PEDIATRIC PHARMACOLOGY AND THERAPEUTICS
Effect of age on ibuprofen pharmacokinetics and antipyretic response Ralph E, K a u f f m a n , MD, a n d Merlin V. Nelson, PharmD From the Divisionof Clinical Pharmacology/Toxicology, Departments of Pediatrics and Pharmacology, Wayne State UniversitySchool of Medicine and Children's Hospital of Michigan, Detroit The effect of a g e on ibuprofen pharmacokinetics and antipyretic effect was studied in 49 infants and children a g e d 3 months to 10.4 years. The relationship of plasma concentration to antipyretic effect was e x a m i n e d in 38 of the children by using an iterative least squares technique that allows estimation of drug concentration with time in a theoretical effect compartment and rate constant for elimination of drug from the effect compartment. There was a d e l a y of 1 to 3 hours between peak ibuprofen plasma concentration and peak temperature decrement. The mean elimination rate constant from the effect c o m p a r t m e n t was 0.6 hour - I , corresponding to a half-life of drug in the effect c o m p a r t m e n t of 1.1 hours. The mean slope of the effect compartment concentration versus temperature regression line was -0.242 ~C / m g per liter. Age did not significantly influence the rate of absorption of ibuprofen, its plasma concentration, its rate of elimination, or the time course of ibuprofen concentration in the effect compartment. However, in younger children the onset of antipyresis was earlier, maximum antipyretic effect was greater, and the area under the curve of the p e r c e n t a g e of change in temperature from baseline versus time was greater than in older children. We c o n c l u d e that the greater relative b o d y surface area in younger children may allow more efficient dissipation of heat in response to antipyretic-induced lowering of the temperature "set point" in the hypothalamus. (J PEDIATR1992;121:969-73)
The antipyretic efficacy of ibuprofen in children during acute febrile illness has been established.l4 Doses ranging from 0.625 to 10 mg/kg produced a dose-dependent reduction in fever, z, 3 In comparative studies, ibuprofen produced greater and more prolonged antipyresis than acetaminophen when administered in equivalent doses (measured in milligrams per kilogram).l, 3, 4 The purpose of our study was to examine the effect of age on ibuprofen pharmacokinetics Supported by a grant from Bristol-Myers Products Research and Development Laboratories, Hillside, N.J. Submitted for publication April 24, 1992; accepted July 28, 1992. Reprint requests: Ralph E. Kauffman, MD, Professor of Pediatrics and Pharmacology, Division of Clinical Pharmacology/Toxicology, Children's Hospital of Michigan, 3901 Beaubien Blvd., Detroit, MI 48201. 9/25/41389
and antipyretic effect, and to evaluate the relationship between drug concentration and antipyretic effect. METHODS Patient selection. Children aged 3 months to 12 years with an acute intercurrent febrile illness and axillary tern%ATempAtjc
%ATempma•
Area under the percentage of change from baseline temperature versus time curve Maximum percentage of change from baseline temperature
perature of ~38.5 ~ C were eligible for the study. Exclusion criteria included ingestion of any antipyretic drug within the previous 4 hours; history of intolerance or hypersensitivity to any nonsteroidal antiinflamatory drug; history of
969
970
Kauffman and Nelson
gastrointestinal disease or bowel resection; presence of chronic renal or hepatic disease; history of cardiopulmonary disease; history of coagulation disorder; and ~ 5 % dehydration. Children who did not require hospital admission for a medical indication were studied in the emergency department and discharged to home after completion of the study. Patients who had a medical indication for hospital admission were studied in the hospital. Informed consent from the parent(s) or legal guardian and assent from the child, when appropriate, were obtained before enrollment. The protocol was reviewed and approved by the Children's Hospital of Michigan Investigational Review Board. Medication administration. Ibuprofen was supplied in a strawberry-flavored suspension that contained 20 mg/ml racemic ibuprofen. A single dose, 8 mg/kg, was administered orally with a syringe, followed immediately by an equal volume of water. The child received