Clin Pharmacokinet 2000 Jun; 38 (6): 505-518 ORIGINAL RESEARCH ARTICLE 0312-5963/00/0006-0505/$20.00/0 © Adis International Limited. All rights reserved. Pharmacokinetic-Pharmacodynamic Modelling of the Antipyretic Effect of Two Oral Formulations of Ibuprofen Iñaki F. Trocóniz,1 Santos Armenteros,2 María V. Planelles,3 Julio Benítez,4 Rosario Calvo5 and Rosa Domínguez2 1 Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Navarra, Pamplona, Spain 2 Medical Department, Laboratorios Knoll S.A., Madrid, Spain 3 Department of Paediatrics, Clinic Hospital, Valencia, Spain 4 Department of Pharmacology, Faculty of Medicine, University of Extremadura, Badajoz, Spain 5 Department of Pharmacology, Faculty of Medicine, University of the Basque Country, Lejona, Spain Abstract Objective: To analyse the population pharmacokinetic-pharmacodynamic relation- ships of racemic ibuprofen administered in suspension or as effervescent granules with the aim of exploring the effect of formulation on the relevant pharmaco- dynamic parameters. Design: The pharmacokinetic model was developed from a randomised, cross- over bioequivalence study of the 2 formulations in healthy adults. The pharmaco- dynamic model was developed from a randomised, multicentre, single dose efficacy and safety study of the 2 formulations in febrile children. Patients and participants: Pharmacokinetics were studied in 18 healthy volun- teers aged 18 to 45 years, and pharmacodynamics were studied in 103 febrile children aged between 4 and 16 years with bodyweight ≥25kg. Methods: The 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 anti- pyretic 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 phar- macodynamic analysis, the predicted typical pharmacokinetic profile (based on the pharmacokinetic model previously developed) was used. Results: The 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 suspen- sion 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, leadingtotimetoreachmaximumdrugconcentration(tmax)valuesof0.9and1.9 506 Trocóniz et al. 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 con- centration 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 T0 is 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. Conclusions: Because 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. The absorption and disposition of many of the usually be related (directly) to drug effect,[8,9] such nonsteroidal anti-inflammatory drugs (NSAIDs), assumptions need revision. For the particular case which are drugs widely used in the treatment of of NSAIDs there is evidence for distribution delays pain, fever and rheumatic and inflammatory diseases, to the biophase and/or indirect response mechanisms. have received considerable attention over the past Kelley et al.[10] developed a pharmacokinetic- 3 decades.[1] Several articles have studied the effect pharmacodynamic model of the antipyretic effect of demographics, food or pathophysiological states for each of the enantiomers of ibuprofen; the model [2-4] on the pharmacokinetics of NSAIDs. In addi- postulated an effect compartment. On the other tion, the impact of using different routes of admin- hand, an indirect mechanism model to account for the istration and/or pharmaceutical formulations on time course of the antipyretic effect of racemic the plasma versus time profiles has also been eval- ibuprofen was proposed by Garg and Jusko[11] in [5-7] uated. 1994. Moreover, the literature contains examples In general, disposition parameters (apparent vol- where pharmacodynamic drug properties vary ume of distribution and total plasma clearance) are depending on the rate of drug administration not (or only slightly) affected by the route or formu- (which can be extended, for example, to changes in lation components. However, absorption profiles the rate of absorption).[12] It is therefore of inter- [usually characterised by C (maximum concentra- max est to address this issue for the particular case of tion of drug in plasma) and t (time to C )], as max max NSAIDs because of the variety of NSAID formula- expected, are highly dependent on those 2 factors.[5-7] tions that are currently being used in therapeutics. Measurements of tmax,Cmax and other parameters such as area under the curve of plasma drug con- In the present paper, the plasma drug concentra- centration versus time curve (AUC) are frequently tion versus time profiles of racemic ibuprofen used to determine bioequivalence between different given in suspension or as effervescent granules to pharmaceutical formulations. Such measurements healthy volunteers were described using an appro- could also be used to make assumptions regarding priate pharmacokinetic model. A population phar- the time course of drug effect. For example, higher macodynamic model (using the pharmacokinetic values of tmax and Cmax could be considered indices model developed previously) describing the mean of delayed and higher therapeutic (or adverse) ef- and individual antipyretic profiles of 103 children fects, respectively. receiving the same formulations as the healthy Taking into account the fact that for most drugs volunteers was built with the goal of exploring the the relationship between exposure and effect is effect of formulation (used as a covariate in the nonlinear and that plasma concentrations cannot population model) on the relevant pharmacodynamic Adis International Limited. All rights reserved. Clin Pharmacokinet 2000 Jun; 38 (6) Modelling the Antipyretic Effects of Ibuprofen 507 parameters and their estimates of interindividual 08.00. They were served breakfast and lunch at variability. 10.00 and 14.00, respectively. Participants left the hospital 12 hours after drug intake unless other- Methods wise indicated, for example because of the occur- This work includes results from a pharmaco- rence of adverse events. kinetic (bioequivalence) study and a pharmacody- Pharmacokinetics namic (efficacy and safety) study. Venous blood samples (5ml) for measurement of racemic ibuprofen were taken from the forearm Pharmacokinetic Study vein at the following times during the 2 study days: Participants just before drug intake, and 0.5, 1, 1.5, 2, 2.5, 3, 18 healthy volunteers participated in the study. 3.5, 4, 5, 6, 8 and 12 hours after intake. Plasma was All participants gave signed informed written con- obtained after centrifugation of blood samples and sent, and approval was obtained from the ethics plasma drug concentrations were determined by a committee of the Infanta Cristina University Hos- validated high resolution liquid chromatography pital, Badajoz, Spain. The study was conducted ac- nonstereoselective method published previously.[13] cording to the guidelines in the Declaration of In the ibuprofen plasma concentration range of 0.5 Helsinki. Males (n = 10) and females (n = 8) aged to 50 mg/L the method showed linearity, the mean between 18 and 45 (mean 21) years and weighing intra- and interassay coefficients of variation were between 50 and 70 (mean 62) kg participated in the less than 5%, and the accuracy of the assay was study. Inclusion criteria were: no evidence of car- higher than 95%. diovascular, pulmonary, hepatic, renal or gastroin- testinal disease, and results from routine laboratory Pharmacodynamic Study tests, including complete blood count, chemistry tests with liver panel, urinalysis and ECG, within Patients the normal range. Smokers (<15 cigarettes/day) 103 febrile children participated in the study. were eligible for the study. No other medication Signed informed written consent was obtained was allowed during the month before the start of from each patient’s parent or legal guardian, and the study and during the study (except oral contra- approvals were obtained from the ethics committee ceptives). Individuals who had participated in an- of the centres in which the study was carried out. other clinical trial within 90 days prior to the entry The study was conducted according to the guide- to this study were excluded. lines in the Declaration of Helsinki. Inclusion cri- Study Design teria were children (male or female) with body- This was a randomised, single dose, nonblind weight ≥25kg and oral temperature before drug phase I study with a crossover design. It consisted intake ≥38°C. Exclusion criteria were severe