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.

Nanostructured SBA-15 host applied in ketorolac tromethamine release system.

The ordered mesoporous silica SBA-15 has been applied in studies of ketorolac tromethamine adsorption and release. The SBA-15 materials with hexagonal and regular structure were obtained using a triblock copolymer Pluronic P123 as a template and TEOS as a silica source. Ketorolac tromethamine was adsorbed into SBA-15 silica nanochannels using ethanol as solvent. The physicochemical and textural properties of SBA-15 and ketorolac tromethamine/SBA-15 were characterized by X-ray diffraction, thermogravimetric analysis, transmission electron microscopy, fourier transform infrared spectroscopy and BET surface studies. Drug release was evaluated by soaking the loaded silica mesoporous material into a solution of HCl (0.1 N) at initial time (0-2 h) and buffer pH 7 at high times at 37 °C under continuous stirring. Oral commercial Keto tablets (Dolten®) and Keto solution (Keto power) were study for the contrast. Release studies were performed in order to evaluate the required therapeutic efficacy. SBA-15 provides significant improvement in the controlled release of ketorolac tromethamine. Release profile of KETO from SBA-15/KETO and control releases.

Pharmacokinetics of ketorolac tromethamine in horses after intravenous, intramuscular, and oral single-dose administration.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are an integral component of equine analgesia, yet currently available NSAIDs are both limited in their analgesic efficacy and have adverse effects. The NSAID ketorolac tromethamine (KT) is widely used in humans as a potent morphine-sparing analgesic drug but has not been fully evaluated in horses. The purpose of this study was to determine the pharmacokinetic profile of KT in horses after intravenous (i.v.), intramuscular (i.m.), and oral (p.o.) administration. Nine healthy adult horses received a single 0.5-mg/kg dose of KT via each route of administration. Plasma was collected up to 48 h postadministration and analyzed for KT concentration using HPLC/MS/MS. Noncompartmental analysis of i.v. dosage indicated a mean plasma clearance of 8.4 (mL/min)/kg and an estimated mean volume of distribution at steady-state of 0.77 L/kg. Noncompartmental analysis of i.v., i.m., and p.o. dosages indicated mean residence times of 2.0, 2.6, and 7.1 h, respectively. The drug was rapidly absorbed after i.m. and p.o. administration, and mean bioavailability was 71% and 57% for i.m. and p.o. administration, respectively. Adverse effects were not observed after i.v., i.m., and p.o. administration. More studies are needed to evaluate the analgesic and anti-inflammatory properties of KT in horses.

A Novel Formulation of Ketorolac Tromethamine (NTM-001) in Continuous Infusion in Adults with and without Renal Impairment: A Randomized Controlled Pharmacologic Study.

INTRODUCTION: There is a medical need for a safe, effective nonopioid postoperative analgesic for older subjects, including those with mild to moderate renal impairment. METHODS: Participants (≥ 65 years) were stratified by no, mild, or moderate renal impairment defined as creatinine clearance 60-89 mL/min for mild and 30-59 mL/min for moderate. Subjects were randomized to receive a loading dose of 6.25 mg of ketorolac tromethamine drug candidate NTM-001 followed by a 1.75 mg/h continuous intravenous (IV) infusion over 24 h or an IV bolus injection of ketorolac tromethamine (KETO-BOLUS) of 15 mg every 6 h. There were four treatment periods of 24 h for each subject with a minimum 7-day washout between them. This was a crossover study so subjects served as their own controls. Blood drawn from the subjects was used to plot concentration-time profiles against target profiles. Adverse events were monitored. RESULTS: Thirty-nine subjects enrolled. Concentration-time profiles showed low intersubject variability. Model-predicted curves for those with renal impairment closely matched observed plasma concentrations. Continuous infusion maintained higher mean plasma concentrations than the bolus regimen. No serious or unexpected adverse events were observed. No deaths occurred. CONCLUSIONS: NTM-001 was considered safe and well tolerated in this population of participants ≥ 65 years, including in those with mild or moderate renal impairment. There were fewer adverse events in the continuous infusion group. The predictable pharmacologic properties and blood concentration levels suggest that continuous IV infusion of ketorolac can be used as an effective postoperative pain reliever in older subjects.