nothing by mouth for 1 hour after the dose of ibuprofen. Clear liquids were allowed as desired during the second hour after dosing, and a snack was provided, if desired, after 2 hours. Temperature measurements. Axillary temperature was measured in duplicate by the same research nurse within 10 minutes before dosing, and at 30 minutes and 1, 11/2, 2, 3, 4, 5, 6, 7, and 8 hours after the dose with an IVAC model 2000 digital electronic thermometer (IVAC Corp., San Diego, Calif.). The thermometer tip was placed deeply in the apex of the axilla and the arm held in full adduction until the audible tone signaled completion of the temperaturemeasurement cycle. The mean of each pair of temperature determinations was used for data analysis. If the temperature did not decline by at least 0.5 o C within 4 hours of ibuprofen administration, or if it exceeded 40.0 ~ C at any time during the study, administration of acetaminophen, 12.5 mg/kg, and institution of nondrug antipyretic measures were permitted. If acetaminophen was administered, the time of the acetaminophen dose was recorded and all subsequent scheduled temperature measurements were completed and recorded. However, temperatures and ibuprofen concentrations obtained after administration of acetaminophen were excluded from pharmacokinetic-pharmacodynamic analysis. Blood sampling and ibuprofen assay. A 0.5 ml sample of heparinized whole blood was obtained by venipuncture or capillary stick immediately before dosing and at 1, 2, 4, 6, and 8 hours after the dose. Plasma was separated and frozen at - 2 0 ~ C until assayed for.ibuprofen. The predose sample was assayed for acetaminophen and salicylate, in addition to ibuprofen, to ensure that no detectable antipyretic agent was present at the time that the study dose of ibuprofen was administered.
The Journal of Pediatrics December 1992
The concentration of total racemic ibuprofen in plasma was determined by using a previously published high-performance liquid chromatographic assay. 5 The method requires 50 #1 of plasma, is sensitive to 1.0 mg/L, and has a coefficient of variation of 3%. Acetaminophen and salieylate concentrations were determined with the Abbott TDx fluorescence polarization immunoassay (Abbott Laboratories, Diagnostics Division, Abbott Park, Ill). Adverse effects. Respiratory rate, pulse, and blood pressure were documented during the study, and all adverse events potentially related to ibuprofen were recorded. In addition, parents of the children were contacted by telephone the day after the study to inquire about any subsequent adverse events. Data analysis. Measures of antipyretic response were as follows: time (minutes) at onset of antipyresis after the dose of ibuprofen; percentage of change from baseline temperature at time t after the dose of ibuprofen; maximum temperature change from baseline temperature; duration of antipyresis; maximum percentage of change from baseline temperature; and area under the percentage of temperature change versus time curve. Time at onset of antipyretic effect was defined as the earliest time that the temperature was ~ 1.0 ~ C below baseline. The percentage of temperature change from baseline (%2x Temp) at each time t was defined as follows: %ATemp = (Baseline t e m p e r a t u r e Temperature at time t)/(Baseline t e m p e r a t u r e - 3 6 . 5 ~ C) X 100. Duration of antipyresis was defined as the time from onset of antipyresis to the time that the temperature was >_ 1.0 ~ C above the lowest measured temperature and more than 37 ~ C. Area under the curve was calculated by using the trapezoid method. Ibuprofen plasma concentrations with time for each patient were fit to a one-compartment model with first-order absorption by using RSTRIP (MicroMath, Inc., Salt Lake City, Utah), a weighted nonlinear least squares regression analysis program. The model selection criterion, based on the Akaike information criterion, 6 was used for model discrimination. Pharmacokinetic data from patients with a model selection criterion _6 yr of a g e (n = 44)
38.9 1.8 74 109 285 325
_+ 0.5 _+ 0.5 _+ 17 + 64 +_ 89 _+ 150
p
NS 0.002 0.001 0.03 0,11" 0,001
Statistical comparison is between children _--6years of age (mean • SD). NS, Not significant; s maximum change in temperature from baseline. *Power to detect a differenceof this magnitude with n = 14 and ce= 0.05 is 0.35.
