GIT Absorption Simulation
- 1. Computer – aided biopharmaceutical characterization
- 2. Basic principles of Gastro intestinal simulation Guided by- Dr . Vijayakumar M.R. Department of Pharmaceautical Sciences Babasaheb Bhimrao AmbedkarUniversity, Lucknow Presented by – Jaskiran Kaur Department of Pharmaceautical Sciences Babasaheb Bhimrao AmbedkarUniversity, Lucknow 2
- 3. Contents In-silico Simulation Significance of simulation modelling Conventional drug discovery process Computational simulated model of drug discovery process Aim of simulation in absorption Model & its characteristics Physiologically based pharmacokinetic (PBPK) models General modelling and simulation strategy Gastric absorption simulation ACAT Model Gastroplus™ INPUTS in this model Simcyp Future of computer-aided simulation studies
- 4. In- Silico • In silico (literally alluding the mass use of silicon for semiconductor computer chips) is an expression used to performed on computer or via computer simulation • In silico tools capable of identifying critical factors (i.e. drug physicochemical properties, dosage form factors) influencing drug in vivo performance, and predicting drug absorption based on the selected data set (s) of input factors.
- 5. Simulation Simulation is the imitation of the operation of a real-world process or system over time. A Simulation of a system require model to imitate the process in the computer based systems. Computer simulation reproduce the behavior of a system using a mathematical model.
- 6. Computer simulations have become useful tool for the mathematical modeling of many natural systems in physics, astrophysics, climatology, chemistry and biology in human systems. It involves generation of artificially history of system and drawing inference from it. It express the assumption of mathematical, logical and symbolic relationship between system.
- 7. Significance of simulation modeling It enable the study of system and experimentation with the internal interaction of a complex system, or of a subsystem within a complex system Informational, organizational and environmental changes can be simulated and the effect of those alternation on the model's behavior can be observed. It is very important for the suggestion improvement in the system under investigation. By changing the simulation input and observing the resulting outputs, valuable insight may be obtained into which variables are most important and how variable interact.
- 8. It is also used as a device to reinforce analytical solution methodology Also used to verify analytical solution. It can be used to experiment with new designs or policies prior to implementation, so as to prepare for what to happen. It is design for training, flow with learning without the cost and disruption of on the job learning. The modern system are so complicated so the interaction can be treated only through simulation.
- 14. Gastric absorption simulation Biopharmaceutical characterization of drugs/pharmaceutical products increased the interest in development and evaluation of in silico tools capable of identifying critical factors (ie. drug physicochemical properties, dosage form factors) influencing drug in vivo performance, and predicting drug absorption based on the selected data set(s) of input factors. Drug absorption from the gastrointestinal (GI) tract is a complex interplay between a large number of factors (i.e. drug physicochemical properties, physiological factors, and formulation related factors), and its correct representation in the in silico models has been a major challenge.
- 16. Aim of simulation in absorption Absorption is an important process in order to achieve the therapeutic effect of drug that has been administered. During drug discovery, potential drug candidates are often filtered based on their absorption-distribution-metabolism excretion (ADME) properties determined using in vitro assays and in vivo animal models. Biopharmaceutical evaluation can be used to guide formulation strategy or to predict the effect of food on drug absorption. Development and evaluation of in-silico tools capable of identifying critical factors influencing drug in vivo performance.
- 17. Model & its characteristics The model is similar to a real system, which helps the analyst predict the effect of changes to the system. It helps analyze the performance of an existing or a proposed system Characteristics- Easy to understand Target direction Nearly real system- Produce results fast Easy to control and operate Updateable-Effective Report.
- 18. Physiologically based pharmacokinetic (PBPK) models Physiologically based pharmacokinetic(PBPK) modeling is mathematical modeling technique for predicting the absorption, distribution, metabolism and excretion (ADME) of synthetic or natural chemical substances in humans and other animal species. Physiologically-based pharmacokinetic (PBPK) models are describe biological processes in order to mimic biology. They are dynamic in nature and are defined by series of differential equations. PBPK models differ in that they are mechanistic in nature and incorporate physiological processes such as GI transit time and organ blood flows.
- 19. Various qualitative/quantitative approaches have been proposed, starting from the pH-partition hypothesis (Shore et al., 1957), and later moving to the more complex models, such as the Compartmental Absorption and Transit (CAT) model. In recent years, substantial effort has been allocated to develop and promote dynamic models that represent GI tract physiology in view of drug transit, dissolution, and absorption. Among these are the 1. Advanced Dissolution, Absorption and Metabolism (ADAM) model 2. Grass model 3. GI-Transit-Absorption (GITA) model 4. CAT model 5. Advanced CAT (ACAT) model
- 20. Some of them have been integrated in commercial software packages, such as 1. GastroPlus™M 2. SimCYP, PK-SimⓇ 3. IDEATM (no longer available) 4. Cloe @PK, 5. CloeⓇHIA, 6. INTELLIPHARM www.Simulator.plus.com www.Symcyp.com www.Cyprotex.com www.Intellipharm.com
- 23. ACAT Model The ACAT model of the human GI tract consists of nine compartments linked in series, each of them representing a different segment of the GI tract 1. Stomach 2. Duodenum 3. Two jejunum compartments 4. Three ileum compartments 5. Caecum 6. Ascending colon. These compartments are further subdivided to comprise the drug that is 1. Unreleased 2. Undissolved 3. Dissolved 4. Absorbed (entered into the enterocytes)
- 25. The rate change of dissolved drug concentration in each GI compartment depends on ten processes. Transit of drug into the compartment. Transit of drug out of the compartment. Release of drug from the formulation into the compartment. Dissolution of drug particles. Precipitation of drug.
