(M1430-05-27) Integration of a Novel First-Order Release Z-Factor Dissolution Model with Global Sensitivity Analysis to Guide Formulation Development Using Physiologically-Based Biopharmaceutics in OSPSuite v12

Purpose: 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 library².

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 (weakly acidic, pKa 4.5, poorly water-soluble, highly permeable with a logP of 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 time, 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)³ 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 model⁵, 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 PK-SIM® 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 Sobol’ sensitivity indices produced in the GSA (Figure 1) 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 (Figure 2) were used to demonstrate that a particle size increase from 10-100 µm would result in a 20% Cmax reduction and a 1 h Tmax delay, and that absorption was dose-proportional for small particles ( < 100 µm) and sub-proportional for large particles (~500 µm), for which dissolution is rate-limiting.  Contour plots (Figure 3) were also used to show that a slower release rate leads to reduced Cmax, delayed Tmax, and increased sensitivity to particle size.

Conclusion: The release and Z-factor MoBi® extensions were successfully applied to characterize Ibuprofen’s release and dissolution using in vitro data, and then predict in vivo performance. A GSA was effectively applied to perform a biopharmaceutics risk assessment and identify the rate-limiting steps of solid dose ibuprofen during oral absorption 7. The developed approach is suitable for applying different modalities of MR formulations and their combinations with drug classes. In future work, the applicability of the release framework for developing mechanistic simulations of MR formulations should be investigated.

References: 1. Takano R, Sugano K, Higashida A, et al. Oral Absorption of Poorly Water-Soluble Drugs: Computer Simulation of Fraction Absorbed in Humans from a Miniscale Dissolution Test. Pharm Res. 2006;23(6):1144-1156. doi:10.1007/s11095-006-0162-4
2. Najjar A. Global sensitivity analysis of Open Systems PharmacologySuite physiologically based pharmacokinetic models. CPT: Pharmacometrics & Systems Pharmacology. 2024;13(12):2052-2067.
3. Tsume Y, Ashworth L, Bermejo M, et al. Harmonizing Biopredictive Methodologies Through the Product Quality Research Institute (PQRI) Part I: Biopredictive Dissolution of Ibuprofen and Dipyridamole Tablets. AAPS J. 2023;25(3):45. doi:10.1208/s12248-023-00793-7
4. Statelova M, Holm R, Fotaki N, Reppas C, Vertzoni M. Factors Affecting Successful Extrapolation of Ibuprofen Exposure from Adults to Pediatric Populations After Oral Administration of a Pediatric Aqueous Suspension. AAPS J. 2020;22(6). doi:10.1208/s12248-020-00522-4
5. Lockwood GF, Albert KS, Gillespie WR, et al. Pharmacokinetics of ibuprofen in man. I. Free and total area/dose relationships. Clin Pharmacol Ther. 1983;34(1):97-103. doi:10.1038/clpt.1983.136
6. Willmann S, Thelen K, Becker C, Dressman JB, Lippert J. Mechanism-based prediction of particle size-dependent dissolution and absorption: cilostazol pharmacokinetics in dogs. Eur J Pharm Biopharm. 2010;76(1):83-94. doi:10.1016/j.ejpb.2010.06.003
7. Tamilvanan S, Sa B. In vitro and in vivo evaluation of single-unit commercial conventional tablet and sustained-release capsules compared with multiple-unit polystyrene microparticle dosage forms of ibuprofen. AAPS PharmSciTech. 2006;7(3):E126-E134. doi:10.1208/pt070372


Figure 1. Sobol’ sensitivity indices (first order and total order) of Cmax and tmax in a GSA exploring the effect of physiological variability on ibuprofen exposure following oral solid dose administration


Figure 2. Contour plots showing predicted ibuprofen Cmax and tmax variability against different particle size and doses, generated using a GSA.


Figure 3. Contour plots showing predicted ibuprofen Cmax and tmax variability against different particle size and first order release rate constants, generated using a GSA.