antipyresis (correlation coefficient = - 0 . 3 2 2 ; r 2 = 0.102; p = 0.0154) and no significant effect on %~xTempmax and %ATempAuc. The mean time to onset of antipyresis was 69 minutes in the 14 youngest children, in contrast to 109 minutes in the 14 oldest children; mean maximum decrease in temperature from baseline was 2.8 ~ C in the youngest patients and 1.8 ~ C in the oldest group. This difference in response was also reflected in the difference of mean %2xTempA~c between the two age groups (Table II). N o adverse effects attributable to ibuprofen were observed. DISCUSSION The delay between peak ibuprofen serum concentration and peak antipyretic response observed in our patients was also reported by Walson et al. 3 and Brown et al., 9 both of whom observed a 21A-hour lag between peak ibuprofen concentration and peak antipyretie response. The lag between plasma concentration and antipyretic effect is not surprising when one considers the complex sequence ofevents that mediate heat dissipation after administration of an antipyretic drug. 1~ 11 The drug must diffuse from the plasma compartment into the central nervous system, where it inhibits synthesis of prostaglandin E2 in the hypothalamic temperature-regulatory center. This leads to a lowering of the hypothalamic "set point," which puts into play a series of physiologic responses, including decreased heat production, increased blood flow to the skin, and increased heat loss through the skin by radiation, convection, and evaporation, ultimately resulting in a reduction in body temperature. The wide interindividual variation in slope of the regression of ibuprofen concentration in the effect compartment versus antipyretic response reftec~s the fact that a complex interaction of numerous factors, in addition to drug concentration, determines the antipyretic response. We were unable tO estimate the antipyretic median effective concentration of ibuprofen because the dose used did not result in concentrations that produced a maximum antipyretic re-
sponse in the majority of patients. Walson et al. 3 and Wilson et al. 4 also reported less than the m a x i m u m antipyretic effect with 10 mg ibuprofen per kilogram, a dose slightly higher than the one used in our study. The clearance of many drugs is age dependent; preschool children typically have higher clearances than do newborn infants or older children. 12 However, we found no correlation between age and any of the pharmacokinetic variables for ibuprofen across an age range of 3 months to 10 years. Both the plasma concentrations and the rate constants for absorption and elimination observed in this study are comparable to those in children and adults reported by others.3,9, 13-15 N a h a t a et al. 15 also observed no relationship between age and ibuprofen kinetics in children aged 3 to 10 years. Brown et al. 9 found no age-related differences in absorption and elimination half-lives of ibuprofen but observed that children 21/2 years of age, primarily because of a larger apparent volume of distribution. Wilson et al. 4 observed a significant positive correlation of baseline temperature with antipyretie response. In contrast, baseline temperature had a negligible effect on the antipyretic response of our patients; the discrepancy may be due to selecffon of patients with baseline temperatures within a relatively narrow range for our study, thereby negating any baseline temperature effect. Although the time course of ibuprofen concentration was not influenced by age, the younger children had a significantly greater antipyretic response than that in the older children. Wilson et al. 4 also observed an age effect on antipyr'esis. The absence of an age effect on ibuprofen pharmacokinetics indicates that the age-related difference in antipyretic response must be due to mechanisms other than an age-related difference in drug concentration. The change in relative body surface area with development offers an attractive explanation. Relative surface area in the youngest of our patients was 1.7 times that in the oldest. The skin is the primary organ through which heat is dissipated, so the
