Chirality matters: physiologically based pharmacokinetic modelling of ibuprofen enantiomers
Cuquerella-Gilabert, Marina1,2; Reig-López, Javier1,2; Merino-Sanjuán, Matilde1,2; Mangas-Sanjuán, Víctor1,2; García-Arieta, Alfredo3
1Department of Pharmacy, Pharmaceutical Technology and Parasitology, University of Pharmacy, Universitat de València, Valencia, Spain; 2Interuniversity Institute of Molecular Recognition Research and Technological Development, 46100 Burjassot, Valencia, Spain; 3Division of Pharmacology and Clinical Evaluation, Department of Medicines for Human Use, Spanish Agency of Medicines and Health Products, Madrid, 28022, Spain
Introduction/Objective: Ibuprofen is a non-steroidal anti-inflammatory drug administered in its racemic form containing equal amounts of R-ibuprofen (pharmacologically inactive) and S-ibuprofen (pharmacologically active). The characterization of the time course of each enantiomer as well as of the racemic mixture can be useful in the selection of the most sensitive analyte in bioequivalence assays [1]. A predictive physiologically based pharmacokinetic (PBPK) model could support the waiver of bioequivalence studies by means of virtual bioequivalence trials or by validating the biopredictive power of in vitro dissolution profiles. The main objective of the present work was to develop and validate a sufficiently predictive PBPK model for ibuprofen enantiomers incorporating non-linearity and stereoselectivity in plasma protein binding.
Methods: A full PBPK model for R- and S-ibuprofen was developed in the Simcyp® Simulator V21 following a "middle-out" approach. Non-linearity and stereoselectivity in plasma protein binding was implemented varying the fraction unbound in plasma (fu) for each enantiomer and dose level [2]. The Rodgers and Rowland method to predict tissue partition coefficients (KTp) was selected and a KTp scalar of 1.5 was applied to match the observed volume of distribution at steady state (Vss) of 0.1-0.2 L/Kg. Elimination of ibuprofen was mainly modelled through hepatic metabolism, with a minimal contribution of renal clearance (0.05 L/h) [3]. The Advanced Dissolution, Absorption and Metabolism model was selected to evaluate different oral formulations containing a racemic mixture of ibuprofen (i.e., oral solution of the arginine salt and 2% and 4% oral suspensions). The Particle Population Balance (PPB) model in the Diffusion Layer Model (DLM) was selected to better account for the dissolution process of the ibuprofen particles in suspension with a radius of 39±11 mcm [4]. Additionally, self-buffering capacity of ibuprofen was considered to model particle surface solubility. Model performance was assessed with results from phase I clinical trials after IV infusion (4 trials, 96 IDs, 1784 observations for each enantiomer), and oral administration of solutions (4 trials, 96 IDs, 1784 observations for each enantiomer) and suspensions (2 trials, 98 IDs, 1507 observations for each enantiomer). Different infusion times (15, 20 and 30 min), dose levels (200, 400 and 600 mg) and intake volumes were evaluated. Simulations performed included 100 individuals (10 trials of 10 individuals each) and matched clinical trial design and demographic characteristics of the individuals enrolled. The predictive power of the PBPK models was evaluated both graphically, plotting observed vs predicted plasma concentration-time profiles, and numerically determining the Prediction Error (PE), Average fold-error (AFE), absolute AFE (AAFE) and percent prediction error (PPE), for AUC0-t and Cmax. Results were considered satisfactory if observations fell between 5th and 95th percentiles of predicted profiles and error metrics were in the range of 0.8-1.25.
Results: The stereoselective distribution model predicted a 2% higher Vss for S-ibuprofen and higher tissue penetration at 600 mg dose level when compared to lower doses because of the saturation of albumin binding sites that results in a 15% higher fu. Stereoselectivity was also relevant in the elimination of both enantiomers, with higher CLint for R-ibuprofen (400 mcL/min/mg protein) than for S-ibuprofen (150 mcL/min/mg protein). The 5th and 95th percentiles of the simulated plasma concentration-time profiles for both enantiomers captured the observed data in all scenarios assessed. The PBPK model developed predicted complete absorption (fa=0.998) and high bioavailability for both enantiomers. In this line, model predicted R- and S-ibuprofen bioavailability after oral administration resulted in 91% and 93%, respectively. PE for AUC0-t and Cmax fell within the 0.8-1.25 range in 97 and 83% of scenarios, respectively, and within 0.68 and 1.32 in all cases. Overall, the PBPK model here presented predicted ibuprofen enantiomers PK with accuracy and precision, with AFE, AAFE and PPE for AUC of 1.01, 1.08 and 6%, and 1.02, 1.11 and 8% for R- and S-ibuprofen, respectively, and 0.91, 1.16 and 11%, and 0.97, 1.14 and 8%, for R- and S-ibuprofen Cmax, respectively.
Conclusions: The developed PBPK model properly described the time course of ibuprofen enantiomers of multiple formulations in healthy volunteers. As far as we know, the current PBPK framework incorporates for the first time the chirality of ibuprofen, which showed high relevance for disposition processes.
References:
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