Controlling postoperative pain can lead to faster recovery. Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID), like ibuprofen and naproxen, that can be as effective as morphine without the same risks. In hospitals, ketorolac is usually administered intravenously (IV) either continuously or as a bolus injection. A bolus of ketorolac may result in adverse gastrointestinal side effects. In this study, a new formulation of ketorolac tromethamine, NTM-001, was administered IV as a continuous 24 h infusion compared to IV boluses of ketorolac tromethamine every 6 h in volunteers. Volunteers were older (≥ 65 years) and had no, mild, or moderate kidney dysfunction. One randomized group received a starting IV dose of 6.26 mg followed by a continuous IV infusion of 1.75 mg/h of over 24 h. The other group received single NTM-001 IV bolus injections of ketorolac tromethamine 15 mg every 6 h over 24 h (4 doses, 60 mg) over the 24 h. After completing the first study, subjects waited at least a week and then switched groups, giving the study a crossover design so it could be observed how each subject responded to both regimens. Blood drawn from the subjects was tested for standard pharmacokinetic (PK) parameters. The data show that blood concentrations of NTM-001 can be reliably predicted. Side effects were mild and the continuous infusion reduced side effects. No unexpected adverse events occurred. These data show that NTM-001 can be used safely in older individuals, including those with mild or moderate kidney impairment.

The impact of pregnancy on urinary ketorolac metabolites after single intravenous bolus.

Compared to female volunteers or postpartum, ketorolac clearance is higher at delivery. To explore the alterations that explain this higher clearance, urinary ketorolac metabolites collected at delivery (n = 40) were compared to female volunteers (unpaired, n = 8) or postpartum (paired, n = 8) following intravenous administration of 30 mg ketorolac tromethamine. A mean 38 (SD 9) % of the ketorolac dose was retrieved in 8-h urine collections. This was based on mean portions of 56 (20), 10 (14) and 33 (12) % for free ketorolac, ketorolac-glucuronide and p-hydroxy-ketorolac, respectively. The mean ketorolac-glucuronide portion at delivery (5 %) was lower compared to female volunteers (21 %) or postpartum (21 %) (p = 0.003 and p = 0.002, respectively). Similarly, there was a difference in mean portion of free urinary ketorolac at delivery when compared to healthy female volunteers (60-45 %, p = 0.046). Using paired statistics, the mean portion of total urinary ketorolac was lower (62-73 %, p = 0.015) while the portion retrieved as p-hydroxy-ketorolac was significantly higher at delivery compared to postpartum (38-28 %, p = 0.031). The differences in urine metabolites suggest that the increased ketorolac clearance at delivery is in part explained by increased metabolic clearance to p-hydroxy-ketorolac, reflecting increased oxidation activity.

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).

Pharmacokinetic comparison of ketorolac after intracameral, intravitreal, and suprachoroidal administration in rabbits.

