Physiologically Based Biopharmaceutics Model (PBBM) of Minimally Absorbed Locally Acting Drugs in the Gastrointestinal Tract-Case Study: Tenapanor.

A physiologically based biopharmaceutics model (PBBM) was developed to predict stool and urine sodium content in response to tenapanor administration in healthy subjects. Tenapanor is a minimally absorbed small molecule that inhibits the sodium/hydrogen isoform 3 exchanger (NHE3). It is used to treat irritable bowel syndrome with constipation (IBS-C). Its mode of action in the gastrointestinal tract reduces the uptake of sodium, resulting in an increase in water secretion in the intestinal lumen and accelerating intestinal transit time. The strategy employed was to perform drug-drug interaction (DDI) modelling between sodium and tenapanor, with sodium as the "victim" administered as part of daily food intake and tenapanor as the "perpetrator" altering sodium absorption. Food effect was modelled, including meal-induced NHE3 activity using sodium as an inducer by normalising the induction kinetics of butyrate to sodium equivalents. The presented model successfully predicted both urine and stool sodium content in response to tenapanor dosed in healthy subjects (within 1.25-fold error) and provided insight into the clinical observations of tenapanor dosing time relative to meal ingestion. The PBBM model was applied retrospectively to assess the impact of different forms of tenapanor (free base vs. HCl salt) on its pharmacodynamic (PD) effect. The developed modelling strategy can be effectively adopted to increase confidence in using PBBM models for the prediction of the in vivo behaviour of minimally absorbed, locally acting drugs in the gastrointestinal tract, when other approaches (e.g., biomarkers or PD data) are not available.

Use of In Vitro Dynamic Colon Model (DCM) to Inform a Physiologically Based Biopharmaceutic Model (PBBM) to Predict the In Vivo Performance of a Modified-Release Formulation of Theophylline.

A physiologically based biopharmaceutic model (PBBM) of a modified-release formulation of theophylline (Uniphyllin Continus® 200 mg tablet) was developed and implemented to predict the pharmacokinetic (PK) data of healthy male volunteers by integrating dissolution profiles measured in a biorelevant in vitro model: the Dynamic Colon Model (DCM). The superiority of the DCM over the United States Pharmacopeia (USP) Apparatus II (USP II) was demonstrated by the superior predictions for the 200 mg tablet (average absolute fold error (AAFE): 1.1-1.3 (DCM) vs. 1.3-1.5 (USP II). The best predictions were obtained using the three motility patterns (antegrade and retrograde propagating waves, baseline) in the DCM, which produced similar PK profiles. However, extensive erosion of the tablet occurred at all agitation speeds used in USP II (25, 50 and 100 rpm), resulting in an increased drug release rate in vitro and overpredicted PK data. The PK data of the Uniphyllin Continus® 400 mg tablet could not be predicted with the same accuracy using dissolution profiles from the DCM, which might be explained by differences in upper gastrointestinal (GI) tract residence times between the 200 and 400 mg tablets. Thus, it is recommended that the DCM be used for dosage forms in which the main release phenomena take place in the distal GI tract. However, the DCM again showed a better performance based on the overall AAFE compared to the USP II. Regional dissolution profiles within the DCM cannot currently be integrated into Simcyp®, which might limit the predictivity of the DCM. Thus, further compartmentalization of the colon within PBBM platforms is required to account for observed intra-regional differences in drug distribution.

Integrating In Vitro Biopharmaceutics into Physiologically Based Biopharmaceutic Model (PBBM) to Predict Food Effect of BCS IV Zwitterionic Drug (GSK3640254).

A strategy followed to integrate in vitro solubility and permeability data into a PBBM model to predict the food effect of a BCS IV zwitterionic drug (GSK3640254) observed in clinical studies is described. The PBBM model was developed, qualified and verified using clinical data of an immediate release (IR)-tablet (10-320 mg) obtained in healthy volunteers under fasted and fed conditions. The solubility of GSK3640254 was a function of its ionization state, the media composition and pH, whereas its permeability determined using MDCK cell lines was enhanced by the presence of mixed micelles. In vitro data alongside PBBM modelling suggested that the positive food effect observed in the clinical studies was attributed to micelle-mediated enhanced solubility and permeability. The biorelevant media containing oleic acid and cholesterol in fasted and fed levels enabled the model to appropriately capture the magnitude of the food effect. Thus, by using Simcyp® v20 software, the PBBM model accurately predicted the results of the food effect and predicted data were within a two-fold error with 70% being within 1.25-fold. The developed model strategy can be effectively adopted to increase the confidence of using PBBM models to predict the food effect of BCS class IV drugs.

Dissolution testing of modified release products with biorelevant media: An OrBiTo ring study using the USP apparatus III and IV.

During the OrBiTo project, our knowledge on the gastrointestinal environment has improved substantially and biorelevant media composition have been refined. The aim of this study was to propose optimized biorelevant testing conditions for modified release products, to evaluate the reproducibility of the optimized compendial apparatus III (USP apparatus III) and compendial apparatus IV (USP apparatus IV, open-loop mode) dissolution methods and to evaluate the usefulness of these methods to forecast the direction of food effects, if any, based on the results of two «ring¼ studies and by using two model modified release (MR) products, Ciproxin / Cipro XR and COREG CR. Six OrBiTo partners participated in each of the ring studies. All laboratories were provided with standard protocols, pure drug substance, and dose units. For the USP apparatus III, the dissolution methods applied to Ciproxin / Cipro XR, a monolithic MR product of an active pharmaceutical ingredient (API) with moderate aqueous solubility, were robust with low intra- and inter-laboratory data variability. Data from all partners were in line on a qualitative basis with food effect data in humans. For the USP apparatus IV, the dissolution methods applied to COREG CR, a multiparticulate, pH dependent, MR product of an API with low and pH dependent solubility led to high intra- and inter- laboratory data variability. Data from all partners were in line, on a qualitative basis, with the previously observed food effects in humans.