An Investigation into the Utility of a Multi-compartmental, Dynamic, System of the Upper Gastrointestinal Tract to Support Formulation Development and Establish Bioequivalence of Poorly Soluble Drugs

Abstract

Abstract. In recent years mechanical systems have been developed that more closely mimic the full dynamic, physical and biochemical complexity of the GI Tract. The development of these complex systems raises the possibility that they could be used to support formulation development of poorly soluble compounds and importantly may be able to replace clinical BE studies in certain circumstances. The ability of the TNO Simulated Gastro-Intestinal Tract Model 1 (TIM-1) Dynamic Artificial Gastrointestinal System in the 'lipid membrane' configuration to support the development of Biopharmaceutics Classification System Class 2 compounds was investigated by assessing the performance of various AZD8055 drug forms and formulations in the TIM-1 system under standard fasting and achlorhydric physiological conditions. The performance data were compared with exposure data from the phase 1 clinical study. Analysis of the AZD8055 plasma concentrations after tablet administration supported the conclusions drawn from the TIM-1 experiments and confirmed that these complex systems can effectively support the product development of poorly soluble drugs. Particularly, the TIM-1 system was able to show that AZD8055 exposure would increase in an approximately dose proportional manner and not be limited by the solubility or dissolution. Additionally, the investigations also showed that the exposure produced by a solution and a tablet would be the same. Specific instances when the TIM-1 system may not be predictive of clinical product performance have also been identified.

In vitro dissolution methodology, mini-Gastrointestinal Simulator (mGIS), predicts better in vivo dissolution of a weak base drug, dasatinib

“…Several in vivo predictive dissolution (IPD) methodologies have been developed and evaluated to predict and understand better in vivo dissolution of drugs which have pH-dependent solubility and/or high lipophilicity (Barker et al, 2014;Brouwers et al, 2011;Carino et al, 2006Carino et al, , 2010Dickinson et al, 2012;Kostewicz et al, 2004;Koziolek et al, 2013aKoziolek et al, , 2013dMudie et al, 2010).…”

“…Incorporating those in vivo environmental factors into an in vitro dissolution apparatus would be necessary to predict more reasonable in vivo dissolution. Newer dissolution methodologies, that consider the in vivo physiological conditions, have been investigated (Barker et al, 2014;Bevernage et al, 2013;Brouwers et al, 2011;Carino et al, 2010;Carlert et al, 2010;Dickinson et al, 2012;Dressman et al, 1998;Koziolek et al, 2013aKoziolek et al, , 2013dKrieg et al, 2014;Mudie et al, 2012;Perez de la Cruz Moreno et al, 2006;Psachoulias et al, 2012Psachoulias et al, , 2011Takeuchi et al, 2014;Vertzoni et al, 2010). TNO intestinal model (TIM-1), especially, is an advanced dissolution model to capture most of the physiological conditions in the GI tract (Barker et al, 2014;Brouwers et al, 2011;Dickinson et al, 2012;Koziolek et al, 2013aKoziolek et al, , 2013d.…”

Evolution of a mini-scale biphasic dissolution model: Impact of model parameters on partitioning of dissolved API and modelling of in vivo-relevant kinetics

“…In contrast, the TNO Intestinal Model (TIM-1-model) combines dissolution with intestinal absorption systems to predict oral bioavailability. Dickinson et al claim that this system accounts for all of the human in vivo physiological processes that occur within the lumen of the small intestine and drug absorption via membrane diffusion (perfusion or artificial membrane) [7]. This physiologically relevant dissolution apparatus offers the potential to study in vivo-relevant PK processes for use in drug development [7].…”

Summary Workshop Report: Facilitating Oral Product Development and Reducing Regulatory Burden Through Novel Approaches to Assess Bioavailability/Bioequivalence

“…TNO TIM-1 Dynamic Artificial Gastrointestinal System Role in Formulation Development and Establishing BE Paul Dickinson, Ph.D. (AstraZeneca) described the use of an in vitro dissolution system, the TNO-TIM-1 system, as a surrogate for the conduct of in vivo studies in formulation development (6). The TIM-1 system is a dynamic dissolution system that simulates various physiological parameters in each of four compartments such as pH control, secretion of buffers (e.g., bicarbonate), mechanical mixing at each stage, transit times, and removal of solubilized drug to simulate absorption.…”