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Pharmacokinetics of Single-Dose Intravenous Ketorolac in Infants Aged 2–11 Months

Cohen, Mindy N., MD*; Christians, Uwe, MD, PhD; Henthorn, Thomas, MD; Vu Tran, Zung, PhD; Moll, Vanessa, MD; Zuk, Jeannie, PhD*; Galinkin, Jeffrey, MD*

doi: 10.1213/ANE.0b013e3182075d04
Pediatric Anesthesiology: Research Reports
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BACKGROUND: Ketorolac is a parenterally available nonsteroidal antiinflammatory drug that nonselectively inhibits cyclooxygenase. Ketorolac is an attractive alternative to opioids in the pediatric population because of its favorable side effect profile; it provides postoperative analgesia similar to morphine, but is associated with significantly less respiratory depression, pruritus, and emesis. Despite the efficacy of ketorolac in young patients, there are minimal data to characterize the pharmacokinetic variables of ketorolac in infants younger than 6 months.

METHODS: In this study, 17 infants younger than 1 year old, without renal or liver disease, undergoing elective surgery received a single-dose of IV ketorolac 0.5 mg/kg. Blood was sampled at 0, 5, 10, 15, 30, 60, and 120 minutes, and at 4, 6, 12, and 24 hours. Ketorolac levels were analyzed using a specific and validated high-performance liquid chromatography method with mass spectrometry (LC-LC/MS/MS). Pharmacokinetic analysis of individual subjects and population pharmacokinetic modeling was performed using SAAM II and PopKinetics, respectively (SAAM Institute, University of Washington).

RESULTS: Characterization of pharmacokinetic parameters was possible in 14 subjects. The data were best described by a 2-compartment model. Estimated individual parameters were clearance 1.49 ± 1.12 mL/min/kg, Vss (volume of distribution at steady state) 0.31 ± 0.11 L/kg, and half-life of 236 ± 169 minutes. Estimated population pharmacokinetic parameters were clearance 1.52 mL/min/kg and Vss 0.29 L/kg. There was a trend toward lower clearances in younger patients.

CONCLUSION: This is the first report of individualized pharmacokinetic parameters of ketorolac in children in which the majority of subjects were younger than 6 months old.

Published ahead of print January 13, 2011

From the *Department of Anesthesiology, The Children's Hospital, and the Department of Anesthesiology and School of Pharmacy, University of Colorado Denver, Aurora, Colorado.

Supported by grant no. 5 M01 RR00069 General Clinical Research Centers Program, National Centers for Research Resources, National Institutes of Health.

The authors declare no conflicts of interest.

Address correspondence and reprint requests to Mindy N. Cohen, MD, The Children's Hospital, 13123 East 16th Ave., B090, Aurora, CO 80045. Address e-mail to mindycohenmd@gmail.com.

Accepted October 20, 2010

Published ahead of print January 13, 2011

Ketorolac is a parenterally available nonsteroidal antiinflammatory drug that acts by nonselectively inhibiting the function of the cyclooxygenase enzymes.13 Ketorolac is an attractive alternative to opioids in the treatment of perioperative pain in the pediatric population because of its favorable side effect profile. Intraoperative ketorolac provides postoperative analgesia similar to that associated with morphine, but is associated with significantly less emesis, respiratory depression, pruritus, and sedation compared with opioids in adult subjects.49

Ketorolac possesses a chiral center and is comprised of (+)R and (−)S enantiomers in equal portions. Pharmacologic activity resides almost exclusively with the (−)S enantiomer.10 The ketorolac (−)S enantiomer has an increased clearance and shorter half-life compared with (+)R.1113 The majority of studies have analyzed racemic ketorolac.1418 Clearance and half-life values of enantiomers do not routinely correlate with racemic values.

Ketorolac undergoes a minimal amount of metabolism, with >96% of the drug-related material circulating in the plasma being the parent drug. The remaining drug is the pharmacologically inactive p-hydroxyketorolac. The products of metabolism and unchanged drug are eliminated primarily by the kidneys, with 90% of an administered dose excreted in the urine. Ketorolac is water soluble and highly bound in adult human plasma (99.2%) in a concentration-independent manner.19 Neonates and infants have a relatively higher fractional volume of body water and an increase in the unbound fraction of drugs because of lower plasma protein concentrations. Extrapolation of dosing regimens from results obtained in adult subjects should be done with caution.

