Computer aided biopharmaceutical characterization

Gastrointestinal simulation, Theoretical background, Model construction, Parameters sensitivity analysis, Virtual trial, Fed vs Fasted state, Biowaiver consideration

1. Department of Pharmacy Guru Ghasidas Vishwavidyalaya, Bilaspur (CG) Topic: C omputer Aided Biopharmaceutical characterization: Gastrointestinal absorption Simulation Presented by- Sourav Paul Department of Pharmaceutics, 2 nd Semester Roll no.: 23082112 Guided by- Dr. DINESH K. MISHRA PROFESSOR Department of Pharmaceutics

2. Introduction 01 TABLE OF CONTENTS 03 02 06 Theoretical background 05 04 07 08 Model construction Parameter Sensitivity Analysis Fed vs fasted state Biowaiver Considerations I nvitro disso. & Invtro invivo corelation V irtual Trial 09 Conclusion References 10

3. INTRODUCTION Concept of gastrointestinal simulation absorption studied using in silico methodology. Biopharmaceutical assessment of drugs is of crucial importance in different phases of drug discovery, development and evaluation of in silico tools for identifying critical factors. Real world Process Mathematical model Simulation Process Advantages of in silico modelling In silico model: experiment is one performed on computer or via computer 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.

4. Drug absorption from the gastrointestinal (GI) tract is a complex process depends on large number of factors including drug physicochemical properties, physiological factors, and formulation related factors. Physiochemical Physiological Formulation Particle Size Surface Area Dissolution Rate Amorphism Polymorphism Drug Solubility SaltForm Lipophilicity pka of Drug  Drug Stability Nature of cell membrane Transport mechanism Gastric emptying rate Surface area of Git Intestinal transit Blood flow pH of Git Effects of food Disintegration time Method of preparation Nature and type of dosage Pharmaceutical ingredients Storage conditions

5. Various qualitative/quantitative approaches have been proposed, starting from the pH-partition hypothesis and later moving to the more complex models, such as the Compartmental Absorption and Transit (CAT) model gave a good review of these models, classifying them into quasi-equilibrium, steady-state, and dynamic models categories. Following are the various models available :- Advanced Dissolution, Absorption and Metabolism ( ADAM ) model Grass model GI- Transit-Absorption ( GITA ) model CAT model Advanced CAT ( ACAT ) model . Some of them have been integrated in commercial software packages, such as GastroPlus™, SimCYP , PK-Sim®, IDEA™ (no longer available), Cloe® PK, Cloe® HIA, and INTELLIPHARM® PKCR

6. THEORETICAL BACKGROUND Simulation software packages, such as GastroPlus™, are advanced technology computer programs designed to predict PK , and optionally, pharmacodynamic effects of drugs in humans and certain animals. The underlying model in GastroPlus™ is the ACAT model . The ACAT model of the human GI tract Figure consists of nine compartments linked in series, each of them representing a different segment of the GI tract (stomach, duodenum, two jejunum compartments, three ileum compartments, caecum, and ascending colon).

7. Fig1: ACAT model for interpreting of invivo drug behaviour (GastroPlus version 8.0)

8. Movement of the drug between each sub-compartment is described by a series of differential equations. In general, the rate of 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; 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; and Exsorption of drug from portal vein via paracellular pathway

9. The time scale associated with each of these processes is set by an adequate rate constant. Transfer rate constant (kt), associated with lumenal transit, is determined from the mean transit time within each compartment. The dissolution rate constant ( kd ) for each compartment. Absorption rate constant (ka) depends on drug effective permeability multiplied by an absorption scale factor (ASF) for each compartment. Systemic Circulation First pass metabolism

10. By integrating the key input parameters regarding drug absorption, distribution, metabolism, and excretion (e.g. partition coefficients, metabolic rate constants, elimination rate constants, permeability coefficients, diffusion coefficients, protein binding constants), We can not only estimate drug PK parameters and plasma and tissue concentration-time profiles, but also gain a more mechanistic insight into the properties of a compound. 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 data. The other input parameters include drug physicochemical properties (i.e . solubility, permeability, logP, pKa, diffusion coefficient ) PK parameters like clearance (CL), volume of distribution, along with certain formulation characteristics (e.g. particle size distribution and density, drug release profiles for controlled-release formulations) are determined .

