quantifying ketorolac (the free acid of the tromethamine salt) in human plasma by high-performance thin-layer chromatography. The stationary phase was silica gel 60, and the composition of the mobile phase was n-butanol-chloroform-acetic acid-ammonium hydroxide-water (9 + 3 + 5 + 1 + 2, v/v). The densitometric analysis of ketorolac was performed at 323 nm. The method was validated for precision (repeatability and reproducibility), accuracy, and sensitivity. Repeatability was 10.11% [coefficient of variation (CV)] and reproducibility was 12.18% (CV) as the maximum variation. Accuracy was determined at 3 different concentration levels, and results were within +/-15% of the predetermined range. Data were fitted by a linear mathematical function (linear regression). The calibration graph was linear in the range of 200-2000 ng/mL. Average recovery was 73.67%. The method proved to be accurate, precise, and sensitive for the ketorolac tromethamine quantification.

Fatal adverse reaction to ketorolac tromethamine in asthmatic patient.

A case of an asthmatic woman who collapsed within a few minutes after intramuscular ketorolac tromethamine (KT) injection is reported. Autopsy findings revealed anatomic evidence of a recent asthma attack. KT was found to be present in the blood at a concentration within the therapeutic range and consistent with the administered dose. Based on the timing of the collapse in relation to the KT administration, death was attributed to an adverse reaction to KT, resulting in acute bronchospasm and cardiac arrest, with asthma as an underlying contributing factor. In this case, asthma alone was not responsible for the death of the patient but only a contributing factor. Physicians have to be aware that in asthmatic patients bronchospasm can be induced by drugs among which aspirin or nonsteroidal anti-inflammatory drugs such as KT are the most common; therefore, death may have an iatrogenic cause. The paper also describes the pathogenic mechanism of an adverse reaction to such drugs and analytical methods for the isolation and detection of KT in postmortem blood.

Spectrofluorometric determination of ketorolac tromethamine via its oxidation with cerium(IV) in pharmaceutical preparations and biological fluids.

A simple and sensitive fluorometric method for determination of ketorolac tromethamine was studied. The method depends on oxidation of the drug with cerium(IV) and subsequent monitoring of the fluorescence of the induced cerium(III) at lambda(em) 365 nm after excitation at 255 nm. Different variables affecting the reaction conditions, such as the concentrations of cerium(IV), sulfuric acid concentration, reaction time, and temperature, were carefully studied and optimized. Under the optimum conditions, a linear relationship was found between the relative fluorescence intensity and the concentration of the investigated drug in the range of 0.1-0.8 microg/mL. No interferences could be observed from the excipients commonly present in dosage forms. The proposed method was successfully applied to the analysis of the investigated drug in its pure form, pharmaceutical preparations, and biological fluids with good accuracy and precision. The recoveries for pharmaceutical formulations ranged from 99.8-101.0 +/- 0.6% for tablets, 98.5-101.0 +/- 1.0% for ampoules, and 99.0-100.5 +/- 0.7% for eye drops. The results obtained by the proposed method were satisfactory compared with those obtained by the official method. The recoveries for biological fluids were 99.1-100.4 +/- 0.7 and 99.0-100.0 +/- 0.5% for plasma and urine, respectively.

Death due to anaphylactic shock secondary to intravenous self-injection of Toradol: a case report and review of the literature.

A fatality due to the intravenous self-injection of Ketorolac (Toradol) is reported. Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) with marked analgesic activity. There is limited information of fatalities attributed to ketorolac toxicity. Here we report the case of a 53-year-old woman with a medical history of depression that was found deceased at home with no evidence of trauma or injuries. Near the body, a syringe and three empty vials (30 mg) of Toradol were found. A fresh needle mark on the right arm was noticed. Toxicological analyses were performed using a gas chromatography-mass spectrometry (GC/MS) technique. The estimated ketorolac concentration in the blood was 8 mug/ml; urine and gastric content were negative for this compound. Based on the autopsy, histologic findings and toxicological results of anaphylactic shock associated with ketorolac self-administration was assumed to be the underlying pathophysiological mechanism of death and the manner, suicide.

Postoperative ketorolac tromethamine use in infants aged 6-18 months: the effect on morphine usage, safety assessment, and stereo-specific pharmacokinetics.

