Integrating Drug- and Formulation-Related Properties With Gastrointestinal Tract Variability Using a Product-Specific Particle Size Approach: Case Example Ibuprofen

Abstract

Keywords:absorption dissolution physiologically based pharmacokinetic (PBPK) modeling in vitro-in vivo (IVIVC) correlation(s) mechanistic modeling particle size a b s t r a c tIn the present study, an in vitroein vivo extrapolation of dissolution integrated to a physiologically based pharmacokinetics modeling approach, considering a product-specific particle size distribution and a selfbuffering effect of the drug, is introduced and appears to be a promising translational modeling strategy to support drug product development, manufacturing changes and setting clinically relevant specifications for immediate release formulations containing ibuprofen and other weak acids with similar properties.

Assessing the impact of cystic fibrosis on the antipyretic response of ibuprofen in children: Physiologically‐based modeling as a candle in the dark

“…Chronic conditions other than the one being studied in a clinical (Figures 1 and 2). 10,28 Alternatively, in the lack of comprehensive understanding of the disease impact on drug absorption, simultaneous fitting of physiology parameters across multiple studies for different compounds affected by the pathophysiological condition under study might be useful to guide exploratory analysis and hypothesis generation. 29,30 The qualification of the overarching model was carried out by applying a reverse translation approach, in other words, fitting the model to observed data and optimizing the drug or system parameters for which prior confidence was not high (e.g., paediatric gastric emptying time after intake of a light-fat breakfast).…”

“…Motrin ® and Nurofen ® tablets have been shown to be bioequivalent, 15 a previously developed and verified PBPK model for Nurofen ® tablets was used in this research. 10 Briefly, a stepwise IVIVE modelling approach for ibuprofen solubility and dissolution was applied to mitigate identifiability issues when estimating parameters from in vitro experiments. Firstly, the Simcyp In Vitro Data Analysis Toolkit (SIVA ® v3) was used to model in vitro results in order to improve mechanistic understanding of drug release from Nurofen ® tablets.…”

“…Lastly, using the in vivo simulations of dissolved fraction permeating through the enterocyte compartment, the amount of drug reaching the portal vein could be determined as a function of ibuprofen intestinal permeability (P eff ) and small intestine radius. 10…”

“…7 Gelfond et al have demonstrated a significant delay in the small intestinal transit and a deficient buffering capacity required to neutralize gastric acid in the proximal small bowel of CF patients. 8 These deficiencies have the potential to impair intraluminal dissolution rate of modified release formulations 9 and immediate release formulation containing poorly soluble drugs, 10 with consequent impact on oral absorption.…”

“…The built-in Rodgers & Rowland equation in Simcyp was used to predict perfusion-limited tissue distribution using a bottom-up approach. On the other hand, ibuprofen metabolic clearance was set under a top-down perspective, since metabolic clearance was not predicted by the simulator but based on a clinically obtained, publi-shed result 10,16.…”