Volume 121 Number 6
individual with the greatest skin surface area relative to body mass will be most efficient at decreasing body temperature once the hypothalamic thermoregulatory center is reset to a lower temperature. An alternative hypothesis is that there is a developmental change in metabolic inversion of R-ibuprofen to S-ibuprofen. Although ibuprofen is administered as the racemate, its pharmacologic activity resides almost exclusively with the S-enantiomer. 16 After administration of racemic ibuprofen, R-ibuprofen undergoes inversion to active S-ibuprofenIV; thus the concentration of S-ibuprofen eventually.. exceeds that of R-ibuprofen. This shift in the ratio of S- to R-ibuprofen would not be detected by the assay used in this study. Although there currently is no evidence for a change in the rate or extent of enantiomeric inversion of ibuprofen with development, more extensive metabolic inversion of R-ibuprofen to the active S-enantiomer in the younger patients could theoretically produce a greater antipyretic response without an age-related difference in total ibuprofen concentration. Studies of age-related antipyretic response with acetaminophen have not been reported, so it is unclear whether this is a general phenomenon or is specific to certain antipyretic drugs. Most likely it is not drug specific and is related to greater thermoregulatory efficiency in younger children. Regardless of the mechanism, it is fortuitous that the population of younger children who most frequently have acute febrile illness are the most adept at responding to antipyretic medication. REFERENCES
1. Kauffman RE, Sawyer LA, Scheinbaum ML. Antipyretic efficacy of ibuprofen vs acetaminophen. Am J Dis Child 1992; 146:622-5. 2. Marriott SC, Stephenson T J, Hull D, Pownall R, Smith CM, Butler A. A dose ranging study of ibuprofen suspension as an antipyretic. Arch Dis Child 1991 ;66:1037-42. 3. Walson PD, Galletta G, Braden N J, Alexander L. Ibuprofen,
Effect o f age on response to ibuprofen
4.
5.
6. 7.
8.
9.
10. 11. 12.
13.
14.
15.
16.
17.
973
acetaminophen, and placebo treatment of febrile children. Clin Pharmacol Ther 1989;46:9-17. Wilson JT, Brown RD, Kearns GL, et al. Single-dose, placebo-controlled comparative study of ibuprofen and acetaminophen antipyresis in children. J PEDIATR 1991;119:803-10. Aravind MK, Miceli JN, Kauffman RE. Determination of ibuprofen by high-performance liquid chromatography. J Chromatogr 1984;308:350-3. Akaike H. An information criterion (AIC). Mathematical Science 1976; 14:5-9. Fuseau E, Sheiner LB. Simultaneous modeling of pharmacokinetics and pharmacodynamics with a nonparametric pharmacodynamic model. CIin Pharmacol Ther 1984;35:733-41. Holford NHG, Sheiner LB. Understanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet 1981;6:429-53. Brown DR, Wilson JT, Kearns GL, et al. Single-dose pharmacokinetics of ibuprofen and acetaminophen in febrile children. J Clin Pharmacol 1992;32:231-41. Dinarello CA, WolffSM. Pathogenesis of fever in man. N Engl J Med 1978;298:607-12. Clark WG. Minireview: mechanisms of antipyretic action. Gen Pharmacol 1979;10:71-7. Kauffman RE. Drug therapeutics in the infant and child. In: Yaffe S J, Aranda JV, eds. Pediatric pharmacology: therapeutic principles in practice. Philadelphia: WB Saunders, 1992: 212-9. Lockwood GF, Albert KS, Gillespie MS, Bole GG, et al. Pharmacokinetics of ibuprofen in man. I. Free and total area/ dose relationships. Clin Pharmacol Ther 1983;34:97-103. Benvenuti C, Cancellieri V, Gambaro V, Lodi F, Marozzi E, Scaroni C. Pharmacokinetics of two new oral formulations of ibuprofen. Int J Clin Pharmacol Ther Toxicol 1986;24:308-12. Nahata MC, Durrell DE, Powell DA, Gupta N. Pharmacokinetics of ibuprofen in febrile children. Eur J Clin Pharmacol 1991 ;40:427-8. Adams SS, Bresloff P, Mason CG. Pharmacological differences between the optical isomers of ibuprofen: evidence for metabolic inversion of (-)isomer. J Pharm Pharmacol 1976; 28:256-7. Rudy AC, Knight PM, Brater DC, Hall SD. Stereoselective metabolism of ibuprofen in humans: administration of R-, Sand racemic ibuprofen. J Pharmacol Exp Ther 1991;259: 1133-9.