BACKGROUND: Nonsteroidal antiinflammatory drugs have been useful for treating postoperative pain in children. The only parenteral nonsteroidal antiinflammatory drug currently available in the United States is ketorolac tromethamine with cyclooxygenase-1 and cyclooxygenase-2 effects. Information on the pharmacokinetics of ketorolac in infants is sparse, making dosing difficult. Ketorolac is administered as a racemic mixture with the S(-) isomer responsible for the analgesic effect. In this study, we describe the population pharmacokinetics of ketorolac in a group of 25 infants and toddlers who received a single IV administration of racemic ketorolac and evaluate the potential influence of patient covariates on ketorolac disposition. METHODS: In this double-blind, placebo-controlled study, ketorolac pharmacokinetic, safety, and analgesic effects were studied in 37 infants and toddlers (aged 6-18 mo) postoperatively. On postoperative day 1, infants were randomized to receive placebo, 0.5, or 1 mg/kg ketorolac as a 10-min IV infusion. Blood samples were collected up to 12-h after dosing. The data were analyzed using noncompartmental and compartmental (nonlinear mixed-effects model) means. The patient covariates, including body weight, age, and surgical procedure, were analyzed in a stepwise fashion to identify their potential influence on ketorolac pharmacokinetics. RESULTS: The data were best described by a two-compartmental model. Inclusion of covariates did not significantly decrease the nonlinear mixed-effects model objective function values and between-subject variability in the pharmacokinetic parameters of nested models. The mean and standard error of the estimates of the R(+) isomer were central volume of distribution 1200 +/- 163 mL (coefficient of variation of interindividual variability, 13.6%), peripheral volume of distribution 828 +/- 108 mL (13.0%), clearance from the central compartment 7.52 +/- 0.7 mL/min (9.3%), and extrapolated elimination half-life 238 +/- 48 min. Those of the S(-) isomer were 2320 +/- 34 (14.6%), 224 +/- 193 mL (86.2%), 45.3 +/- 5.5 mL/min (12.1%), and 50 +/- 42 min respectively. Dosing simulations, using population pharmacokinetic parameters, showed no accumulation of S(-) ketorolac but steady increases in R(+) ketorolac. Safety assessment showed no adverse effects on renal or hepatic function tests, surgical drain output, or continuous oximetry between placebo and ketorolac groups. Cumulative morphine administration showed large interpatient variability and was not different between groups. CONCLUSION: The stereo-isomer-specific clearance of ketorolac in infants and toddlers (aged 6-18 mo) shows rapid elimination of the analgesic S(-) isomer. No adverse effects on surgical drain output, oximetry measured saturations, renal or hepatic function tests were seen. Simulation of single dosing at 0.5 or 1 mg/kg every 4 or 6 h does not lead to accumulation of S(-) ketorolac, the analgesic isomer, but does result in increases in R(+) ketorolac. Shorter dose intervals may be needed in infants older than 6 mo.

Age-stratified pharmacokinetics of ketorolac tromethamine in pediatric surgical patients.

UNLABELLED: Published data suggest that ketorolac pharmacokinetics are different in children than in adults. We sought to better characterize ketorolac pharmacokinetics in children. Thirty-six children, aged 1-16 yr, were stratified into four age groups: 1-3 yr, 4-7 yr, 8-11 yr, and 12-16 yr. Each child received 0.5 mg/kg of ketorolac tromethamine IV after completion of elective surgery. A maximum of 16 venous blood samples (mean, 13 +/- 2) were collected at predetermined times up to 10 h after drug administration. Plasma ketorolac concentrations were measured by high-performance liquid chromatography after solid-phase extraction. Individual concentration-versus-time relationships were best fit to a two-compartment pharmacokinetic model by using SAAM II. Body weight-normalized pharmacokinetic variables did not differ among the age groups and were similar to those reported for adults, including a volume of distribution at steady state of 113 +/- 33 mL/kg (mean +/- SD) and an elimination clearance of 0.57 +/- 0.17 mL x min(-1) x kg(-1). Our study demonstrates that a single dose of ketorolac (0.5 mg/kg) results in plasma concentrations in the adult therapeutic concentration range for 6 h in most children. Our data provide no evidence that children require either larger weight-adjusted doses or shorter dosing intervals than adults to provide similar plasma drug concentrations. IMPLICATIONS: The literature suggests that ketorolac disposition differs between children and adults. We characterized ketorolac pharmacokinetics in 36 children. Body weight-normalized two-compartment pharmacokinetic variables did not differ among pediatric patients <17 yr old and were similar to adult values.

Development and evaluation of nasal formulations of ketorolac.

Ketorolac tromethamine is a potent non-narcotic analgesic with moderate anti-inflammatory activity. Clinical studies indicate that ketorolac has a single dose efficacy greater than morphine for postoperative pain and has excellent applicability in the emergency treatment of pain. Due to incomplete oral absorption of ketorolac, several approaches have been tried to develop a nonoral formulation in addition to injections, especially for the treatment of migraine headache. The aim of our study was to develop a nasal formulation of ketorolac with a dose equivalent to the oral formulation. A series of spray and lyophilized powder formulations of ketorolac were administered into the nasal cavity of rabbits, and their pharmacokinetics profiles were assessed. The spray and powder formulations were compared through their pharmacokinetics parameters and absolute bioavailability. Drug plasma concentration was determined using solid phase extraction, followed by an HPLC analysis. Nasal spray formulations were significantly better absorbed than powder formulations. A nasal spray formulation of ketorolac tromethamine showed the highest absorption with an absolute bioavailability of 91%. Within 30 min of administration, the plasma concentration was comparable to that resulting from an intravenous injection. The absolute bioavailability of a solution of ketorolac acid was 70%. Apparently, the dissolution of ketorolac acid into the mucous layer limits its absorption. There were no significant differences in absorption between different powder formulations. Even the reduction of particle size from 123 microm to 63 microm did not indicate better absorption of ketorolac tromethamine from powder formulations. Interestingly, the absolute bioavailability of ketorolac tromethamine from a powder formulation is only 38%, indicating that the drug may not be totally released from the polymer matrix before it is removed from nasal epithelium by mucociliary clearance.