Anesth Analg 2004;99:1347-1351
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000132777.00967.A3
PEDIATRIC ANESTHESIA
The Pharmacokinetics of the Intravenous Formulation of Fentanyl Citrate Administered Orally in Children Undergoing General Anesthesia
Melissa Wheeler, MD*,
Patrick K. Birmingham, MD*,
Ralph A. Lugo, PharmD
,
Corri L. Heffner, RN*, and
Charles J. Coté, MD*,
Department of *Anesthesiology and the
Pediatrics, Children’s Memorial Hospital, The Feinberg School of Medicine at Northwestern University, Chicago, Illinois, and the
University of Utah College of Pharmacy and School of Medicine, Salt Lake City, Utah
Address correspondence and reprint requests to Melissa Wheeler, MD, Department of Pediatric Anesthesiology, #19, Children’s Memorial Hospital, 2300 Children’s Plaza, Chicago, IL 60614. Address email to mwheeler{at}northwestern.edu
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Abstract
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The bioavailability of oral transmucosal fentanyl citrate (OTFC) in children is similar to that of fentanyl solution administered orally to adults. We hypothesized that administering an oral fentanyl solution to children would result in similar fentanyl plasma concentrations and pharmacokinetic variables as administering comparable doses of OTFC. In this pilot study, 10 healthy children requiring postoperative analgesia were enrolled. Each received the undiluted IV fentanyl formulation orally (approximately 10–15 µg/kg; maximum, 400 µg). Venous blood samples were collected from 15 to 600 min after administration. Pharmacokinetic variables were determined using noncompartmental analysis and were compared with a previously studied population of children who received a similar dose of OTFC. Pharmacokinetic variables for the orally administered IV fentanyl formulation were as follows: time to reach peak concentration = 1.7 ± 1.6 h, peak concentration = 1.83 ± 1.19 ng/mL, half-life = 4.7 ± 2.8 h, area under the plasma concentration time curve = 6.46 ± 3.96 h · ng–1 · mL–1, apparent oral volume of distribution (V/F) = 17.5 ± 7.2 L/kg, apparent oral clearance (CL/F) = 3.33 ± 2.25 L · kg–1 · h–1. Although both OTFC and orally administered IV fentanyl resulted in similar pharmacokinetic variables and plasma concentrations for a given dose, there was marked interpatient variability, particularly in the early hours after oral administration of the IV formulation of fentanyl. This suggests that this method of administration be used with caution until further data are available.
IMPLICATIONS: In this pilot study of 10 children undergoing general anesthesia, we found pharmacokinetic variables and plasma concentrations with the IV formulation of fentanyl given by mouth to be similar to those described for oral transmucosal fentanyl. Further studies of efficacy and safety are required before this method of fentanyl administration can be safely recommended.
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Introduction
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Studies in adults indicate that the administration of the fentanyl Oralet® (oral transmucosal fentanyl citrate [OTFC]) (Abbott Laboratories, Abbott Park, IL) results in a fentanyl bioavailability ranging from 34% to 59% (mean, 47% ± 8%) (1,2). The package insert states that absorption pharmacokinetics of OTFC in adults is a combination of an initial rapid absorption from the buccal mucosa (25% of the dose) and a more prolonged absorption from the gastrointestinal tract (3). The package insert further states that approximately 25% of the OTFC escapes first pass metabolism and is bioavailable (3). Thus, in adults who receive OTFC, buccal absorption and gastrointestinal absorption contribute equally to an overall bioavailability of approximately 50% (1–3). However, studies conducted by our group indicate less bioavailability of OTFC in children (33% and 36% ± 1%) (4,5). These values are very similar to those reported in adults administered an oral fentanyl solution made from OTFC (32% ± 10%) (1). These observations suggest that buccal absorption in children receiving OTFC may contribute less to the overall bioavailability than does gastrointestinal absorption. We hypothesized that oral administration of the IV formulation of fentanyl citrate bypasses buccal absorption and therefore results in similar plasma concentrations and pharmacokinetics as an equivalent dose of OTFC.