PURPOSE: To investigate the concentrations and pharmacokinetics of ketorolac in the rabbits by three different routes of administrations: a single intracameral, intravitreal, and suprachoroidal injection. METHODS: Fifty-four New Zealand white rabbits received ketorolac (250 µg/0.05 mL) in one eye by a single intracameral injection (group A, n = 18), single intravitreal injection (group B, n = 18), and single suprachoroidal injection (group C, n = 18). Drug concentrations in the vitreous, retina-choroid (RC), and plasma were determined by the methods of high-performance liquid chromatography at 0.5, 1, 2, 4, 8, and 24 hours after injection. The concentrations in the opposite eyes were also investigated. RESULTS: The mean maximum concentrations (Cmax) of ketorolac in the vitreous and RC were 0.378 ± 0.19 µg/mL and 3.15 ± 0.49 µg/g (at 0.5 hours), respectively, in group A; 156.2 ± 20.74 µg/mL (at 0.5 hours) and 208.0 ± 21.67 µg/g (at 1 hours), respectively, in group B; and 0.873 ± 0.34 µg/mL and 56.71 ± 22.64 µg/g (at 0.5 hours), respectively, in group C. In the RC, the area under the curve (AUC0-t) in group B (866.1 ± 52.67 µg/g·h) was higher (P < 0.01) than that in group C (77.10 ± 25.90 µg/g·h). The elimination half-life (t1/2) in group B (3.09 hours) was longer (P < 0.01) than that in group C (1.19 hours). In the control eyes, a drug level below 2 µg/g was detected in the RC in group C. Plasma concentrations were below 0.4 µg/mL in all 3 groups. Ketorolac was detectable in the RC till 24 hours after the intravitreal injection and 8 hours after the suprachoroidal injection. CONCLUSION: Intravitreal injection of ketorolac produced higher intraocular drug concentrations for a longer period compared with the other two routes. Suprachoroidal injection of ketorolac could reach an effective drug level in the RC with short half-lives and low drug levels in the vitreous. The plasma drug concentrations were low by all three routes.

Paracetamol and ketorolac pharmacokinetics and metabolism at delivery and during postpartum.

During pregnancy, changes in renal elimination, body composition and metabolic activity occur. Since these important alterations in physiology also affect drug disposition, pregnancy warrants a focused approach. Despite these differences, even commonly administered drugs have not undergone pharmacokinetic evaluation in pregnant women or at delivery. This is also true for analgesics routinely administered by anesthesiologists during pregnancy or at delivery, like intravenous (i.v.) paracetamol or ketorolac. We report on our observations on i.v. paracetamol and ketorolac disposition following cesarean delivery to illustrate the feasibility of such focused studies and the impact of pregnancy on drug disposition. The clinical relevance of these observations are subsequently discussed, and some future research directions are suggested.

Compression-coated pulsatile chronomodulated therapeutic system: QbD assisted optimization.

Pulsatile drug delivery systems have drawn attention in contemporary research for designing chronotherapeutic systems. The current work aims to design pulsatile ketorolac tromethamine tablets using compression coating for delayed delivery with a lag time suitable for the treatment of morning stiffness in arthritis. Rapidly disintegrating core tablets of ketorolac tromethamine were formulated using super-disintegrants, and the optimized formulation was compression using PEO WSR coagulant and Eudragit RLPO for delaying the release. The central composite design and response surface methodology were employed to optimize the formulation and process parameters namely PEO WSR Coagulant (X1), Eudragit RLPO (X2), and Hardness (X3). The dependent variables optimized were lag time and time required for 95% drug release. Analysis using response surface graphs and mathematical modeling of the results allowed identifying and quantifying the formulation variables active on the selected responses. A polynomial equation fitted to the data was used to predict the composition with optimum responses. Compression-coated pulsatile tablets' optimized composition exhibited a lag time of 9 h and released 95% of the ketorolac tromethamine in 17.42 h. Validation of the mathematical model assured the reliability of QBD in formulation design. In vivo X-ray imaging and pharmacokinetic studies established a strong relationship between the coated polymers maintaining the desired lag time for delayed delivery of the active to coincide with the chronobiology for enhanced bioavailability at the right time when needed.

Ketorolac tromethamine: stereo-specific pharmacokinetics and single-dose use in postoperative infants aged 2-6 months.

