Enr J Clin Pharmacol (1991) 40:427-428 003169709100104W Eo,opeanJ .... ,of PSGe G GB©@g © Springer-Verlag 1991 Pharmacokinetics of ibuprofen in febrile children M. C. Nahata 1, D. E. Durrell 2, D. A. Powell s, and N. Gupta 4 ~. s Colleges of Pharmacy and Medicine, The Ohio State University and ~' 2, s Children's Hospital, Columbus, Ohio 43205, 4 Bristol Myers Products, Hillside, New Jersey, USA Received: May 22, 1990/Accepted in revised form: August 4,1990 Summary. Ibuprofen may be an alternative to acetami- nophen to control fever in children but little is known about its pharmacokinetics in pediatric patients. We stud- ied 17 patients (age 3-10 yr) with fever; the most preva- lent diagnoses were streptococcal pharyngitis and otitis media. Ibuprofen liquid was given as a single dose, 5 mg/kg (9 patients) or 10 mg/kg (8 patients). Multiple blood samples were collected over 8 hours and analyzed by HPLC. The maximum observed serum concentrations of ibu- profen ranged from 17-42 btg. ml 1 at 5 mg. kg- 1 and 25- 53 btg.m1-1 at 10 mg.kg 1 doses. Pharmacokinetics did not appear to be affected by ibuprofen dose. Mean t .... oral clearance and elimination half life were 1.1 h, 1.2 ml. min-1, kg-1, and 1.6 h, respectively in patients at 5 mg.kg -1 doses; the corresponding values were 1.2 h, 1.4ml.min-l.kg-1, and 1.6h in those receiving 10 mg. kg -1 doses. There was no relationship between age and ibuprofen kinetics. No adverse effects occurred in any patients. These data suggest that ibuprofen pharmacokinetics may not be affected by dose between 5 and 10 mg/kg or age between 3 and 10 years. Key words: Ibuprofen, children; fever, pharmacokinetics, adverse effects Fever is one of the most common symptoms seen in chil- dren. Because aspirin is contraindicated in many cases due to its association with Reye's syndrome, acetaminophen is the most frequently prescribed drug for the treatment of fever in pediatric patients. Ibuprofen has recently become available as an alternative to acetaminophen for use in children with fever. A liquid formulation (The Boots Company, Sherev- port, USA) has been found to be well tolerated and more effective than placebo in febrile children [1]. It should be noted, however, that limited data are available about the pharmacokinetics of ibuprofen in children with fever. Fur- thermore, the influence of patient age and ibuprofen dose on its pharmacokinetics has not been studied in children. We designed a study to determine the pharmacokinetics of ibuprofen in relation to age and dose in pediatric pa- tients receiving an investigational ibuprofen liquid for the treatment of fever. Methods Children between the age of 2 and 12 y, who had rectal tempera- ture > 38.3°C were eligible for the study. The study protocol was ap- proved by the Human Subjects Research Committee of our hospital. A written informed consent was obtained from the parent or legal guardian before enrollment of patients into the study. Seventeen febrile patients (age 3.1-9.6 y) were studied; age ranged from 3 to 4.9 y in 6 patients, 5 to 6.9 y in 6 patients and 7 to 9.6 y in 5 patients. The two most frequent diagnoses were strepto- coccal pharyngitis and ofitis media. Ibuprofen liquid (Bristol Myers Products, Hillside, USA) was given as a single dose of 5 mg. kg- 1 to 9 patients and 10 mg. kg-~ to 8 patients. Blood samples were collected just prior to the dose (0 h), and at 0.5, 1, 2, 4, 6, and 8 h after the dose. Serum was separated and ibu- profen concentrations were measured by a specific high-perfor- mance liquid chromatographic (HPLC) method [2]. This method measures racemic mixture of ibuprofen rather than its enantiomers, R( - ) and S( + ). The stereoselective disposition of ibuprofen enantiomers has been studied in adults but not in children. The peak plasma concentrations of the two enantiomers were simi- lar; it was difficult to assess the significance of pharmacokinetic dif- ferences since the inversion of R(-) to pharmacologically active S( + ) for inhibition of prostaglandin synthetase takes place in vivo [3]. The coefficient of variation of the assay at the observed concen- trations was < 7%. Area under the serum concentration-time curve (AUC) was cal- culated by a trapezoidal method and extrapolated to infinity. Oral clearance was calculated by dividing the oral dose by the AUC. Elimination rate constant (k) was determined by a linear regression analysis of log serum concentration-time data. Elimination half-life was calculated as ln2/k. Both the maximum serum concentration (Cm,x) and the time to achieve maximum concentration (tmax) w e r e noted as observed values. The t ...... oral clearance, and elimination half-life at 5 vs 10 rag. kg 1doses were compared using a nonpaired Student t test as well as Wilcoxon rank sum test. The a priori value of P was < 0.05. Physical examination and laboratory data to assess haematologic, liver and renal function were performed to assess safety.