- 26. Lumenal degradation of drug. Absorption of drug into the enterocytes. Exsorption of drug from the enterocytes back into the lumen. Absorption of drug into portal vein via paracellular pathway. Exsorption of drug from portal vein via paracellular pathway
- 27. Movement of drug in between compartments
- 28. Transfer rate constant (kt), associated with lumenal transit, is determined from the mean transit time within each compartment. The dissolution rate constant (k d) for each compartment at each time step is calculated based on the relevant formulation parameters and the conditions (pH, drug concentration, % fluid, and bile salt concentration) in the compartment at that time. Absorption rate constant (k a) depends on drug effective permeability multiplied by an absorption scale factor (ASF) for each compartment. The ASF corrects for changes in permeability due to changes in physiological conditions along the GI tract (eg, surface area available for absorption, pH. expression of transport/efflux proteins). Default ASF values are estimated on the basis of the so-called logD model, which considers the influence of logD of the drug on the effective permeability. According to this model, as the ionized fraction of a compound increases, the effective permeability decreases
- 29. Besides passive absorption, including both transcellular and paracellular routes, the ACAT model also accounts for influx and efflux transport processes, and presystemic metabolism in the gut wall. Luminal degradation rate constant (k degrad) Finally, the rates of absorption and exsorption depend on the concentration gradients across the apical and basolateral enterocyte membranes. The total amount of absorbed drug is summed over the integrated amounts being absorbed/exsorbed from each absorption/transit compartment
- 30. Once the drug passes through the basolateral membrane of enterocytes, it reaches the portal vein and liver, where it can undergo first pass metabolism. From the liver, it goes into the systemic circulation from where the ACAT model is connected to either a conventional PK compartment model or physiologically based PK (PBPK) disposition model. PBPK is an additional feature included in more recent versions of GastroPlus™M. This model describes drug distribution in major tissues, which can be treated as either perfusion limited or permeability limited.
- 31. Gastroplus™ The GastroPlus TM SOFTWARE based on the ACAT model, an improved version of the original CAT model described by Yu and Amidon. This semi-physiological absorption model is based on the concept of the Bio-pharmaceutics Classification System BCS and prior knowledge of Gl physiology. It is modeled by a system of coupled linear and nonlinear rate equations used to simulate the effect of physiological conditions on drug absorption as it transits through successive Gl compartments.
- 32. INPUTS in this model GastroPlus™ ACAT modeling requires a number of input parameters, which should adequately reflect drug biopharmaceutical properties. Default physiology parameters under fasted and fed states e.g. transit time, pH, volume, length, radii of the corresponding GI region are population mean values obtained from published mean values obtained from published data. The other input parameters include physicochemical parameters Pharmacokinetics parameters Formulation parameters
- 35. Depending on the known solubility at any single pH and drug pka value(s), GastroPlus™ calculates regional solubility based on the fraction of drug ionized at each compartmental pH according to the Henderson- Hasselbalch equation. One of the major obstacles for the wider application of this model has been the vast number of input data required
- 36. Simcyp The Advanced Dissolution Absorption and Metabolism (ADAM) model is a multi-compartmental GI transit model fully integrated into the Simcyp human population-based Simulator as well as the rat, mouse and dog simulators .The Simulator provides both pharmacokinetic and pharmacodynamics models and a separate pediatric module. As per ADAM model treats the GI tract classified into 1. one stomach, 2. seven small intestine compartment 3. one colon compartment
- 37. Within each compartment, drug can exist in several states simultaneously viz. unreleased, undissolved (solid particles), dissolved or degraded. Drug can be dosed in a supersaturated state or super saturation may be attained as a consequence of solubility change when moving from one region of the GI tract to another. When running a simulation the appropriate population should be selected and then the trial size (numbers and groups) together with age-range, gender proportions, fasted/fed status, fluid taken with dose and dosing regimen including staggering for up to four co-dosed drugs.
- 38. Future of computer-aided simulation studies An engineer of the future would only require describing the use-case of the part, and the computer will autonomously optimize the part using modeling and simulation. As digital design solutions evolve with advancements in technology, simulation-driven product development is expected to grow exponentially