Effect of age on ibuprofen pharmacokinetics and antipyretic response Ralph E, K a u f f m a n , MD, a n d Merlin V. Nelson, PharmD From the Divisionof Clinical Pharmacology/Toxicology, Departments of Pediatrics and Pharmacology, Wayne State UniversitySchool of Medicine and Children's Hospital of Michigan, Detroit The effect of a g e on ibuprofen pharmacokinetics and antipyretic effect was studied in 49 infants and children a g e d 3 months to 10.4 years. The relationship of plasma concentration to antipyretic effect was e x a m i n e d in 38 of the children by using an iterative least squares technique that allows estimation of drug concentration with time in a theoretical effect compartment and rate constant for elimination of drug from the effect compartment. There was a d e l a y of 1 to 3 hours between peak ibuprofen plasma concentration and peak temperature decrement. The mean elimination rate constant from the effect c o m p a r t m e n t was 0.6 hour - I , corresponding to a half-life of drug in the effect c o m p a r t m e n t of 1.1 hours. The mean slope of the effect compartment concentration versus temperature regression line was -0.242 ~C / m g per liter. Age did not significantly influence the rate of absorption of ibuprofen, its plasma concentration, its rate of elimination, or the time course of ibuprofen concentration in the effect compartment. However, in younger children the onset of antipyresis was earlier, maximum antipyretic effect was greater, and the area under the curve of the p e r c e n t a g e of change in temperature from baseline versus time was greater than in older children. We c o n c l u d e that the greater relative b o d y surface area in younger children may allow more efficient dissipation of heat in response to antipyretic-induced lowering of the temperature "set point" in the hypothalamus. (J PEDIATR1992;121:969-73)
The antipyretic efficacy of ibuprofen in children during acute febrile illness has been established.l4 Doses ranging from 0.625 to 10 mg/kg produced a dose-dependent reduction in fever, z, 3 In comparative studies, ibuprofen produced greater and more prolonged antipyresis than acetaminophen when administered in equivalent doses (measured in milligrams per kilogram).l, 3, 4 The purpose of our study was to examine the effect of age on ibuprofen pharmacokinetics Supported by a grant from Bristol-Myers Products Research and Development Laboratories, Hillside, N.J. Submitted for publication April 24, 1992; accepted July 28, 1992. Reprint requests: Ralph E. Kauffman, MD, Professor of Pediatrics and Pharmacology, Division of Clinical Pharmacology/Toxicology, Children's Hospital of Michigan, 3901 Beaubien Blvd., Detroit, MI 48201. 9/25/41389
and antipyretic effect, and to evaluate the relationship between drug concentration and antipyretic effect. METHODS Patient selection. Children aged 3 months to 12 years with an acute intercurrent febrile illness and axillary tern%ATempAtjc
%ATempma•
Area under the percentage of change from baseline temperature versus time curve Maximum percentage of change from baseline temperature
perature of ~38.5 ~ C were eligible for the study. Exclusion criteria included ingestion of any antipyretic drug within the previous 4 hours; history of intolerance or hypersensitivity to any nonsteroidal antiinflamatory drug; history of
969
970
Kauffman and Nelson
gastrointestinal disease or bowel resection; presence of chronic renal or hepatic disease; history of cardiopulmonary disease; history of coagulation disorder; and ~ 5 % dehydration. Children who did not require hospital admission for a medical indication were studied in the emergency department and discharged to home after completion of the study. Patients who had a medical indication for hospital admission were studied in the hospital. Informed consent from the parent(s) or legal guardian and assent from the child, when appropriate, were obtained before enrollment. The protocol was reviewed and approved by the Children's Hospital of Michigan Investigational Review Board. Medication administration. Ibuprofen was supplied in a strawberry-flavored suspension that contained 20 mg/ml racemic ibuprofen. A single dose, 8 mg/kg, was administered orally with a syringe, followed immediately by an equal volume of water. The child received nothing by mouth for 1 