11. MODEL CONSTRUCTION

12. Table 2: Summary of Nimesulide Input parameters employed for GI simulation

13. According to the obtained data, both Models 1 and 2 gave accurate predictions of nimesulide average plasma profile after oral administration. In both cases, the percentage prediction errors for Cmax and area under the curve (AUC) values were less than 10%. The largest deviation was observed for tmax . The predicted values of 3.15 h (Model 1) and 3.4 h (Model 2) were considered as reasonable estimates, since the reported tmax values after oral administration of nimesulide IR tablets varied between 1 and 4 h (Jovanovic et al., 2005; Rainsford, 2006)

14. Parameter Sensitivity Analysis

15. Virtual Trial Inter-subject variability may influence oral drug absorption is determined using virtual trails. Virtual trials were performed on virtual 12 subjects (equal to the number of subjects used in the clinical study), and the results were presented as mean Cp vs. time profile with 90% confidence intervals. The Virtual Trial mode can also be used to conduct virtual BE studies on 25 subjects. Results of the simulations are expressed as means and coefficients of variation for the fraction of drug absorbed, bioavailability, t max, C max, and AUC values.

16. Fed vs fasted state The presence of food may affect drug absorption via a variety of mechanisms; by impacting For example, lipophilic drugs often show increased systemic exposure with food due to higher bile salt and lipid concentrations. Considering that, these models are built based on a prior knowledge of GI physiology in the fasted and fed states. GI tract physiology (e.g. food-induced changes in gastric emptying time, gastric pH, intestinal fluid composition, hepatic blood flow), Drug solubility and dissolution , Drug permeation

17. IVIVC In vitro dissolution and in vitro-in vivo correlation (IVIVC) are concepts commonly used in pharmaceutical research and development to assess the performance and predict the behavior of drugs. In vitro dissolution : it's a process of release of drug from dosage form as measured in an in vitro dissolution apparatus. In vivo dissolution : process of dissolution of drugs in the GI tract. Correlation : relationship between in vitro dissolution rate and in vivo absorption rate as used in bio-equivalence guidance IVIVC: has been defined as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response”

18. IVIVC shortens the drug development period, economizes the resources and leads to improved product quality. A mean of assuring the bioavailability of active ingredients from a dosage form. Supports and or validates the use of dissolution methods and specifications IVIVC assists in supporting  biowaivers .

19. Level A Correlation: It represents point to point correlation . Level B Correlation: Mainly uses the principle of statistical moment analysis . Mean in vitro dissolution of the drug is compared with mean in vivo residence time of the drug. Level C Correlation: It represents single point correlation . One dissolution time point is compared to one PK parameter.

20. The role of biowaivers in the drug approval process has been emphasized since the introduction of BCS and the release of FDA. The term biowaiver refers to the situations in which in vivo BE studies can be substituted with the relevant in vitro data. The main premise, when adopting the biowaiver concept, was to reduce time and costs , and to offer benefits in terms of ethical considerations. The most common type of biowaiver adopted by the regulatory authorities includes the application of the BCS-based scheme or the application of IVIVC. Biowaiver considerations are applied to determine if in vivo bioequivalence studies can be waived for generic drug products. This involves demonstrating similarity between the generic and reference products in terms of formulation, in vitro dissolution profiles, and expected pharmacokinetic behavior. Biowaiver Considerations

21. CONCLUSION: The various examples presented demonstrate that GI modeling has become a powerful tool to study oral drug absorption and pharmacokinetics. By understanding the complex interplay between drug physicochemical and PK properties, formulation factors, and human physiology characteristics, we might gain an insight into the influence of a particular factor or set of factors on drug absorption profile, and understand possible reasons for poor oral bioavailability

22. Erik Sjögren   ,  Helena Thörn   ,  Christer Tannergren In Silico Modeling of Gastrointestinal Drug Absorption: Predictive Performance of Three Physiologically Based Absorption Models. https://www.sciencedirect.com/science/article/abs/pii/B9781907568275500068 accessed on 08.04.24 A text book on Computer Aided Drug Development, Abhang S. Snehal, Sharma Prerna PV Books. REFERENCES: