Iñaki F. Trocóniz1, Santos Armenteros2, MarÃa V. Planelles3, Ju lio BenÃtez4, Rosa DomÃnguez2
1) Department of Pharmacy and Pharmaceutical Technology; Faculty of Pharmacy; University of Navarra; Pamplona 31080 Spain. 2) Medical Department; Laboratorios Knoll S.A; Avda de Burgos 91; Madrid 28050; Spain. 3) Department of Pediatrics; Clinic Hospital; Valencia; Spain. 4) Department of Pharmacology; Faculty of Medicine; University of Extremadura; Badajoz; Spain.
The population pharmacokinetic-pharmacodynamic relationships of racemic ibuprofen administered in suspension or effervescent granules were analyzed. Pharmacokinetics was studied in eighteen healthy volunteers. The study consisted of two 1-day study occasions, each separated by a 1-week washout period. On each occasion 400 mg ibuprofen was administered orally in suspension or granules. The time course of the antipyretic effect was evaluated in 103 children receiving a single oral dose of 7 mg/kg in suspension or 200 or 400 mg oral dose in effervescent granules. During the pharmacodynamic analysis, the predicted typical pharmacokinetic profile (based on the pharmacokinetic model previously developed) was used.
The disposition of ibuprofen was described by a two compartmental model. No statistical differences (p>0.05) were found between the two formulations in the distribution and elimination parameters. Absorption of ibuprofen given in suspension was adequately described by a first order process; however, a model with two parallel first-order input sites was used in the case of the drug given in effervescent granules. Time to achieved the peak in plasma concentrations were 0.9 h and 1.7 h for the drug given in suspension and granules, respectively. However mean observed time course of temperature was almost superimposable between the two formulations. The time course of the antipyretic effect was best described using an indirect response model. The estimates (estimate (coefficient of variation)) of Emax (maximum inhibition of the zero-order synthesis rate of the factor causing fever), C50 (plasma concentration eliciting half of Emax) and kout (first order rate constant of degradation) were 0.067*T0 (10), 5.4 (5) mg/L, and 0.81 (5) 1/h, respectively, where T0, is the estimate of the basal temperature, 38.8 (10) ºC. No significant (p>0.05) covariate effects (including pharmaceutical formulation) were detected in any of the pharmacodynamic parameters. This study is an example of using data from different clinical trials to evaluate the sources of pharmacodynamic variability, and shows once again that moderate differences in the plasma drug concentration vs time profiles have less impact on the therapeutic response when the drug acts indirectly.
Reference: PAGE 9 () Abstr 89 [www.page-meeting.org/?abstract=89]
Poster: oral presentation