OBJECTIVE: We determined the postoperative pharmacokinetics (PK), safety, and analgesic effects of ketorolac in 14 infants (aged <6 months) receiving a single intravenous (IV) administration of racemic ketorolac or placebo. BACKGROUND: Information on the PK of ketorolac in infants is limited. Unblinded studies suggest ketorolac may be useful in infants. METHODS: This double-blinded, placebo-controlled study enrolled 14 infants (aged <6 months) postoperatively. At 6-18 h after surgery, infants were randomized to receive placebo, 0.5 mg·kg(-1), or 1 mg·kg(-1) ketorolac IV. All infants received morphine sulfate as needed for pain control. Blood was collected up to 12-h postdosing. Analysis used noncompartmental and compartmental population modeling methods. RESULTS: In addition to noncompartmental and empirical Bayes PK modeling, data were integrated with a previously studied data set comprising 25 infants and toddlers (aged 6-18 months). A two-compartmental model described the comprehensive data set. The population estimates of the R (+) isomer were (%CV): central volume of distribution 1130 (10%) ml, peripheral volume of distribution 626 (25%) ml, and clearance from the central compartment 7.40 (8%) ml·min(-1). Those of the S (-) isomer were 1930 (15%) ml, 319 (58%) ml, and 39.5 (13%) ml·min(-1). Typical elimination half-lives were 191 and 33 min, respectively. There was a trend for increased clearance and central volume with increasing age and weight. The base model suggested that clearance of the S (-) isomer was weakly related to age; however, when body size adjustment was added to the model, no covariates were significant. Safety assessment showed no changes in renal or hepatic function tests, surgical drain output, or continuous oximetry between groups. Cumulative morphine administration showed large inter-patient variability and was not different between groups. CONCLUSION: Stereo-isomer-specific clearance of ketorolac in infants (aged 2-6 months) shows rapid elimination of the analgesic S (-) isomer as reported in infants aged 6-18 months. No adverse effects were seen after a single IV ketorolac dose.

Effect of salts on gelation and drug release profiles of methylcellulose-based ophthalmic thermo-reversible in situ gels.

The poor bioavailability and therapeutic response exhibited by conventional ophthalmic solutions may be overcome by the use of thermo-reversible in situ gel. The purpose of this study was to examine the influence of different salts on the gelation, rheology and drug release of in situ gel based on methylcellulose. The gel temperature of 1% w/v methylcellulose (MC) was 60?C. It was found that 5?7% w/v sodium chloride (NaCl), 8?9% w/v potassium chloride (KCl), or 5% w/v sodium bicarbonate (NaHCO(3)) was capable of decreasing the gel temperature below physiological temperature, i.e. 37?C. Rheological studies indicated a large increase in viscosity at 37?C with the addition of salts in MC solutions. The duration of drug release from MC solution was 1.5?h. The significant observation was that the duration of drug release increased from 1.5?h to 3?5?h from salted MC solutions depending on the concentration and the type of salt. So, it can be concluded that the salted MC solutions were a better alternative than the MC solution to enhance the ocular bioavailability of the drug.

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.

Eudragit RL100 Based Moxifloxacin Hydrochloride and Ketorolac Tromethamine Combination Nanoparticulate System for Ocular Drug Delivery.

BACKGROUND: Bacterial conjunctivitis is a serious ocular infection if left untreated. It is caused by several species of bacteria like Pseudomonas, Staphylococcus and Mycobacterium. OBJECTIVE: The present investigation explores the development and characterization of moxifloxacin hydrochloride and ketorolac tromethamine combination loaded Eudragit RL 100 nanosuspension for ocular drug delivery in order to overcome the problems associated with conventional dosage forms. METHODS: The nanosuspension prepared by nanoprecipitation technique showed successful entrapment of both water-soluble drugs in the polymer matrix indicated by their % entrapment efficiencies. RESULTS: Formulations showed a mean particle size <200 nm with narrow size distribution and positive surface charge due to the presence of quaternary ammonium groups of Eudragit RL100. FTIR study revealed compatibility among the components, while a reduction in the crystallinity of formulation was observed in the PXRD study. The release of both the drugs was found to be sustained in nanosuspension as compared to commercial eyedrops. Ex vivo studies showed increased transcorneal permeation of drugs from nanosuspension, where approximately 2.5-fold and 2-fold increase in the permeation was observed for moxifloxacin hydrochloride and ketorolac tromethamine, respectively. The formulation was stable at 4°C and room temperature. CONCLUSION: Due to their sustained release, positive surface charge and higher transcorneal permeation, this will be a promising ocular drug delivery.