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Methods
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This study was approved by our IRB. Parents provided written informed consent. Subjects were healthy children (ASA physical status I–II) between ages 5 and 11 yr. We chose to enroll 10 children in this exploratory study because a similar number of adult volunteers was used to compare the pharmacokinetics of OTFC with an oral fentanyl solution (1). All children enrolled in the study were scheduled for elective surgical procedures that had minimal anticipated blood loss, required overnight hospitalization, and were anticipated to require postoperative analgesia. The undiluted IV formulation of fentanyl citrate (50 µg/mL; Abbott Laboratories, Abbott Park, IL) was administered orally (by syringe or medicine cup) in a dose of approximately 10–15 µg/kg (maximum dose, 400 µg). The dose range was chosen to be similar to the dose of OTFC used in our previous studies (4,5). The largest OTFC dose approved by the Food and Drug Administration at the time of our previous studies was 400 µg; therefore, the largest dose of liquid fentanyl used in the current study was limited by our IRB to 400 µg. After the administration of liquid fentanyl, subjects were instructed to "swish and swallow" 2 5-mL aliquots of water to minimize transmucosal absorption of fentanyl (1). Although the children were not specifically questioned about the taste of the medication, the same observer noted facial expressions and recorded any spontaneous comments the children made regarding the taste. A research nurse continuously monitored oxygen saturation and observed for side effects such as pruritus, vomiting, and desaturation.
Up to 16 2-mL blood samples were obtained from a peripheral IV catheter that was placed after induction of anesthesia. All blood samples were collected by the same research nurse at 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 180, 240, 300, 360, 480, and 600 min after fentanyl ingestion. Plasma was separated and frozen at –20°C for later analysis. Fentanyl stock solutions were prepared at 0.01, 0.1, 1, and 10 ng/mL. Standard curves consisted of plasma fortified with fentanyl at 0.05, 0.08, 0.1, 0.5, 1, 2, 3, 5, 10, 25, 50, and 100 ng/mL. Quality controls for the fentanyl assay were prepared in duplicate or triplicate at 0.1, 0.5, 1, and 10 ng/mL. Deuterated internal standards (FT-d5) were added to 250 µL of plasma (final concentration = 0.5 ng/mL). Ammonium hydroxide (50 µL) was added to adjust pH (>9.0) and specimens were extracted with butyl chloride and acetonitrile (4:1; v/v). After centrifugation, the organic phase was transferred to clean, silanized glass tubes and solvent evaporated at <40°C under a stream of air. Extracts were reconstituted in mobile 0.1% formic acid and methanol (9:1; v/v). Analyses were performed on a THERMO TSQ7000 LC/MS/MS in ESI mode (electrospray ionization). Peak/height ratios were calculated and the concentration of each analyte was determined from least-squares regression analysis of standards. Intra- and interassay coefficient of variation for fentanyl was <18% at 0.1 ng/mL, <10% at 0.5 and 1 ng/mL, and <5% at 10 ng/mL. The limit of quantification was 0.05 ng/mL.
Several methods of pharmacokinetic analysis were initially attempted. Concentrations were fit to a one- and two-compartmental model using first order input with and without a lag time (WinNonlin version 3.1; Pharsight Corp, Cary, NC) using each patient’s own concentration data. In addition, aggregate concentration data were analyzed using a naïve pooled data analysis. Goodness-of-fit for each analysis was determined by 1) analysis of residuals and symmetric distribution about the mean; 2) analysis of the precision of variable estimates; 3) Akaike information criteria; and 4) condition number, which measures the stability of the final model solution and the precision with which variables can be measured (6). Overall, individual and aggregate data fit poorly to one- and two-compartment models. Accordingly, a noncompartmental analysis (WinNonlin) was chosen to analyze the data.
Plasma concentrations obtained for each patient after the administration of a single oral dose of the IV formulation of fentanyl were used to calculate area under the plasma concentration time curve (AUC) and area under the moment curve (AUMC) from time 0 to infinity using the linear trapezoidal rule. The area from the last measured concentration (Cpfinal) to infinity was extrapolated by dividing Cpfinal by the slope of the terminal elimination phase (mean extrapolated AUC ranged from 27.5% to 37%). Apparent oral fentanyl clearance (CL/F) was calculated by dividing the oral dose by the AUC. Apparent oral volume of distribution at steady state (V/F) was calculated by dividing the oral dose by (
z x AUC), where z is the slope of the terminal elimination phase that was calculated using 3 to 6 data points selected by WinNonlin. The peak concentration (Cmax) and the time to reach Cmax (Tmax) were read directly from the concentration time profiles.
