Enr J Clin Pharmacol (1991) 40:427-428
Eo,opeanJ....,of
PSGe GB©@g G
003169709100104W
© Springer-Verlag 1991
P h a r m a c o k i n e t i c s o f i b u p r o f e n in f e b r i l e c h i l d r e n 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. I b u p r o f e n m a y be an alternative to acetamin o p h e n to control fever in children but little is k n o w n about its p h a r m a c o k i n e t i c s in pediatric patients. We studied 17 patients (age 3-10 yr) with fever; the most prevalent diagnoses were streptococcal pharyngitis and otitis media. I b u p r o f e n 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 H P L C . T h e m a x i m u m observed serum concentrations of ibup r o f e n r a n g e d f r o m 17-42 btg. ml 1 at 5 mg. k g - 1 and 2 5 53 btg.m1-1 at 10 m g . k g 1 doses. Pharmacokinetics did not a p p e a r to be affected by ibuprofen dose. M e a n 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 m g . k g -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. T h e r e was no relationship b e t w e e n age and ibuprofen kinetics. N o adverse effects o c c u r r e d in any patients. These data suggest that ibuprofen pharmacokinetics m a y not be affected by dose b e t w e e n 5 and 10 mg/kg or age b e t w e e n 3 and 10 years. Key words: Ibuprofen, children; fever, pharmacokinetics, adverse effects
F e v e r is one of the m o s t c o m m o n s y m p t o m s seen in children. Because aspirin is contraindicated in m a n y cases due to its association with Reye's syndrome, a c e t a m i n o p h e n is the m o s t frequently prescribed drug for the t r e a t m e n t of fever in pediatric patients. I b u p r o f e n has recently b e c o m e available as an alternative to a c e t a m i n o p h e n for use in children with fever. A liquid formulation (The B o o t s Company, Sherevport, U S A ) has b e e n f o u n d to be well tolerated and m o r e effective than p l a c e b o in febrile children [1]. It should be noted, however, that limited data are available a b o u t the pharmacokinetics of ibuprofen in children with fever. Furthermore, the influence of patient age and ibuprofen dose
on its pharmacokinetics has not b e e n studied in children. We designed a study to determine the pharmacokinetics of ibuprofen in relation to age and dose in pediatric patients receiving an investigational ibuprofen liquid for the t r e a t m e n t of fever.
Methods Children between the age of 2 and 12 y, who had rectal temperature > 38.3°C were eligible for the study. The study protocol was approved 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 streptococcal pharyngitis and ofitis media. Ibuprofen liquid (Bristol Myers Products, Hillside, USA) was given as a single dose of 5 mg. kg- 1to 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 ibuprofen concentrations were measured by a specific high-performance 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 similar; it was difficult to assess the significance of pharmacokinetic differences 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 concentrations was < 7%. Area under the serum concentration-time curve (AUC) was calculated 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.
M. C. Nahata et al.: Ibuprofen kinetics in febrile children
428 Table 1. Pharmacokinetics of ibuprofen in pediatric patients
Ibuprofen dose 5 mg/kg 10 mg/kg (,~ : 9) (n : 8) Age, y C..... gg/ml tm~x,h Oral clearance, ml. rain 1.kg- 1 Elimination half-life, h
6.7 (2.5) 28.4 (7.5)
6.2 (2.1) 43.6 (18.6)
1.1 (0.3) 1.2 (0.4) 1.6 (0.6)
1.2 (0.6) 1.4 (0.5) 1.6 (0.5)
Results
The pharmacokinetic data of ibuprofen in 17 pediatric patients are presented in Table 1. As expected, the m e a n Cmax of ibuprofen was higher in patients receiving 10 mg. k g - 1 doses vs those receiving 5 mg. kg-~ doses. However, the other pharmacokinetics parameters (t .... oral clearance and elimination half-life were similar at 5 m g . k g 1 and 10 mg. k g - ~doses (P > 0.1). No relationship was observed between patient age and ibuprofen kinetics. In all patients as one group, the m e a n t .... oral clearance and elimination half-life of ibuprofen was 1.2 (0.5) h, 1.2 (0.4) ml. m i n - 1. kg- 1, and 1.6 (0.5) h respectively. No adverse effects were seen in any patients.