Despite its common administration in pediatric patients, characterization of the pharmacokinetic parameters of ketorolac in infants is incomplete. Renal function, liver function, and protein binding in infants differ from older children, often having a profound effect on drug metabolism and distribution. Because of age-related lower renal clearance, it has been hypothesized that the clearance of ketorolac will be lower in younger infants. Previous studies have produced conflicting results regarding pharmacokinetic changes observed in various age groups. Whereas some studies report differences in ketorolac pharmacokinetics in children compared with adults,12,15,17,2022 one study demonstrated that body weight–normalized pharmacokinetic variables were similar to those reported for adults.16

Recent publications have reported population-based pharmacokinetic parameters in children aged 6 to 18 months13 and in neonates and infants aged 0.4 to 32 weeks.18 We are reporting results of a prospective study of individual pharmacokinetic parameters in infants aged 11 months or younger who received single-dose IV ketorolac. This is the first study to report full pharmacokinetic parameters of ketorolac in individual subjects, compared with pooled population pharmacokinetics in previous studies.

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METHODS

Clinical Trial

After approval by the local IRB, parents or guardians of infants younger than 1 year old, meeting ASA classification I to III, undergoing elective surgery at The Children's Hospital in Denver, who were expected to require >24 hours of postoperative inpatient stay were approached for enrollment. Children with a history of prematurity (<37 weeks); low birth weight (<2500 g); hepatic, renal, cardiac, or hematologic disease; weight <3000 g at the time of surgery; allergy to ketorolac; current use of aspirin; or a high risk of postoperative bleeding as predicted by the surgeon were excluded from consideration. Written informed parental consent was obtained before beginning any study procedures. After induction of general anesthesia, a second IV cannula was placed and heparin-locked to be used exclusively for blood sample collection. Upon completion of the surgery, ketorolac (APP Pharmaceuticals, LLC, Schaumburg IL) 0.5 mg/kg was administered IV. One milliliter venous blood was sampled at 0, 5, 10, 15, 30, 60, and 120 minutes, and at 4, 6, 12, and 24 hours. Blood was collected in heparinized tubes, centrifuged, and the plasma component was stored at −70°C until analyzed.

If the IV cannula failed postoperatively, collection of further samples was terminated. Blood samples were not collected past the 15-minute time point in 3 of the subjects because of failure of the IV cannula; these 3 subjects were not included in the pharmacokinetic analysis. Ten of the 14 remaining sampling catheters failed prematurely: 14 samples were collected at 2 hours, 10 samples at 4 hours, 6 samples at both 6 hours and 12 hours, and 4 samples at 24 hours.

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Drug Quantification

Human plasma calibration standards of racemic ketorolac (0, 0.01, 0.025, 0.05, 0.1, 0.25, 0.5, 1, 2.5, 5, 10, and 25 μg/mL) were prepared by spiking the appropriate amount of the working standard solution of ketorolac into drug-free human plasma. Quality-control samples at 0.01, 0.1, 0.5, 2.5, and 15 μg/mL were prepared in bulk by adding the appropriate working standard solution to drug-free human plasma. Purified standards for individual enantiomers, (−)S and (+)R, were not commercially available because of discontinuation of manufacturing at the time of sample analysis. Therefore, enantioselective drug quantification was not performed.