Noncompartmental analysis (WinNonlin version 3.1, Pharsight Corp, Cary, NC) was used to re-examine OTFC data from two previous studies by our group (4,5). Pharmacokinetic data from these studies were combined and statistically compared to the pharmacokinetics of orally administered liquid fentanyl in the current study. The Student’s t-test and analysis of variance (SigmaStat, SPSS, Inc., Chicago, IL) were used to compare the pharmacokinetic variables, demographics, and doses among the different groups.
Because Tmax is dependent in part on sampling times and because it does not necessarily reflect the onset of clinical analgesia, we determined the time to achieve a minimum effective concentration. We defined the minimum effective fentanyl plasma concentration as 
0.6 ng/mL. This value was derived from our previous OTFC studies and the current study and was defined as the time of rescue analgesic requirement after both IV and OTFC administration (4). These values were 0.7 ± 0.48 ng/mL (range, 0.12–1.37 ng/mL) for the combined OTFC data and 0.50 ± 0.33 ng/mL (range, 0.14–1.30 ng/mL) for the IV fentanyl administered orally. These were similar to fentanyl levels obtained from an IV patient-controlled analgesia study in adults (0.63 ± 0.25; range, 0.23–1.18 ng/mL) (7). We empirically noted the average of these values to be approximately 0.6 ng/mL. The time to achieve a fentanyl concentration of 0.6 ng/mL was read directly from the concentration time profiles, and this time was statistically compared among the different groups using analysis of variance (SigmaStat, SPSS, Inc., Chicago, IL).
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Results
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Ten children were enrolled in the study. The mean age was 7.9 ± 1.9 yr (range, 5–10.3 yr), and the mean weight was 28.2 ± 10.2 kg (range, 17.8–47.4 kg). The mean fentanyl dose was 13.9 ± 1.41 µg/kg (range, 9.40–15.1 µg/kg). Seven children received 14.8–15.1 µg/kg; three children received a lesser amount (9.4, 12.3, and 13.1 µg/kg) because of the upper dose limit of 400 µg. Three children were taking concomitant medications (one albuterol inhaler, two oxybutynin). Neither of these medications affects fentanyl metabolism or distribution. All children readily swallowed the entire dose of the IV formulation of fentanyl and successfully completed the "swish and swallow" of water. No patient spit out a dose or had his stomach suctioned during the course of the anesthetic. Two of the 10 patients were noted to grimace and described the taste as "sour;" the remaining patients neither grimaced nor commented on taste. No episodes of nausea, vomiting, or desaturation occurred during the 10–25 min observation period before induction. Two patients complained of an "itchy nose" at 7–8 min after fentanyl ingestion; this side effect did not correlate with plasma fentanyl concentration, as 1 patient had the lowest measurable levels and the other had the highest. No episodes of desaturation occurred postoperatively.
Because the primary purpose of the study was to analyze pharmacokinetics, an antiemetic was given at the discretion of the anesthesia team. Five patients received ondansetron intraoperatively (0.1 mg/kg, up to 4 mg IV); 2 of these patients still vomited in the postoperative period. Of the 5 patients who did not receive ondansetron, 3 had postoperative vomiting.
The mean anesthetic time was 184 ± 87 min (range, 100–454 min). Anesthesia consisted of inhaled induction with sevoflurane and N2O in O2 and maintenance with isoflurane and N2O in O2. All patients received a nondepolarizing muscle relaxant, either pancuronium or rocuronium. Analgesic effect was not studied; therefore, additional analgesia (excluding fentanyl) was administered at the discretion of the anesthesia team. All patients received some form of analgesia in addition to the fentanyl. Four patients received ketorolac either intraoperatively or postoperatively. Three patients, including one who also received ketorolac, had a field block placed by the surgeon. Three patients received a caudal block. One patient received intraoperative morphine.
