(T-050) A review of OSP suite PBBM capabilities: looking ahead

Mariana Guimaraes, PhD – Scientist Systems Pharmacology, ESQlabs GmbH; Jeremy Perrier, PhD – Senior Scientist Systems Pharmacology, ESQlabs GmbH; Stephan Schaller, PhD – CEO, ESQlabs GmbH; Marco Siccardi, PhD – Team Lead Systems Toxicology, ESQlabs GmbH

Objectives: This abstract aims to review the current OSP suite (PK-SIM® and MoBi®) capabilities in Physiologically Based Biopharmaceutics Modeling (PBBM), focusing on its application in drug development. The main objectives of this work are to a) showcase the versatility and efficiency of the OSP suite in relevant research scenarios and b) outline future directions for enhancing its utility in predicting drug absorption.

Methods: A literature review focused on PBBM studies employing PK-SIM® as modeling software. Additionally, a case study was developed for metoprolol to showcase a mechanistic IVIVC workflow using PK-SIM®. In vivo PK after administering an oral solution was used to estimate permeability and verify the prediction of distribution, metabolism, and elimination [1]. Sequentially, parameter estimation was used to deconvolute Weibull dissolution profiles for 3 extended-release formulations: slow, medium, and fast. Estimated in vivo dissolution was extracted from PK-SIM® and correlated with in vitro dissolution collected from the literature. The convoluted dissolution profiles were input into the model to predict plasma concentration vs time profiles and respective PK parameters.

Results: Four literature case studies were selected to illustrate the wide range of applications, from developing new oral formulations to establishing clinically relevant dissolution conditions for complex parenteral formulations [2]. The reviewed case studies underscore the value of PK-SIM® in addressing key challenges in drug development, such as formulation design and selection [3], the use of virtual bioequivalence tools during development [4,5], and IVIVC establishment. The flexibility and efficiency of PK-SIM®, facilitated by frameworks like MoBi® and efficient R workflows, position it as a versatile tool for modeling complex pharmacokinetic scenarios. An IVIVC was successfully developed for metoprolol, and the proposed IVIVC workflow can be applied to other compounds and different formulations.

Conclusions: The developed IVIVC demonstrates that the OSP suite can be used in drug development programs to optimize formulation development and support the setting of dissolution specifications. Future developments of OSP suite capabilities will include mechanistic dissolution models, IVIVE across in vitro and specific transcellular permeability, and improved virtual bioequivalence and IVIVC workflows. Enhancing model capabilities for modeling food effects and supersaturating formulations represents relevant elements to support the integration of OSP and streamline the development of novel formulations.

Citations: [1] N. D. Eddington, P. Marroum, R. Uppoor, A. Hussain, and L. Augsburger, “Development and internal validation of an in vitro-in vivo correlation for a hydrophilic metoprolol tartrate extended release tablet formulation,” Pharm Res, vol. 15, no. 3, pp. 466–473, Mar. 1998, doi: 10.1023/a:1011988601696.

[2] R. Díaz de León-Ortega, D. M. D’Arcy, D. A. Lamprou, and N. Fotaki, “In vitro - in vivo relations for the parenteral liposomal formulation of Amphotericin B: A clinically relevant approach with PBPK modeling,” Eur J Pharm Biopharm, pp. 177–187, Mar. 2020, doi: 10.1016/j.ejpb.2020.03.001.

[3] A. Denninger, T. Becker, U. Westedt, and K. G. Wagner, “Advanced In Vivo Prediction by Introducing Biphasic Dissolution Data into PBPK Models,” Pharmaceutics, vol. 15, no. 7, Art. no. 7, Jul. 2023, doi: 10.3390/pharmaceutics15071978.

[4] M. Ibarra et al., “Integration of in vitro biorelevant dissolution and in silico PBPK model of carvedilol to predict bioequivalence of oral drug products,” Eur J Pharm Sci, vol. 118, pp. 176–182, Jun. 2018, doi: 10.1016/j.ejps.2018.03.032.

[5] F. Severino Martins, L. Borges, R. Oliveira do Couto, S. Schaller, and O. de Freitas, “Integration of artificial neural network and physiologically based biopharmaceutic models in the development of sustained-release formulations,” Biopharm Drug Dispos, vol. 44, no. 4, pp. 335–343, Aug. 2023, doi: 10.1002/bdd.2376.