Pharmacokinetics and pharmacodynamics of ibuprofen isomers and acetaminophen in febrile children.

The pharmacokinetics of racemic ibuprofen and its stereoisomers have been described in adults, but little has been reported for children. The pharmacodynamics of acetaminophen and ibuprofen have not been well described in either adults or children. Children (N = 39; age range, 11 months to 11 1/2 years) were randomly selected to receive a single dose of either 6 mg/kg of liquid ibuprofen or 10 to 15 mg/kg of liquid acetaminophen (mean +/- dose given, 11.6 +/- 0.7). Pharmacokinetic and pharmacodynamic analyses were performed with temperature as the effect parameter and mean acetaminophen, total ibuprofen, and ibuprofen stereoisomer concentrations over time. Time of maximum serum concentrations for ibuprofen was 54.05 minutes versus 27.0 minutes for acetaminophen, time to maximum temperature decrease was 183 minutes for ibuprofen and 133 minutes for acetaminophen. Temperature reduction for the ibuprofen dose was significantly different than that of the acetaminophen dose at later time points (240, 300, 360, 420, and 480 minutes). Further pharmacokinetic-pharmacodynamic studies with use of individual ibuprofen stereoisomers and other dosing regimens are indicated.

Pharmacokinetics of clonazepam in developing rats.

Time-concentration studies of clonazepam (CZP) were performed in 7-, 14-, and 28-day-old Sprague-Dawley rats. Blood samples and brains were collected at specific intervals following a single subcutaneous (SC) injection of 2.5 mg/kg of CZP. CZP concentrations were measured both in plasma and brain samples by high performance liquid chromatography. Pharmacokinetic parameters were calculated using R-Strip for each age group. The results were compared between the age groups and with those of a similar study in our laboratory using lower dose CZP (1 mg/kg) SC injections in adult Sprague-Dawley rats. Younger rats had slower, delayed and higher peak concentrations, larger areas under the curve (AUC), longer elimination half lives (T1/2), smaller volumes of distribution (Vd) and slower clearances (C1). 28-day-old rats showed the fastest C1, smallest AUC and largest Vd. These data suggest that the pharmacokinetic behavior of CZP is age-dependent. If this is true in human, it is implicated in dosing of neonatal or pediatric patients.

Clonazepam disposition in pediatric patients.

Plasma clonazepam (CZP) and its metabolite [7-aminoclonazepam (7ACZP) and 7-acetamidoclonazepam (7AACZP)] concentrations were measured during a single dosing interval in 10 pediatric epilepsy patients (2-18 years, 11-102 kg) who had been receiving CZP therapeutically from 2 weeks to 4 years. These concentrations were used to determine CZP and metabolite pharmacokinetics. With controlled dosing and postdose sample collection times, large variations were observed in calculated CZP nitroreduction rates [clearance (CL/F) ranged from 7 to 64 ml/h/kg] as well as 7ACZP acetylation rates (CL/F from 10 to 85 ml/h/kg). No 7AACZP (i.e., < 5 ng/ml) was detected by the methods used. Acetylation rates are known to be under genetic control. Further studies are needed to determine whether nitroreduction rates are also under genetic control and whether differences in either of these metabolic rates can explain intraindividual differences in clinical responses observed in CZP-treated patients.

Clonazepam and 7-aminoclonazepam in human plasma.

The purpose of our study was to evaluate the hypothesis that much of the reported variability in the range of concentrations of plasma clonazepam (and also in the range of concentrations of its major metabolite, 7-aminoclonazepam) encountered in pediatric epilepsy patients is due to collection of samples at random times after dosing. High-performance liquid chromatographic analyses were performed on routinely ordered blood samples collected from chronically dosed outpatients during regular clinic visits. Thirty-six samples from 26 different children (age 0.25-19.6 years, mean 6.3 years) were analyzed. Specific dosing and sample collection times were obtained at the time of blood collection; demographic data were obtained from the clinic charts. A portion of the variation for both clonazepam and its major metabolite was accounted for by differences in daily dosage used. However, by accurate recording of dosage, administration times, and sample collection time, we graphically demonstrated that the majority of the variations in measured clonazepam and 7-aminoclonazepam concentrations was due to the time elapsed between the last dose and the time of sample collection. Thus, random sample collection times (especially during the drug distribution phase and following frequent dosing) may account, in part, for the poor correlation between plasma concentrations and reported anticonvulsant or toxic effects.