One-hundred-thirty-four of 160 possible samples were collected and quantified; 3 patients had all 16 samples, 3 patients had 15 samples, and 3 patients had 11 samples. One patient had only 8 samples collected because of IV failure at 150 min. Seven samples were below the limits of detection, leaving 127 samples for final analysis. The plasma concentration time curves are illustrated in Figure 1.
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Figure 1. Measured plasma fentanyl concentrations versus time for 10 children administered the IV formulation of fentanyl citrate orally.
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Pharmacokinetic variables are listed in Table 1. These were compared with the reanalyzed data from our two previous studies of children who received OTFC (Table 2) (4,5). Only two variables, Tmax and V/F, were statistically different between the combined OTFC data and the oral liquid fentanyl data. Although failing to reach statistical significance, there was a trend toward a larger Cmax in the current study as compared with the Cmax in the combined OTFC studies (P = 0.068). Although the target dose ranges were the same for all studies, there was a small but statistically significant difference in the mean dose of fentanyl (µg/kg) between the studies (12.2 versus 12.7 versus 13.9 µg/kg; P = 0.02, analysis of variance); the largest mean dose was in the current study. With or without dose normalization, the fentanyl concentrations achieved after administration of both formulations were comparable and similarly variable. A further observation is that the terminal elimination phase of the plasma concentration time curves appears to be relatively flat at approximately 3 h with the OTFC compared to approximately 5 h with the oral liquid fentanyl. However, the time to achieve a fentanyl concentration of 0.6 ng/mL was not significantly different between the two previous OTFC studies and the current study of orally administered IV formulation of fentanyl (Table 2).
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Table 1. Pharmacokinetic Variables of the IV Formulation of Fentanyl Administered Orally in Preoperative Children
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Table 2. Noncompartmental Analysis of Fentanyl Concentrations in Children: Oral Administration of IV Fentanyl Versus Fentanyl Oralet®
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Discussion
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The Fentanyl Oralet® was developed to provide a transmucosal drug delivery system that would obviate the need for IM injection and minimize the first-pass metabolism of orally administered fentanyl. However, when used in children, there are a number of disadvantages. These include chewing of the lozenge, large time variability for complete consumption of the lozenge, the need for constant supervision during this variable consumption time, and patient refusal to consume the lozenge either initially or "midstream." In contrast to OTFC, oral administration of the IV formulation of fentanyl provides some distinct advantages, including ease of administration, rapid administration consisting of a single swallow, thus avoiding the variable and often prolonged consumption of a lozenge (range, 5–45 min), and avoidance of administering a partial dose as a result of patient refusal to consume the lozenge (4,5).
Consistent with our hypothesis, the concentration time curves demonstrate that the IV formulation of fentanyl administered by mouth is rapidly absorbed from the gastrointestinal tract, producing a prolonged concentration time profile with a relatively flat terminal elimination phase, which is similar to findings in our previous studies of OTFC (4,5). However, this plateau appears to occur later with the liquid formulation. Some of the patients who received the oral liquid fentanyl achieved larger plasma concentrations than were observed in patients receiving the OTFC. This may be a result of the rapid (bolus-like) administration of the liquid as compared with the prolonged administration time required for the OTFC. A few of the patients who received the oral liquid fentanyl had a small and relatively late Cmax. The observations in this study may have important pharmacodynamic implications; i.e., rapid uptake in some patients may result in relatively excessive drug delivery, prolonged high blood levels, and late respiratory complications. In contrast, in those patients with a small and late Cmax, adequate analgesic levels may not be attained at the intended time.
Pharmacokinetic variables of the orally administered IV formulation of fentanyl were also comparable to the noncompartmental variables of the OTFC. CL/F, AUC, and half-life were all similar between children who received OTFC and those who received the orally administered liquid fentanyl. Although not statistically significant, there was a trend toward a larger Cmax in the current study as compared with the combined OTFC data from our previous studies. This may be explained by the slightly larger mean dose in this study as compared with the previous 2 studies of OTFC. The reason for the smaller average dose in the OTFC studies is because of the dosing constraints of OTFC; that is, with the unit-based OTFC (e.g., 200 µg, 400 µg), it is impossible to precisely dose on a µg/kg basis. However, even after normalizing Cmax for dose, the concentration achieved with the liquid fentanyl remained somewhat larger. We also observed waxing and waning of fentanyl levels that is similar to many other reports of fentanyl pharmacokinetics (1,3,8,9). Nine patients in the current study exhibited multiple secondary peaks on the concentration time curves. This phenomenon has been observed in both children and adults administered fentanyl IV and in those who have received OTFC (1,3,8,9).