hour after the dose of ibuprofen. Clear liquids were allowed as desired during the second hour after dosing, and a snack was provided, if desired, after 2 hours. Temperature measurements. Axillary temperature was measured in duplicate by the same research nurse within 10 minutes before dosing, and at 30 minutes and 1, 11/2, 2, 3, 4, 5, 6, 7, and 8 hours after the dose with an IVAC model 2000 digital electronic thermometer (IVAC Corp., San Diego, Calif.). The thermometer tip was placed deeply in the apex of the axilla and the arm held in full adduction until the audible tone signaled completion of the temperaturemeasurement cycle. The mean of each pair of temperature determinations was used for data analysis. If the temperature did not decline by at least 0.5 o C within 4 hours of ibuprofen administration, or if it exceeded 40.0 ~ C at any time during the study, administration of acetaminophen, 12.5 mg/kg, and institution of nondrug antipyretic measures were permitted. If acetaminophen was administered, the time of the acetaminophen dose was recorded and all subsequent scheduled temperature measurements were completed and recorded. However, temperatures and ibuprofen concentrations obtained after administration of acetaminophen were excluded from pharmacokinetic-pharmacodynamic analysis. Blood sampling and ibuprofen assay. A 0.5 ml sample of heparinized whole blood was obtained by venipuncture or capillary stick immediately before dosing and at 1, 2, 4, 6, and 8 hours after the dose. Plasma was separated and frozen at - 2 0 ~ C until assayed for.ibuprofen. The predose sample was assayed for acetaminophen and salicylate, in addition to ibuprofen, to ensure that no detectable antipyretic agent was present at the time that the study dose of ibuprofen was administered.
The Journal of Pediatrics December 1992
The concentration of total racemic ibuprofen in plasma was determined by using a previously published high-performance liquid chromatographic assay. 5 The method requires 50 #1 of plasma, is sensitive to 1.0 mg/L, and has a coefficient of variation of 3%. Acetaminophen and salieylate concentrations were determined with the Abbott TDx fluorescence polarization immunoassay (Abbott Laboratories, Diagnostics Division, Abbott Park, Ill). Adverse effects. Respiratory rate, pulse, and blood pressure were documented during the study, and all adverse events potentially related to ibuprofen were recorded. In addition, parents of the children were contacted by telephone the day after the study to inquire about any subsequent adverse events. Data analysis. Measures of antipyretic response were as follows: time (minutes) at onset of antipyresis after the dose of ibuprofen; percentage of change from baseline temperature at time t after the dose of ibuprofen; maximum temperature change from baseline temperature; duration of antipyresis; maximum percentage of change from baseline temperature; and area under the percentage of temperature change versus time curve. Time at onset of antipyretic effect was defined as the earliest time that the temperature was ~ 1.0 ~ C below baseline. The percentage of temperature change from baseline (%2x Temp) at each time t was defined as follows: %ATemp = (Baseline t e m p e r a t u r e Temperature at time t)/(Baseline t e m p e r a t u r e - 3 6 . 5 ~ C) X 100. Duration of antipyresis was defined as the time from onset of antipyresis to the time that the temperature was >_ 1.0 ~ C above the lowest measured temperature and more than 37 ~ C. Area under the curve was calculated by using the trapezoid method. Ibuprofen plasma concentrations with time for each patient were fit to a one-compartment model with first-order absorption by using RSTRIP (MicroMath, Inc., Salt Lake City, Utah), a weighted nonlinear least squares regression analysis program. The model selection criterion, based on the Akaike information criterion, 6 was used for model discrimination. Pharmacokinetic data from patients with a model selection criterion _6 yr of a g e (n = 44)
38.9 1.8 74 109 285 325
_+ 0.5 _+ 0.5 _+ 17 + 64 +_ 89 _+ 150
p
NS 0.002 0.001 0.03 0,11" 0,001
Statistical comparison is between children _--6years of age (mean • SD). NS, Not significant; s maximum change in temperature from baseline. *Power to detect a differenceof this magnitude with n = 14 and ce= 0.05 is 0.35.