Samples were extracted as previously described.23 Analysis of the plasma samples was performed using a mass spectrometry (LC-LC/MS/MS) system, using tolmetin as an internal standard. High-performance liquid chromatography (HPLC) I was used for on-line sample extraction, HPLC II for sample analysis. The 2 HPLC systems consisted of the following components (all series 1100; Agilent Technologies, Palo Alto, CA): HPLC I: G1312A binary pump, G1379A degasser; HPLC II: G1312A binary pump, and a G1316A column thermostat. A Sciex API 4000 triple-stage quadrupole mass spectrometer was used as detector (Applied Biosystems, Foster City, CA). The HPLC systems were connected via a 6-port column switching valve mounted on a step motor (Rheodyne, Cotati, CA). Details have been previously described by our group.24 The HPLCs, switching valve, and the mass spectrometer were controlled by Analyst software (version 1.4.1; Applied Biosystems). For on-line sample cleanup, 10 μL supernatant was loaded onto an extraction column (4.6 × 12.5 mm, Eclipse XDB-C8; Agilent) and was washed with a high flow (5 mL/min). The switching valve was activated and the analytes were then backflushed onto the C8 analytical column (4.6 × 100 mm, ZORBAX Eclipse XDB-C8; Agilent). A linear gradient was used: 70% methanol to 95% in 4 minutes and was kept at 100% for 1 minute. Flow rate was 1 mL/min. The triple quadrupole mass spectrometer and HPLC system interfaced with a turbo-ion spray source. Nitrogen (purity: 99.999%) was used as collision-activated dissociation gas. The mass spectrometer was run in the positive multiple reaction monitoring mode. The declustering potential was set to 36 V. The interface was heated to 450°C. Detection of the ions was performed by monitoring the transitions of m/z 256.0→178.0 for ketorolac and m/z 258.05→119.0 for tolmetin (internal standard). Ketorolac was quantified based on the area-under-the-peak ratios of analyte and internal standard. Calibration curves were constructed using quadratical 1/x regression by plotting nominal concentration versus analyte area/IS area ratios. Ketorolac concentrations were quantified using the calibration curves that were included in each batch. The retention times of ketorolac and tolmetin were 3.4 and 3.6 minutes, respectively. There was no evidence of carryover of matrix components or analytes between runs. The method was linear over a concentration range of 10 ng to 25 μg/mL. Limit of detection, lower limit of quantification, and upper limit of quantification were 5 ng/mL, 10 ng/mL, and 25 μg/mL, respectively. The correlation coefficient of the calibration curves was consistently more than r2 = 0.99. The intraday and interday coefficients of variation were ±7.1% and ±6.9%, respectively. The absolute recovery of ketorolac from human plasma matrix at concentrations of 1, 5, and 25 ng/mL was 87.9%, 66.2%, and 63.0%, respectively. The absolute recovery of tolmetin from human plasma matrix at concentrations of 1, 5, and 25 ng/mL was 62.3%, 63.1%, and 62.2%, respectively. To test whether ion suppression compromised quantification of ketorolac, the effect of plasma samples (n = 6) was tested following the recommendations by Müller et al.25 When using an atmosphere pressure chemical ionization interface, ion suppression in human plasma was detected only during the time of the injection peak and did not interfere with the detection of ketorolac or the internal standard.

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Pharmacokinetic Analysis

The data from 14 subjects were used to develop a model for evaluation of individual pharmacokinetic parameters. Plasma ketorolac concentration versus time data were fitted with 1-, 2-, and 3-compartment pharmacokinetic models with the SAAM II software system (SAAM Institute, Seattle, WA) by using a relative error model as described previously.26,27 A 2-compartment model revealed the best fit for the data. The parameters of the model were defined as clearance (mL/min/kg), volume of central compartment V1 (L/kg), and volume of peripheral compartment V2 (L/kg). Steady-state volume of distribution (Vss) (L/kg) was defined as V1 + V2. Data were weighted by the reciprocal of their standard deviation, assuming a fractional standard deviation of 0.5. Visual inspection of the measured and predicted plasma concentrations versus time relationships revealed suspected model misspecification. The appropriateness of the model was verified using the Akaike information criterion and the Schwarz criterion. Final estimates of the terminal exponential rate constants of the fitted function were used to calculate elimination half-lives.

Data were also analyzed using noncompartmental statistical moments analysis to determine the area under the concentration-time curve, volume of distribution, and clearance using commercially available PK Solutions 2.0 software (Summit Research Services, Montrose, CO; www.SummitPK.com). Terminal elimination half-lives and the volume of distribution were obtained by stripping the concentration-time plots and fitting an exponential curve using PK Solutions software.

In addition to determining each subject's individual pharmacokinetic parameters, an iterated 2-stage population pharmacokinetics analysis was performed using PopKinetics software (SAAM Institute).

Individual subject's ketorolac clearance versus age was plotted to analyze for trends with renal maturation through the first year.

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RESULTS

Twenty-one subjects were enrolled in the study. Four subjects were withdrawn because either a second IV cannula could not be placed or because the patient did not receive the study drug. Fourteen subjects were ultimately analyzed (Table 1 shows demographics for all 17 subjects). The mean (range) age and weight were 6.2 (2–11) months and 6.77 (4.70—9.39) kg, respectively. Six of the 14 subjects were younger than 6 months old.

Table 1

Table 1

Ten of the 14 remaining sampling catheters failed prematurely, as described above. Sampling catheter failure did not correlate with subject age. Mean age remained similar at all time points.

The plasma concentration versus time is displayed in Figure 1. Both compartmental and noncompartmental individual observed clearance, Vss, and half-life values are presented in Table 2. Two-compartment 2-stage iterated population pharmacokinetic analysis revealed a clearance of 1.52 (mL/min/kg) and Vss of 0.29 (L/kg).