ly, the nonlinearity in ibuprofen pharmacokinetics has not been observed at the normal doses in adults. The m e a n Cma~of ibuprofen can be c o m p a r e d with another study of liquid ibuprofen as follows: 28.4 gg. m l - ~in our patients vs 23.5 gg.m1-1 at 5 m g . k g -1 doses [1]; and 43.6 ~tg. m l - 1in our patientsvs 39.7 gg. m l - 1at 10 mg- k g doses [1]. The difference can be explained in part by the use of two different formulations or the timing of blood samples. Our data suggest that ibuprofen doses of 5 to 10 mg. kg- 1may be used safely to evaluate efficacy in children with fever.
Acknowledgement. The assistance of Dr. R D. Walson and support of Bristol Myers Products is acknowledged.
References
1. Walson PD, Galletta G, Braden NJ, Alexander L (1989) Ibuprofen, acetaminophen, and placebo treatment of febrile children. Clin Pharmacol Ther 46:9-17 2. Nahata MC (1991) Determination of ibuprofen in human plasma by high performance liquid chromatography. J Liq Chromatogr 14:187-192 3. Day RO, Williams KM, Graham GG, Lee E J, Knihinicki RD, Champion GD (1988) Stereoselective disposition of ibuprofen enantiomers in synovial fluid. Clin Pharmacol Ther 43:480487
Discussion
Our results suggest that ibuprofen pharmacokinetics m a y not depend on patient age between 3 and 10 y or dose between 5 and 10 rag- kg- ~. This can be explained, in part by the fact that the most significant changes in the organ function may occur before 3 y or after 10 y of age. Similar-
Dr. M. C. Nahata College of Pharmacy The Ohio State University 500 West 12th Street Columbus, Ohio 43210 USA
Eo,opeanJ....,of
PSGe GB©@g G
003169709100104W
© Springer-Verlag 1991
P h a r m a c o k i n e t i c s o f i b u p r o f e n in f e b r i l e c h i l d r e n 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. I b u p r o f e n m a y be an alternative to acetamin o p h e n to control fever in children but little is k n o w n about its p h a r m a c o k i n e t i c s in pediatric patients. We studied 17 patients (age 3-10 yr) with fever; the most prevalent diagnoses were streptococcal pharyngitis and otitis media. I b u p r o f e n 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 H P L C . T h e m a x i m u m observed serum concentrations of ibup r o f e n r a n g e d f r o m 17-42 btg. ml 1 at 5 mg. k g - 1 and 2 5 53 btg.m1-1 at 10 m g . k g 1 doses. Pharmacokinetics did not a p p e a r to be affected by ibuprofen dose. M e a n 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 m g . k g -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. T h e r e was no relationship b e t w e e n age and ibuprofen kinetics. N o adverse effects o c c u r r e d in any patients. These data suggest that ibuprofen pharmacokinetics m a y not be affected by dose b e t w e e n 5 and 10 mg/kg or age b e t w e e n 3 and 10 years. Key words: Ibuprofen, children; fever, pharmacokinetics, adverse effects
F e v e r is one of the m o s t c o m m o n s y m p t o m s seen in children. Because aspirin is contraindicated in m a n y cases due to its association with Reye's syndrome, a c e t a m i n o p h e n is the m o s t frequently prescribed drug for the t r e a t m e n t of fever in pediatric patients. I b u p r o f e n has recently b e c o m e available as an alternative to a c e t a m i n o p h e n for use in children with fever. A liquid formulation (The B o o t s Company, Sherevport, U S A ) has b e e n f o u n d to be well tolerated and m o r e effective than p l a c e b o in febrile children [1]. It should be noted, however, that limited data are available a b o u t the pharmacokinetics of ibuprofen in children with fever. Furthermore, the influence of patient age and ibuprofen dose
on its pharmacokinetics has not b e e n studied in children. We designed a study to determine the pharmacokinetics of ibuprofen in relation to age and dose in pediatric patients receiving an investigational ibuprofen liquid for the t r e a t m e n t of fever.