antipyresis (correlation coefficient = - 0 . 3 2 2 ; r 2 = 0.102; p = 0.0154) and no significant effect on %~xTempmax and %ATempAuc. The mean time to onset of antipyresis was 69 minutes in the 14 youngest children, in contrast to 109 minutes in the 14 oldest children; mean maximum decrease in temperature from baseline was 2.8 ~ C in the youngest patients and 1.8 ~ C in the oldest group. This difference in response was also reflected in the difference of mean %2xTempA~c between the two age groups (Table II). N o adverse effects attributable to ibuprofen were observed. DISCUSSION The delay between peak ibuprofen serum concentration and peak antipyretic response observed in our patients was also reported by Walson et al. 3 and Brown et al., 9 both of whom observed a 21A-hour lag between peak ibuprofen concentration and peak antipyretie response. The lag between plasma concentration and antipyretic effect is not surprising when one considers the complex sequence ofevents that mediate heat dissipation after administration of an antipyretic drug. 1~ 11 The drug must diffuse from the plasma compartment into the central nervous system, where it inhibits synthesis of prostaglandin E2 in the hypothalamic temperature-regulatory center. This leads to a lowering of the hypothalamic "set point," which puts into play a series of physiologic responses, including decreased heat production, increased blood flow to the skin, and increased heat loss through the skin by radiation, convection, and evaporation, ultimately resulting in a reduction in body temperature. The wide interindividual variation in slope of the regression of ibuprofen concentration in the effect compartment versus antipyretic response reftec~s the fact that a complex interaction of numerous factors, in addition to drug concentration, determines the antipyretic response. We were unable tO estimate the antipyretic median effective concentration of ibuprofen because the dose used did not result in concentrations that produced a maximum antipyretic re-
sponse in the majority of patients. Walson et al. 3 and Wilson et al. 4 also reported less than the m a x i m u m antipyretic effect with 10 mg ibuprofen per kilogram, a dose slightly higher than the one used in our study. The clearance of many drugs is age dependent; preschool children typically have higher clearances than do newborn infants or older children. 12 However, we found no correlation between age and any of the pharmacokinetic variables for ibuprofen across an age range of 3 months to 10 years. Both the plasma concentrations and the rate constants for absorption and elimination observed in this study are comparable to those in children and adults reported by others.3,9, 13-15 N a h a t a et al. 15 also observed no relationship between age and ibuprofen kinetics in children aged 3 to 10 years. Brown et al. 9 found no age-related differences in absorption and elimination half-lives of ibuprofen but observed that children 21/2 years of age, primarily because of a larger apparent volume of distribution. Wilson et al. 4 observed a significant positive correlation of baseline temperature with antipyretie response. In contrast, baseline temperature had a negligible effect on the antipyretic response of our patients; the discrepancy may be due to selecffon of patients with baseline temperatures within a relatively narrow range for our study, thereby negating any baseline temperature effect. Although the time course of ibuprofen concentration was not influenced by age, the younger children had a significantly greater antipyretic response than that in the older children. Wilson et al. 4 also observed an age effect on antipyr'esis. The absence of an age effect on ibuprofen pharmacokinetics indicates that the age-related difference in antipyretic response must be due to mechanisms other than an age-related difference in drug concentration. The change in relative body surface area with development offers an attractive explanation. Relative surface area in the youngest of our patients was 1.7 times that in the oldest. The skin is the primary organ through which heat is dissipated, so the