Extended delivery of non-steroidal anti-inflammatory drugs through contact lenses loaded with Vitamin E and cationic surfactants.

The purpose of this study is to extend drug release from ACUVUE Oasys® and ACUVUE TruEye® silicone hydrogel contact lenses by incorporation of vitamin E in conjunction with a cationic surfactant. In ACUVUE Oasys® and ACUVUE TruEye®, the release of ketorolac tromethamine and flurbiprofen sodium is extended from hours to several days for 11% and 21% vitamin E, (weight of vitamin E / weight of dry lens) but with a considerable reduction in the amount of drug released. Cetalkonium chloride and stearylamine increased the drug loading capacity which was otherwise compromised by the addition of vitamin E in the contact lenses. In the case of diclofenac sodium, a sustained release over 150 h for both contact lenses can be achieved. It was found that the release-time-increase factor due to vitamin E has a linear dependence with the octanol-water partition coefficient of the drug in ACUVUE Oasys®. The results in this study show that contact lenses loaded with vitamin E in conjunction with cationic surfactants achieved sustained release of non-steroidal anti-inflammatory drugs (NSAIDs) within the therapeutic window.

Bioavailability of two sublingual formulations of ketorolac tromethamine 30 mg: a randomized, open-label, single-dose, two-period crossover comparison in healthy Mexican adult volunteers.

BACKGROUND: Ketorolac tromethamine (ie, ketorolac) is an NSAID that appears to have several mechanisms of action, including inhibition of prostaglandin synthesis, modulatory effect on opioid receptors, and nitric oxide synthesis. Ketorolac is used in the treatment of pain. There are various generic formulations of sublingual ketorolac available in Mexico. However, a literature search did not identify published data concerning the bioavailability of these formulations in the Mexican population. OBJECTIVE: The aim of this study was to compare the bioavailability of 2 sublingual formulations of ketorolac 30-mg tablets in healthy Mexican adult volunteers. METHODS: This was a randomized-sequence, open-label, single-dose, 2-period crossover (2 dosing periods x 2 treatments) study comparing the bioavailability of two 30-mg sublingual tablet formulations of ketorolac. Healthy Mexican adult (aged, 18-55 years) men and women were eligible for inclusion. Subjects were randomly assigned in a 1:1 ratio to receive a single dose of the test formulation or the reference formulation. After a 12-hour overnight fast, subjects received a single dose of the corresponding formulation. There was a 7-day washout period between administration periods. Plasma samples were obtained over a 24-hour period after administration. Plasma ketorolac concentrations were analyzed by high-performance liquid chromatography for analysis of pharmacokinetic properties, including Cmax, AUC0-24, and AUC0-infinity. Blood samples were drawn immediately after sublingual placement of the drug and at 10, 20, 30, 40, 50, 60, 75, and 90 minutes and 2, 4, 6, 8, 10, 12, and 24 hours after dosing. The formulations were considered bioequivalent if the geometric mean ratios of Cmax and AUC were within the predetermined range of 80% to 125% and if P for the 90% CIs was <0.05. Tolerability was assessed by vital sign monitoring, laboratory analysis results, and subject interviews. RESULTS: A total of 27 subjects (18 women, 9 men; mean [SD] age, 27 [9] years [range, 18-47 years]; weight, 61 [8] kg [48-79 kg]; height, 163 [8] cm [150-180 cm]) were enrolled and completed the study. Fourteen subjects received the test formulation first. No period or sequence effect was observed. The 90% CIs for the corresponding differences in natural log Cmax, AUC0-24, and AUC0-infinity were 95.94% to 114.66%, 98.34% to 105.90%, and 99.25% to 108.36%, respectively (all, (P) < 0.05), meeting the predetermined criteria for bioequivalence. Sixteen subjects experienced a total of 20 adverse events (AEs) during the study. None of the AEs were considered serious. One AE (nausea) appeared to be related to use of the reference formulation. CONCLUSIONS: In this small study in 27 healthy Mexican adult volunteers, the test formulation of a single, 30-mg sublingual tablet of ketorolac appeared to be bioequivalent to the reference formulation based on the rate and extent of absorption. Both formulations were well tolerated.