Methods Children between the age of 2 and 12 y, who had rectal temperature > 38.3°C were eligible for the study. The study protocol was approved 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 streptococcal pharyngitis and ofitis media. Ibuprofen liquid (Bristol Myers Products, Hillside, USA) was given as a single dose of 5 mg. kg- 1to 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 ibuprofen concentrations were measured by a specific high-performance 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 similar; it was difficult to assess the significance of pharmacokinetic differences 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 concentrations was < 7%. Area under the serum concentration-time curve (AUC) was calculated 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.
M. C. Nahata et al.: Ibuprofen kinetics in febrile children
428 Table 1. Pharmacokinetics of ibuprofen in pediatric patients
Ibuprofen dose 5 mg/kg 10 mg/kg (,~ : 9) (n : 8) Age, y C..... gg/ml tm~x,h Oral clearance, ml. rain 1.kg- 1 Elimination half-life, h
6.7 (2.5) 28.4 (7.5)
6.2 (2.1) 43.6 (18.6)
1.1 (0.3) 1.2 (0.4) 1.6 (0.6)
1.2 (0.6) 1.4 (0.5) 1.6 (0.5)
Results
The pharmacokinetic data of ibuprofen in 17 pediatric patients are presented in Table 1. As expected, the m e a n Cmax of ibuprofen was higher in patients receiving 10 mg. k g - 1 doses vs those receiving 5 mg. kg-~ doses. However, the other pharmacokinetics parameters (t .... oral clearance and elimination half-life were similar at 5 m g . k g 1 and 10 mg. k g - ~doses (P > 0.1). No relationship was observed between patient age and ibuprofen kinetics. In all patients as one group, the m e a n t .... oral clearance and elimination half-life of ibuprofen was 1.2 (0.5) h, 1.2 (0.4) ml. m i n - 1. kg- 1, and 1.6 (0.5) h respectively. No adverse effects were seen in any patients.
ly, the nonlinearity in ibuprofen pharmacokinetics has not been observed at the normal doses in adults. The m e a n Cma~of ibuprofen can be c o m p a r e d with another study of liquid ibuprofen as follows: 28.4 gg. m l - ~in our patients vs 23.5 gg.m1-1 at 5 m g . k g -1 doses [1]; and 43.6 ~tg. m l - 1in our patientsvs 39.7 gg. m l - 1at 10 mg- k g doses [1]. The difference can be explained in part by the use of two different formulations or the timing of blood samples. Our data suggest that ibuprofen doses of 5 to 10 mg. kg- 1may be used safely to evaluate efficacy in children with fever.
Acknowledgement. The assistance of Dr. R D. Walson and support of Bristol Myers Products is acknowledged.
References
1. Walson PD, Galletta G, Braden NJ, Alexander L (1989) Ibuprofen, acetaminophen, and placebo treatment of febrile children. Clin Pharmacol Ther 46:9-17 2. Nahata MC (1991) Determination of ibuprofen in human plasma by high performance liquid chromatography. J Liq Chromatogr 14:187-192 3. Day RO, Williams KM, Graham GG, Lee E J, Knihinicki RD, Champion GD (1988) Stereoselective disposition of ibuprofen enantiomers in synovial fluid. Clin Pharmacol Ther 43:480487
Discussion
Our results suggest that ibuprofen pharmacokinetics m a y not depend on patient age between 3 and 10 y or dose between 5 and 10 rag- kg- ~. This can be explained, in part by the fact that the most significant changes in the organ function may occur before 3 y or after 10 y of age. Similar-
Dr. M. C. Nahata College of Pharmacy The Ohio State University 500 West 12th Street Columbus, Ohio 43210 USA