The Tmax after orally administered liquid fentanyl occurred significantly later than with OTFC. This observation may be in part an artifact created by differences in sampling times between the studies. It may also reflect an apparent subgroup of patients who achieved a relatively small and late Cmax after administration of the oral liquid fentanyl. When we compared the time to achieve an analgesic plasma concentration (0.6 ng/mL), there was no difference between the OTFC and the current study.
The limitations of our study include the small sample size and the differences in design between the current study and our previous OTFC studies. Although the pharmacokinetic variables were generally similar between studies, the small sample size in the current cohort limited our ability to detect a difference, if one existed. Differences in study design may also have resulted in heterogeneity in study groups, thereby limiting comparison. The reasons for these differences in study design are as follows: the patients in the current study were limited to those older than 5 years because younger children would have been unable to reliably perform a "swish and swallow" of water after consumption of the liquid fentanyl. Additionally, blood sampling could not begin until an IV catheter was placed after the induction of general anesthesia; therefore, unlike our second OTFC study of children with established central venous access, early samples could not be drawn. In this study, we did not include patients presenting for central venous line removal because this is an outpatient procedure. Moreover, in designing this study, we were uncertain of the maximum fentanyl concentrations and the duration of "therapeutic concentrations" after oral liquid fentanyl administration; thus, we limited our study population to children who would be admitted postoperatively and who would likely require postoperative analgesia. Our observations suggest that this was a reasonable precaution.
In summary, we found that both OTFC and oral liquid fentanyl result in similar pharmacokinetic variables and plasma concentrations for a given dose. However, the small sample size of this pilot study and the marked interpatient variability, particularly in the early hours after oral administration of the IV formulation of fentanyl, suggest that this method of administration be used with caution until further data are available. Potential advantages of oral liquid fentanyl administration are acceptable taste, less cost, shorter consumption time, common availability, and more flexible dosing. Further prospective studies of a larger patient population are needed to evaluate the safety and efficacy of the oral administration of IV fentanyl.
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Acknowledgments
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We wish to thank Diana G. Wilkins, PhD, co-director of the Center for Human Toxicology, Department of Pharmacology and Toxicology, University of Utah College of Pharmacy in Salt Lake City, Utah for her assistance with the fentanyl assay.
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Footnotes
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Presented, in part, at the combined meeting of the Society for Pediatric Anesthesia and the Section on Anesthesiology and Pain Medicine of the American Academy of Pediatrics, Miami, FL, March 7–10, 2002, and at the annual meeting of the American Society of Anesthesiologists, Orlando, FL, October 12–16, 2002.
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References
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- Actiq® brand of oral transmucosal fentanyl [package insert]. West Chester, PA: Cephalon, Inc., 2003.
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- Wheeler M, Birmingham PK, Dsida RM, et al. Uptake pharmacokinetics of the Fentanyl Oralet in children scheduled for central venous access removal: implications for the timing of initiating painful procedures. Paediatr Anaesth 2002; 12: 594–9.[ISI][Medline]
- Garielsson J, Weiner D. Pharmacokinetic and pharmacodynamic data analysis: concepts and applications, 3rd ed. Stockholm, Sweden: Swedish Pharmaceutical Society, 2001.
- Gourlay GK, Kowalski SR, Plummer JL, et al. Fentanyl blood concentration-analgesic response relationship in the treatment of postoperative pain. Anesth Analg 1988; 67: 329–37.[Abstract/Free Full Text]
- Stoeckel H, Hengstmann JH, Schuttler J. Pharmacokinetics of fentanyl as a possible explanation for recurrence of respiratory depression. Br J Anaesth 1979; 51: 741–5.[Abstract/Free Full Text]
- Taeger K, Weninger E, Schmelzer F, et al. Pulmonary kinetics of fentanyl and alfentanil in surgical patients. Br J Anaesth 1988; 61: 425–34.[Abstract/Free Full Text]
Accepted for publication May 4, 2004.
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Abstract
Introduction
