Ketorolac tromethamine (ketorolac) is a racemic, nonsteroidal, antiinflammatory drug with analgesic and antiinflammatory activity that can be administered via the IV, IM, and oral route. Ketorolac has significant opioid-sparing effects1,2 and is considered to be a useful postoperative analgesic medication.3–5 Children may benefit from the use of ketorolac after surgery. An alternate route of administration that results in rapid onset would be useful in pediatric patients when IV access is not available or convenient. The IM route is generally avoided in pediatric patients because of associated injection pain. The nasal route for administration of ketorolac may be a useful alternative to parenteral injections.6,7
Assessment of the pharmacokinetics (PK) of drugs associated with new routes of administration is important to ensure that therapeutic concentrations are attained. Determination of PK is important in pediatric patients, in whom the profile of a particular medication may be significantly different than in an adult population.8–10 The recommended IV dose of ketorolac in children is 0.5 mg/kg, which is expected to give concentrations considered analgesic.11–14 We performed this study of ketorolac in adolescents to determine the PK of the drug when administered via the intranasal route.
After IRB approval, 20 adolescents were recruited to participate in this open-label study of the PK of ketorolac after surgery (investigational new drug no. 62,829). Signed informed consent by the parent and signed patient assent were obtained before the study. Inclusion criteria were age 12 to 17 years, body weight ≥30 kg and ≤100 kg, and willingness to cooperate with study procedures; females were required to have a negative pregnancy test. Exclusion criteria were allergy to any nonsteroidal antiinflammatory drugs, upper respiratory tract infection, abnormal screening laboratory results for hematology, biochemistry, and urinalysis, use of intranasal products within 24 hours, history of cocaine use, history of gastric ulcer disease, pregnancy, breastfeeding, or surgical procedure on the head or neck.
When an analgesic drug was indicated after surgery, subjects received intranasal ketorolac 15 mg (weight ≤50 kg; 100 μL of a 15% solution) or 30 mg (weight >50 kg; 200 μL of a 15% solution, 100 μL once in each nostril). The administration system (Sprix; Roxro Pharma, Inc., Menlo Park, CA) was primed by expelling 3 sprays before dosing. The metered delivery system is designed to reproducibly deliver 15 mg of ketorolac tromethamine per spray, but actually delivers 15.75 mg because the density of the 15% concentration of ketorolac is 1.05 and not 1.00. Spray characteristics such as spray content uniformity, spray pattern, and droplet size distribution are controlled during the manufacturing process. A picture of the device is displayed in Figure 1. The spray device was inserted into the nostril so that the tip was slightly angled toward the ear to allow the solution to be deposited on the upper and lateral wall of the nose. Blood samples from a cannula dedicated for IV sampling were obtained for PK assessment 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 unless venous access for phlebotomy was no longer available. A correction factor of 0.678 was used to account for conversion of the dose from the salt.
This was an open-label PK study, and no power calculation was done to determine the sample size. The selection of 20 evaluable subjects for this study was based on similar studies involving ketorolac administered by oral, IM, and intranasal routes.6,15,16 Rich concentration data observations (10 observations per subject) were anticipated for analysis and the high numbers of samples per patient was thought to allow reasonable PK evaluation.
Adverse Event Monitoring
An adverse event (AE) was defined as any untoward medical occurrence in a subject administered ketorolac as part of this clinical investigation, at any dose, that does not necessarily have to have a causal relationship with this treatment. Adverse experiences were elicited by asking the question: “Since you were last asked, have you felt unwell or different in any way?” All AEs were recorded, including onset, maximum severity, duration, outcome, and relationship to the study drug. The type and duration of follow-up of subjects after AEs were also documented. Adverse experiences were also reported spontaneously at any time.
Blood samples were collected into tubes containing sodium heparin and centrifuged at 3000 rpm within 30 minutes of collection. Plasma was removed and stored at −20°C. Plasma concentrations of ketorolac were determined using a validated assay. The analytical procedure involved extraction of ketorolac from plasma by using protein denaturation. The plasma samples were analyzed using a high-performance liquid chromatography method with tandem mass spectrometry detection. Quantification was achieved using analyte to internal standard peak area ratios. The lower limit of quantification for ketorolac was established as 0.05 mg/L and the upper limit of quantification was 4.98 mg/L. The interassay precision (percentage coefficient of variation) ranged from 5.6% to 9.2%. Interassay accuracy values (%bias) ranged from −3.5% to 5.5%.
