ObjectiveTo analyse the population pharmacokinetic-pharmacodynamic relationships of racemic ibuprofen administered in suspension or as effervescent granules with the aim of exploring the effect of formulation on the relevant pharmacodynamic parameters.DesignThe pharmacokinetic model was developed from a randomised, crossover bioequivalence study of the 2 formulations in healthy adults. The pharmacodynamic model was developed from a randomised, multicentre, single dose efficacy and safety study of the 2 formulations in febrile children.Patients and participantsPharmacokinetics were studied in 18 healthy volunteers aged 18 to 45 years, and pharmacodynamics were studied in 103 febrile children aged between 4 and 16 years with bodyweight ≥25kg.MethodsThe pharmacokinetic study consisted of two 1-day study occasions, each separated by a 1-week washout period. On each occasion ibuprofen 400mg was administered orally as suspension or granules. The time course of the antipyretic effect was evaluated in febrile children receiving a single oral dose of 7 mg/kg in suspension or 200 or 400mg as effervescent granules. During the pharmacodynamic analysis, the predicted typical pharmacokinetic profile (based on the pharmacokinetic model previously developed) was used.ResultsThe disposition of ibuprofen was described by a 2-compartment model. No statistical differences (p > 0.05) were found between the 2 formulations in the distribution and elimination parameters. Absorption of ibuprofen from suspension was adequately described by a first-order process; however, a model with 2 parallel first-order input sites was used for the drug given as effervescent granules, leading to time to reach maximum drug concentration (tmax) values of 0.9 and 1.9 hours for suspension and granules, respectively. The time course of the antipyretic effect was best described using an indirect response model. The estimates (with percentage coefficients of variation in parentheses) of Emax(maximum inhibition of the zero-order synthesis rate of the factor causing fever), EC50(plasma concentration eliciting half of Emax), n (slope parameter) and kout(first order rate constant of degradation) were 0.055 (10), 6.16 (14) mg/L, 2.71 (18) and 1.17 (23) h−1, respectively, where T0is the estimate of the basal temperature, 38.8 (1) °C. No significant (p > 0.05) covariate effects (including pharmaceutical formulation) were detected in any of the pharmacodynamic parameters.ConclusionsBecause of the indirect nature of the effect exerted by ibuprofen, the implications of differences found in the plasma drug concentration profiles between suspension and effervescent granules are less apparent in the therapeutic response.