Reig-López, Javier1,2; Cuquerella-Gilabert, Marina1,2; Merino-Sanjuán, Matilde1,2; Mangas-Sanjuán, VÃctor1,2; GarcÃa-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: The characterization of the time course of ibuprofen (IBU) enantiomers can be useful in the selection of the most sensitive analyte in bioequivalence (BE) assays [1]. Physiologically based pharmacokinetic (PBPK) modelling and simulation represents an efficient methodology to virtually assess BE outcomes [2,3].
Objectives: To evaluate the sensitivity of IBU enantiomers to assess BE outcomes of oral formulations containing racemic IBU.
Methods: A minimal PBPK model incorporating a stereoselective and concentration-dependent fraction unbound in plasma for each enantiomer was developed in SimCYP®. An initial estimation of the intrinsic clearance trough a racemase was performed to better characterize the formation of S-IBU from R-IBU in vivo [4]. Stereoselectivity was also incorporated in metabolic processes through CYP2C8 and 2C9 and UGT1A3, 1A9, 2B4 and 2B7. Minimal contribution of renal clearance (0.05 L/h) was also accounted for. The Advanced Dissolution, Absorption and Metabolism (ADAM) model was selected to evaluate different oral formulations containing a racemic mixture of IBU. The diffusion layer model was selected to better account for the dissolution process of IBU particles in suspensions, soft gelatine capsules and tablets. Additionally, self-buffering capacity of IBU was considered to model particle surface solubility. Model performance was assessed with a dataset coming from 11 Phase I clinical trials and providing 14452 observations (7129 for R-IBU and 7323 for S-IBU) in 54 different scenarios (27 per enantiomer). Simulations performed included 25 trials and matched clinical study design. Graphical and numerical evaluation of simulation outcomes (AUC0-t and Cmax) were performed. The model was finally applied to assess the impact of particle size distribution (PSD) generating three representative scenarios for S-IBU: (1) test formulation with a 20% lower Cmax; (2) test formulation with a Tmax 20% shorter; and (3) test formulation with a Tmax 20% longer. Deterministic simulations using the population of healthy volunteers of Simcyp® were performed. Ratios T/R were calculated using different PK parameters: AUC0-t, area under the concentration-time profile from zero to median Tmax of the reference (AUCTmax), Cmax and Tmax.
Results: Prediction Errors (PE) for AUC0-t and Cmax for both enantiomers fell within the 0.8-1.25 range in 50/54 and 42/54 of scenarios, respectively. Moreover, 13/27 and 15/27 of AUC0-t PE and 12/27 and 14/27 of Cmax PE for R- and S-IBU, respectively, fell within the 0.9-1.10 range. High accuracy was demonstrated since all average fold errors (AFE) for AUC0-t fell within the desired range of 0.8-1.25 regardless the formulation and dose level, except for R-IBU from the soft gelatine capsules containing the lysine salt of IBU (0.79). Similar results of AFEs for Cmax for both enantiomers were also obtained, with AFE of 0.65 and 0.77 for soft gelatine capsules with lysine and tablets of R-IBU and an AFE of 0.79 for the tablets of S-IBU as the worst predicted scenarios. The T/R ratio of Cmax (scenario 1) for R- and S-IBU were 77.27 and 80.00, 77.53 and 80.00, and 79.21 and 80.00, for oral suspensions, soft gelatine capsules and tablets, respectively, suggesting the absorption rate of R-IBU is more sensitive to changes in dissolution rate. However, test formulations with different Tmax (scenarios 2 and 3) provided similar ratios for both enantiomers across the PK parameters AUC0-t and Cmax regardless the formulation. Regarding PK outcomes, the evaluation of AUCTmax T/R ratios (ranging from 36 to 82%) suggests it is the most sensitive parameter for test formulations with changes in PSD causing a slower dissolution and absorption rate (scenarios 1 and 3), whereas Tmax is more discriminative to detect formulation changes resulting in an increase in absorption rate (scenario 2). On the other hand, no significant changes in AUC0-t nor Cmax are anticipated when Tmax is varied by 20% (scenarios 2 and 3), as ranges of T/R ratios for these parameters resulted in 99.70-101.54 and 90.13-101.41, respectively.
Conclusions: The deterministic BE risk assessment has revealed R-IBU (distomer) as the most sensitive analyte to detect differences in PSD for oral formulations containing a racemic mixture of IBU. These results suggest achiral bioanalytical methods would increase type II error and declare non-bioequivalence for formulations that are bioequivalent for the eutomer (S-IBU).
References:
[1] E. Gonzalez-Rojano, et al. Chirality. 2020, 32(9), 1169-1177
[2] M. Bego, et al. The AAPS Journal. 2022, 24(21)
[3] I. Loisios-Konstantinidis, et al. Eur. J. Pharm. Sci. 2020, 143, 105170
[4] H. Cheng, et al. Pharm. Res. 1994, 11(6), 824-830
Reference: PAGE 32 (2024) Abstr 10851 [www.page-meeting.org/?abstract=10851]
Poster: Drug/Disease Modelling - Absorption & PBPK