Laurence Dodd1, Stephan Schaller1, Marco Siccardi1, Mariana Guimarães1
1ESQlabs GmbH
Introduction The Z-factor approach [1] is a widely used dissolution model in developing Physiologically Based Biopharmaceutics Models (PBBM) and represents an efficient approach to link the dissolution kinetics of Immediate-Release (IR) formulations to pharmacokinetic (PK) performance. For solid drug product formulations, disintegrating into solid particles precedes dissolution in the gastrointestinal (GI) fluids. The release function enables modeling disintegration-limited formulations, paving the way to mechanistic predictions for Modified-Release (MR) formulations. Overall, the PBBM capabilities of the Open Systems Pharmacology (OSP) software were extended to predict the impact that properties of complex formulations have on drug PK; the base PK-SIM® was extended with PBBM workflows in MoBi® for the assessment of formulation-release kinetics and integrated with a Global Sensitivity Analysis (GSA) using the new R ospsuite.globalsensitivity library [2]. Objectives 1.Development of an extended MoBi® Z-factor dissolution model 2.Development of an extended MoBi® release model and associated GI transit 3.Deploying the new framework with an Ibuprofen case-study 4.Integration with GSA to perform a biopharmaceutics risk assessment. Methods A PBPK model was developed for Ibuprofen (weak acidic pKa 4.5, poorly water-soluble, highly permeable with logP 4), with PK-SIM v12 based on published physicochemical and PK properties [3] [4] [5]. The Z-factor dissolution model and first-order release framework were developed in MoBi® v12 using the ‘modularization’ feature, and can be readily applied as an ‘extension module’ for future solid dosage form administrations. The newly calculated release rate is defined by gastric retention, a release constant, and dispersive transit of the tablet. After implementation, the performance of the standard particle dissolution model and Z-factor dissolution for predicting Ibuprofen behavior was assessed. Biorelevant dissolution in simulated intestinal fluids of IR ibuprofen tablets (Stride Pharma Science Ltd) [4] was used to calibrate the molecular diffusivity and the Z-factor for Ibuprofen in the respective dissolution model. In vivo data from the administration of an oral solution was used to calibrate the distribution and elimination kinetics in the model [5], and then the in vivo performance following administration of an IR ibuprofen tablet (Motrin®) was assessed assuming a constant Z-factor between the two studies due to a lack of dissolution data. The GSA was extended to generate contour plots used in a biopharmaceutics risk assessment in addition to the Sobol’ sensitivity analysis index (SI). Results The estimated molecular diffusivity of Ibuprofen for the IR tablet (Stride) using the particle dissolution model was 116 µm²/s. In contrast, diffusivity calculated from molecular weight is 661 µm²/s) [6]. The model-predicted discrepancy may arise from poor wetting, the particle surface, excipient effects, or bile micellization, which are not modeled in PK-Sim® V12. The Z-factor model was applied for the same purpose, wherein Z was reduced from 397 l/min/kg to 85 l/min/kg. The IR tablet (Motrin®) Cmax was not significantly overpredicted (1.14-fold), although Tmax was underpredicted (0.75 vs 1.5 hours), indicating slower tablet release and gastric retention (estimated release rate constant = 0.05 min-1, gastric retention = 37 min). The GSA showed that Cmax was most sensitive to LogP (SI=0.8) and gastric emptying (GE) (SI=0.25), whilst Tmax was most sensitive to GE (1). Contour plots demonstrated that particle size increase from 10-100 µm would result in a 20% Cmax reduction and a 1 h Tmax delay. Absorption was dose-proportional for small particles (<100 µm) and sub-proportional for large particles (~500 µm), for which dissolution is rate-limiting. Slower release rate leads to reduced Cmax, delayed Tmax, and increased sensitivity to particle size. Conclusion The release and Z-factor extensions were successfully applied to characterize Ibuprofen’s dissolution and predict in vivo performance. GSA was effectively applied to perform biopharmaceutics risk assessment and identify rate-limiting steps [7]. The developed approach is suitable for applying different modalities of MR formulations and their combinations with drug classes. In the future, applicability of the release model for simulating MR formulations should be investigated.
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Reference: PAGE 33 (2025) Abstr 11412 [www.page-meeting.org/?abstract=11412]
Poster: Methodology - New Modelling Approaches