Figure 1

Figure 1

Table 2

Table 2

Graphical comparison of clearance versus age suggested a trend toward higher clearance in older infants (Fig. 2); however, regression calculations were not statistically significant. Body size and age were not included as individual covariates in the model because the number of subjects in this study was too small to support covariate analysis.

Figure 2

Figure 2

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DISCUSSION

This study contributes important, difficult-to-obtain data to the study of pharmacokinetics of ketorolac in infants. This is the first report of individualized pharmacokinetic parameters in infants. In comparison to previous reports of pooled data for a group of subjects, our study presents full pharmacokinetic parameters for each individual infant. Similar to many drugs used in the pediatric population, ketorolac is frequently used without a clear understanding of the appropriate dosing regimen, the goal being maximal benefit and minimal risk.

To provide analgesia to 50% of adults (EC50), the plasma concentration of ketorolac must be ≥0.37 μg/mL.28 Of the 14 subjects who received 0.5 mg/kg IV ketorolac, modeling and/or observation predicted 4 (29%) had plasma levels less than the EC50 only 3 hours after dosing, 7 (50%) had levels less than EC50 4 hours after dosing, and 10 (71%) had levels less than EC50 6 hours after the dose. Based on these findings, a dosing regimen of boluses every 4 to 6 hours would be reasonable to provide plasma levels consistent with analgesia in most infants. This conclusion must be qualified by the fact that the EC50 has not been determined for this young age group. Our study did not examine the pharmacokinetics of repeated doses, and future studies are needed for definitive recommendations. Similarly, this study did not measure the pharmacodynamics of ketorolac in infants. Thus, assumptions extrapolated from the adult EC50 may be incorrect. Future studies of the pharmacodynamics of ketorolac will be important to guide dosing regimens that maximize benefit in infants requiring analgesia.

Ketorolac carries a risk of causing acute renal insufficiency, gastric ulcers, and inhibition of platelet activity if given in high doses and/or for several consecutive days because of inhibition of prostaglandin synthesis. Decreased renal vasodilation can decrease renal blood flow and glomerular filtration rate resulting in acute renal failure. Alternatively, ketorolac can cause interstitial nephritis. It has been reported that 1% of the population receiving ketorolac will experience some form of renal dysfunction as defined by an increase in creatinine from baseline.29 There are case reports of previously healthy children who developed transient acute renal failure after receiving ketorolac30,31 and a case of irreversible renal failure in a child with sickle cell disease.32 As a requisite for enrollment, all subjects had normal renal function, by history, before surgery. This study protocol did not include a scheduled measurement of the subjects' renal function before or after receiving ketorolac because of sample volume restrictions. For 2 of the subjects, creatinine levels were obtained perioperatively in the course of their routine care. Preoperative/postoperative creatinine levels were 0.3/0.2 and 0.3/0.3 in subjects 11 and 16, respectively. There was no evidence of decreased urine output or altered renal function in any of the subjects. Future studies of ketorolac in infants could benefit from including formal analyses of kidney function.

Our results for clearance, volume of distribution, and half-life are similar to those published previously (Table 3). In contrast to previously stated hypotheses, that younger age would be associated with decreased clearance, we have provided evidence to support the findings of other researchers that clearance of ketorolac in infants is similar to that observed in adults.

Table 3

Table 3

A limitation of the current study is the small number of subjects and the large observed standard deviations. However, this sample size and large intersubject variability are typical of most pediatric pharmacokinetic studies. A study with a larger sample size is required to develop a model of ketorolac pharmacokinetics in infants and to offer further advice on dosing recommendations of ketorolac in infants. A second limitation of the study is the inability to develop an assay to measure the pharmacokinetics of the individual ketorolac enantiomers. This was secondary to the lack of a commercially available source for enantiopure standards. Future studies of interest would include multiple-dose pharmacokinetic studies and pharmacodynamic studies in infants younger than 1 year of age.

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DISCLOSURES

Name: Mindy N. Cohen, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Mindy N. Cohen 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: Uwe Christians, MD, PhD.

Contribution: This author helped analyze the data and write the manuscript.

Attestation: Uwe Christians has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Thomas Henthorn, MD.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Attestation: Thomas Henthorn has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Zung Vu Tran, PhD.

Contribution: This author helped analyze the data and write the manuscript.

Attestation: Zung Vu Tran has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Vanessa Moll, MD.

Contribution: This author helped analyze the data and write the manuscript.

Attestation: Vanessa Moll has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Jeannie Zuk, PhD.

Contribution: This author helped design the study, conduct the study, and write the manuscript.

Attestation: Jeannie Zuk has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Jeffrey Galinkin, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Jeffrey Galinkin has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

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