Volume 121 Number 6
individual with the greatest skin surface area relative to body mass will be most efficient at decreasing body temperature once the hypothalamic thermoregulatory center is reset to a lower temperature. An alternative hypothesis is that there is a developmental change in metabolic inversion of R-ibuprofen to S-ibuprofen. Although ibuprofen is administered as the racemate, its pharmacologic activity resides almost exclusively with the S-enantiomer. 16 After administration of racemic ibuprofen, R-ibuprofen undergoes inversion to active S-ibuprofenIV; thus the concentration of S-ibuprofen eventually.. exceeds that of R-ibuprofen. This shift in the ratio of S- to R-ibuprofen would not be detected by the assay used in this study. Although there currently is no evidence for a change in the rate or extent of enantiomeric inversion of ibuprofen with development, more extensive metabolic inversion of R-ibuprofen to the active S-enantiomer in the younger patients could theoretically produce a greater antipyretic response without an age-related difference in total ibuprofen concentration. Studies of age-related antipyretic response with acetaminophen have not been reported, so it is unclear whether this is a general phenomenon or is specific to certain antipyretic drugs. Most likely it is not drug specific and is related to greater thermoregulatory efficiency in younger children. Regardless of the mechanism, it is fortuitous that the population of younger children who most frequently have acute febrile illness are the most adept at responding to antipyretic medication. REFERENCES
1. Kauffman RE, Sawyer LA, Scheinbaum ML. Antipyretic efficacy of ibuprofen vs acetaminophen. Am J Dis Child 1992; 146:622-5. 2. Marriott SC, Stephenson T J, Hull D, Pownall R, Smith CM, Butler A. A dose ranging study of ibuprofen suspension as an antipyretic. Arch Dis Child 1991 ;66:1037-42. 3. Walson PD, Galletta G, Braden N J, Alexander L. Ibuprofen,
Effect o f age on response to ibuprofen
4.
5.
6. 7.
8.
9.
10. 11. 12.
13.
14.
15.
16.
17.
973
acetaminophen, and placebo treatment of febrile children. Clin Pharmacol Ther 1989;46:9-17. Wilson JT, Brown RD, Kearns GL, et al. Single-dose, placebo-controlled comparative study of ibuprofen and acetaminophen antipyresis in children. J PEDIATR 1991;119:803-10. Aravind MK, Miceli JN, Kauffman RE. Determination of ibuprofen by high-performance liquid chromatography. J Chromatogr 1984;308:350-3. Akaike H. An information criterion (AIC). Mathematical Science 1976; 14:5-9. Fuseau E, Sheiner LB. Simultaneous modeling of pharmacokinetics and pharmacodynamics with a nonparametric pharmacodynamic model. CIin Pharmacol Ther 1984;35:733-41. Holford NHG, Sheiner LB. Understanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet 1981;6:429-53. Brown DR, Wilson JT, Kearns GL, et al. Single-dose pharmacokinetics of ibuprofen and acetaminophen in febrile children. J Clin Pharmacol 1992;32:231-41. Dinarello CA, WolffSM. Pathogenesis of fever in man. N Engl J Med 1978;298:607-12. Clark WG. Minireview: mechanisms of antipyretic action. Gen Pharmacol 1979;10:71-7. Kauffman RE. Drug therapeutics in the infant and child. In: Yaffe S J, Aranda JV, eds. Pediatric pharmacology: therapeutic principles in practice. Philadelphia: WB Saunders, 1992: 212-9. Lockwood GF, Albert KS, Gillespie MS, Bole GG, et al. Pharmacokinetics of ibuprofen in man. I. Free and total area/ dose relationships. Clin Pharmacol Ther 1983;34:97-103. Benvenuti C, Cancellieri V, Gambaro V, Lodi F, Marozzi E, Scaroni C. Pharmacokinetics of two new oral formulations of ibuprofen. Int J Clin Pharmacol Ther Toxicol 1986;24:308-12. Nahata MC, Durrell DE, Powell DA, Gupta N. Pharmacokinetics of ibuprofen in febrile children. Eur J Clin Pharmacol 1991 ;40:427-8. Adams SS, Bresloff P, Mason CG. Pharmacological differences between the optical isomers of ibuprofen: evidence for metabolic inversion of (-)isomer. J Pharm Pharmacol 1976; 28:256-7. Rudy AC, Knight PM, Brater DC, Hall SD. Stereoselective metabolism of ibuprofen in humans: administration of R-, Sand racemic ibuprofen. J Pharmacol Exp Ther 1991;259: 1133-9.