Preparation and in vitro evaluation of controlled release hydrophilic matrix tablets of ketorolac tromethamine using factorial design.

Controlled release matrix tablets of ketorolac tromethamine (KT) were prepared by direct compression technique using cellulose derivatives as hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC), and carboxymethyl cellulose (CMC) in different concentrations (10-20%). The effect of polymer type and concentration was investigated on drug release by 2(3) factorial design. For the quality control of matrix tablets, weight deviation, hardness, friability, diameter-height ratio, content uniformity of KT, and in vitro dissolution technique were performed. UV Spectrophotometric method was used to detection of KT in matrix tablets. This method was validated. Dissolution profiles of the formulations were plotted and evaluated kinetically. An increase in polymer content resulted with a slow release rate of drug as was expected. According to the dissolution results, tablets prepared with HPMC + HEC + CMC (F1 and F8) were found to be the most suitable formulation for KT. About 99.27% KT was released from F8 in 7 h.

Prostaglandin E2 inhibition and aqueous concentration of ketorolac 0.4% (acular LS) and nepafenac 0.1% (nevanac) in patients undergoing phacoemulsification.

PURPOSE: To determine the prostaglandin E(2) (PGE(2)) levels and aqueous concentrations achieved with ketorolac 0.4% (Acular LS; Allergan, Inc, Irvine, California, USA) and nepafenac 0.1% (Nevanac; Alcon Laboratories, Inc, Fort Worth, Texas, USA). DESIGN: Single-center, randomized, double-masked study. METHODS: One hundred and thirty-two patients received ketorolac or nepafenac four times daily for two days before cataract extraction. Aqueous samples obtained at surgery were analyzed for PGE(2) levels (competitive enzyme immunoassay) and drug concentrations. RESULTS: More ketorolac eyes than nepafenac eyes had PGE(2) levels less than the level of detection (<100 pg/ml; 26/42 [61.9%] and 7/40 [17.5%], respectively; P < .001). Mean PGE(2) levels in ketorolac eyes were lower than that in nepafenac eyes (159.5 +/- 114.66 pg/ml and 322 +/- 197.8 pg/ml, respectively; P < .001). The mean aqueous level was 1079.1 +/- 881.5 ng/ml with ketorolac and 353.4 +/- 126.0 ng/ml with amfenac. The nepafenac eyes exhibited 588.4 +/- 394.6 ng/ml of the inactive nepafenac molecule (P < .001 vs ketorolac). CONCLUSIONS: Ketorolac 0.4% inhibited PGE(2) and penetrated into aqueous significantly more than nepafenac 0.1%.

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.

Preparation and evaluation of ketorolac tromethamine gel containing genipin for periodontal diseases.

Ketorolac tromethamine gel (KT gel) and ketorolac tromethamine gel containing genipin (KTG gel) were prepared and their therapeutic effects on periodontitis were evaluated. The skin permeation rate of ketorolac from the KT gel and KTG gel was 5.75+/-0.53 and 5.82 +/- 0.74 microg/cm2/ h, respectively. The skin permeation rate of genipin from the KTG gel was 10.13 +/- 1.47 microg/ cm2/h. The tensile strength of the KTG gel was larger than the KT gel. After 4 weeks, the periodontal pocket depth of the KTG gel group (3.22 +/- 0.20 mm) significantly decreased compared with the non-treated group (4.50 +/- 0.25 mm) and the KT group (3.84 +/- 00.26 mm). The KTG gel did not induce separation of the stratum corneum and subcutaneous tissue, and the collagen layers of the corium were closer, more fibrous, and showed longer connections than in the other groups. The KTG gel appears to be effective against gingivitis in the periodontal pocket through its increased anti-inflammatory activity and the crosslinking of genipin with the biological tissue.

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.