Marina Cuquerella-Gilabert(1), Jenifer Serna (2), Almudena Rueda-Ferreiro(2), Matilde Merino-Sanjuan (1,3), Sergio Sánchez-Herrero (2), Victor Mangas-Sanjuan (1,3)
(1) Department of Pharmacy and Pharmaceutical Technology and Parasitology, School of Pharmacy, University of Valencia, Valencia, Spain; (2) Simulation Department, Empresarios Agrupados Internacional S.A., Madrid, Spain; (3) Interuniversity Research Institute for Molecular Recognition and Technological Development, 46100 Burjassot, Valencia, Spain.
Objectives:
Oral drug absorption is a complex process dependent on the interplay between processes depending on both compound and dynamic gastrointestinal physiology properties [1]. In silico methods are the key for testing pharmacokinetic, pharmacodynamics and biopharmaceutic properties of drugs that accelerate the uptake of individualized computer simulations in the regulatory evaluation [2]. The main aims of this project are: 1) to lay the foundations of an Advanced Dissolution, Absorption, and Metabolism (ADAM) model within a population-based mechanistic modeling framework. Concretely, the fundamental physicochemical and biological processes applied for explaining dissolution, pH effect, absorption and transit through the gastrointestinal tract; 2) to externally validate the PBPK framework with in vivo, in vitro and in silico published data [3,4].
Methods:
A Physiologically Based Pharmacokinetics (PBPK) model was proposed including solid, undissolved and dissolved thermodynamic states of the drug. Nine compartments (stomach, duodenum, jejunum 1-2, ileum 1-3, caecum and colon) represent the physiological compartments of the gastrointestinal tract. First-order transit kinetics through the GI tract was assumed for the solid, undissolved and dissolved fractions of the drug. Dissolution processes were described using solubility-independent or solubility-dependent mechanisms and pH effects with the Noyes-Whitney equation and the Henderson-Hasselbach equation [5]. Linear absorption mechanisms were considered to represent the passive diffusion process. Oral administration of standard solid dosage forms together with intestinal transit, dissolution limited by solubility, linear absorption and pH effect through the gastrointestinal tract were assumed. After implementing linear transit and linear absorption, concentration profiles of each compartment for undissolved and dissolved fractions were represented showing progressively diminished AUC and Cmax values as the drugs transited through the gastrointestinal tract.
The model was built using PhysPK, a disruptive multi-libraries Modeling & Simulation (M&S) software tool for optimization, estimation and validation of physiologically based on pharmacokinetic parameters for individuals and populations and EL language [6]. Multilevel object-oriented a-causal simulation language PhysPK tehcnology´s combines PBPK, pharmacokinetics pharmacodynamics and Systems Biology-Pharmacology to M&S from cells to the whole body.
Results:
A PBPK model with a segmented gastrointestinal tract based upon its physiological and anatomical attributes was built. Theoretical scenarios were generated to evaluate the transition throughout the GI tract (kt: 0.013 s-1), dissolution-limited processes (Css: 3.12·10-4 mg/ml) and absorption rate constants (ka: 0.017 s-1). An external validation of the PBPK framework was conducted using in silico and in vivo data on different GI compartments from two drugs (cyclosporine and ibuprofen), which show passive diffusion and dissolution-limited absorption. Physicochemical and study design parameters for each drug were incorporated into the PBPK platform in order to generate the time-course profiles of each drug throughout each GI compartment and plasma. Based on the mean predicted/observed ratios, the PBPK model developed accurately predicted plasma observations of cyclosporine (Cmax ratio: 0.953, Tmax ratio: 0.839, AUC 0-t ratio: 1.123 and AUC 0-inf ratio: 1.056) and ibuprofen (Cmax ratio: 1.027, Tmax ratio: 1.001, AUC 0-t ratio: 0.801 and AUC 0-inf ratio: 0.801).
Conclusions:
Dissolution, absorption, pH effect and intestinal transit were properly implemented and validated in PhysPK setting the basis for building a complete ADAM® model within the theoretical framework. PhysPK biosimulation software is useful for estimating the pharmacokinetic parameters of orally administered drugs since the model showed good descriptive and predictive power of data. However, further research is needed to fully develop the model and establish its applications in other fields.
Aknowledgements:
This project has been funded with support from Empresarios Agrupados Internacional. We thank the University of Valencia and Empresarios Agrupados International for their support and continued commitment.
References:
[1] Lin L., Wong H., Predicting Oral Drug Absorption: Mini Review on Physiologically-Based Pharmacokinetic Models. Pharmaceutics, 9(4), 41, 2017.
[2] Chetty M. et al., Advanced Drug Delivery Reviews,135,85,2018.
[3] Bermejo M., et al., A Mechanistic Physiologically-Based Biopharmaceutics Modeling (PBBM) Approach to Assess the In Vivo Performance of an Orally Administered Drug Product: From IVIVC to IVIVP. Pharmaceutics, 17;12(1):74, 2020.
[4] Anlamlert W. et al., Pomegranate Juice does not Affect the Bioavailability of Cyclosporine in Healthy Thai Volunteers. Curr Clin Pharmacol.15(2):145-151,2020.
[5] Shekunov B., Montgomery ER., Theoretical Analysis of Drug Dissolution: I. Solubility and Intrinsic Dissolution Rate. J Pharm Sci., 105(9):2685-2697,2016.
[6] Reig-Lopez J. et al., A multilevel object-oriented modelling methodology for physiologically-based pharmacokinetics (PBPK): Evaluation with a semi-mechanistic pharmacokinetic model. Comput Methods Programs Biomed, 189, 2020.
Reference: PAGE 30 (2022) Abstr 10048 [www.page-meeting.org/?abstract=10048]
Poster: Methodology - New Modelling Approaches