(a) Population Parameter Estimations
A 1-compartment linear disposition model with first-order absorption and first-order elimination was used to analyze time-concentration profiles. Parameter estimates are confounded by bioavailability (F), which was not estimated with the current study design. The model was parameterized in terms of clearance (CL/F), volume of distribution (V/F), and an absorption rate constant (Ka). The latter was expressed as an absorption half-life (t1/2abs)
Population parameter estimates were obtained using nonlinear mixed-effects modeling (NONMEM VI; Globomax LLC, Hanover, MD).17 This model accounts for population parameter variability (between and within subjects) and residual variability (random effects) as well as parameter differences predicted by covariates (fixed effects). The population parameter variability in model parameters was modeled by a proportional variance model. Residual unidentified variability was described using a combined proportional and additive residual error model for each observation prediction (Err prop, Err add). The population mean parameters between subject variance and residual variance were estimated using the first-order conditional interaction estimate method using ADVAN4 TRANS4 of NONMEM VI. Convergence criterion was 3 significant digits. A Compaq Digital Fortran Version 6.6A compiler with Intel Celeron 333-MHz CPU (Intel Corp., Santa Clara, CA) under MS Windows XP (Microsoft Corp., Seattle, WA) was used to compile NONMEM.
The population parameter variability is modeled in terms of random-effect (η) variables. Each of these variables is assumed to have mean 0 and a variance denoted by ω2, which is estimated. The covariance between 2 elements of η (e.g., CL and V) is a measure of statistical association between these 2 variables. Their covariance is related to their correlation (R), i.e.,
The covariance of clearance and distribution volume variability was incorporated into the model.
(b) Covariate Analysis
The parameter values were estimated standardized for a body weight of 70 kg using an allometric model.18,19
where Pi is the parameter in the ith individual, Wi is the weight in the ith individual, and Pstd is the parameter in an individual with a weight Wstd of 70 kg. This standardization allows comparison of pediatric parameter estimates with those reported for adults. The PWR exponent was 0.75 for clearance, 0.25 for half-times, and 1 for distribution volumes.19 Covariate analysis included a model investigating age-related changes for clearance and volume of distribution using an exponential function20:
where Vstd and CLstd are the population estimates for V and CL, respectively, standardized to a 70-kg person using allometric models; age is expressed in years; SLPage is a slope parameter describing age-related changes of CL, referenced to a 15-year-old adolescent.
The analysis was repeated using the per kilogram model where clearance is expressed as:
(c) Quality of Fit
The quality of fit of the PK model to the data was sought by NONMEM's objective function and by visual examination of plots of observed versus predicted concentrations. Models investigating covariates such as age were nested and an improvement in the objective function was referred to the χ2 distribution to assess significance; e.g., an objective function change (OBJ) of 3.84 is significant at α = 0.05.
Bootstrap methods, incorporated within the Wings for the NONMEM program, provided a means to evaluate parameter uncertainty.21 A total of 1000 replications were used to estimate parameter confidence intervals. A visual predictive check (VPC),22 a modeling tool that estimates the concentration prediction intervals and graphically superimposes these intervals on observed concentrations after a standardized dose, was used to evaluate how well the model predicted the distribution of observed ketorolac concentrations.23,24 Simulation was performed using 1000 subjects with characteristics taken from studied patients. The VPC compares different percentiles of the observed data with percentiles of simulated data, generally grouped together within bins of an independent variable. For data such as these where covariates such as dose, weight, and height are different for each patient, we used a prediction corrected VPC (PC-VPC). In a PC-VPC, the variability coming from binning across independent variables is removed by normalizing the observed and simulated dependent variable based on the typical population prediction for the median independent variable in the bin.25
A simulation study was performed to investigate ketorolac concentrations in a child (15 years, 55 kg) given ketorolac 30 mg intranasally. PK parameter estimates and their variability from this current analysis were used to predict individual time-concentration profiles. Possible effect compartment concentrations were determined using a T1/2keo of 24 minutes.12
Peak concentration (Cmax) and time to peak concentration (Tmax) were calculated based on individual Bayesian parameter estimates. The following equations were used:
Where Ln is the natural logarithm, Ka is the absorption rate constant, K is the elimination rate constant, and EXP is the exponential function.
Demographics of the 20 participating subjects are listed in Table 1. One subject in the 30-mg group was withdrawn from the analysis of AEs (after dosing) because of unexpected early discharge 6 hours before the study end. Earlier concentration data were available for analysis. A further subject (weight 91 kg) refused a second administration spray and only received a 15-mg dose. The analysis comprised 20 subjects and 178 drug assay samples. There were 6 samples below the lower limit of quantification, all from the 24 hours sample time. Six samples were not obtained because of nonfunction of the IV sampling catheters. Individual observed plasma ketorolac concentrations are shown for both the 30-mg dose and the 15-mg dose in Figure 2.
A 2-compartment model was not superior to a 1-compartment model (ΔOBJ 4.427 despite 2 additional parameters required for the 2-compartment model). Application of allometric scaling (ΔOBJ 3.887) and linear per kilogram scaling (ΔOBJ 4.931) both improved fit over a model without size scaling; there was no difference between allometric and per kilogram scaling models. Body surface area scaling had a marginal improvement in objective function (ΔOBJ 3.285). The use of age did not improve the objective function. Parameter estimates for the 1-compartment analysis from both per kilogram and allometric scaling are shown in Table 2. The correlation of between subject variability for CL and V was 0.83 whereas that between CL and t1/2abs was 0.345 and V and t1/2abs was 0.117. Figure 3 shows a satisfactory PC-VPC plot for these PK data when analyzed using the allometric size model. There were no age-related changes of CL or V. Figure 4 demonstrates the quality of fit for PK data using the allometric size model over the study time period; each subject's data are connected by a line. The upper panel displays values from NONMEM's first-order conditional step (post hoc or posterior individual estimates) based on values of the parameters for the specific individual, whereas the lower panel displays values from the population parameters. Figure 5 shows predicted clearance changes with age for both per kilogram and allometric scaling matched to reported clearance estimates from the literature.12,26
Ketorolac time-concentration profiles and the 90% prediction intervals for a child (age 15 years, weight 55 kg) given ketorolac 30 mg intranasally are shown in Figure 6. The mean Tmax was achieved at 52 minutes (SD 6 minutes).
Eleven AEs from 8 subjects occurred after drug dosage; they were considered possibly drug-related. Three occurred in the 15-mg dose group and 8 occurred in the 30-mg dose group. Five of the 11 events were considered “probably related” to the study drug, whereas the others were considered “probably not related.” The former were dysgeusia (decrease in sense of taste; 1 episode), nasal discomfort (3 episodes), and rhinalgia (1 episode). One event of nausea and vomiting was serious enough to be called a serious AE; this event was not considered to be study drug–related.
Administration of intranasal ketorolac was well tolerated in this population of 20 postoperative adolescents, with only 5 events of a minor nature probably related to the ketorolac delivery. Onset of calculated peak drug concentration (Tmax 52 minutes) was similar to that reported after intranasal administration (30–45 minutes) using the same device6,7 and after IM injection (45 minutes) in adults.6,7,15,16,27 These latter estimates of Tmax in adults were taken from direct experimental observations, resulting in estimates that are dependent on sample timing for assay.
The relative bioavailability (Fpo) of ketorolac is 0.81 (range 0.69–0.90).28 Clearance estimates after IV ketorolac administration range from 1.47 L/h/70 kg to 2.31 L/h/70 kg,12,16,28 although it is not clear from those analyses whether dose was corrected for its salt. Jallad et al.15 compared IM administration (CL/F 1.85 L/h/70 kg) with oral administration (CL/F 2.31 L/h/70 kg) in healthy adults with dose correction. Our current estimate of clearance of 2.05 L/h/70 kg is consistent with high relative bioavailability of the intranasal formulation, attributable to bypassing the portal vein and its first-pass effect during absorption. The volume of distribution estimate of 15.2 L/70 kg is also similar to that described by others in both adults12,16,28 and children14 after IV administration. Figure 5 shows that the use of the allometric size model was better than the per kilogram model for predicting clearance in age groups other than the adolescents from this current study; the linear per kilogram model tends to underpredict in younger age groups and overpredict in older age groups. This is a common observation in pediatric PK where clearance in younger children (>2 years after maturation is complete) is greater than adults when expressed as per kilogram. This is an artifact of size scaling. Maturation occurs over the first few years of life so the observed CL of 7.8 mL/min in the 1 to 3 years age group is lower than predicted by allometry.19
An integrated PK-pharmacodynamic analysis for ketorolac postoperative analgesia in adults estimated an effect compartment EC50 (50% effective concentration) of 0.37 mg/L with an equilibration half-time (T1/2keo) of 24 minutes.12 Clearance was 1.86 L/h and volume of distribution at steady-state was 12.8 L in that adult population. Although EC50 is related to the magnitude of the pain stimulus and although any T1/2keo is specific to the PK parameters used and cannot be indiscriminately applied to a different PK parameter set. We might anticipate concentrations of 0.37 mg/L in the effect compartment to be achieved within 30 minutes after a dose of 30 mg in this current population with peak effect compartment concentrations at 1.5 to 2 hours (Fig. 4) because PK parameter estimates are similar to those described by Mandema and Stanski12 and are consistent with postoperative analgesic observations by others7,27 after similar dosing.
Results in adolescents are presented as results for a 70-kg person to allow comparison with adult parameters reported by others.6,7 Our study demonstrates that the PK of intranasal ketorolac in adolescents is similar to those reported in adults, assuming use of the same nasal administration device. 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. The current study design comprised a limited age range of 12 to 17 years because the delivery system used only allowed administration of a fixed dose of 15 mg. Future studies evaluating the PK of intranasal ketorolac in younger children would be useful with devices capable of delivering smaller doses.
Name: David R. Drover, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: David R. Drover has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Gregory B. Hammer, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Gregory B. Hammer has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Brian J. Anderson, PhD, FANZCA.
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Brian J. Anderson has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
This manuscript was handled by: Peter J. Davis, MD.
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