(W1230-09-52) Using PBPK to Establish In Vitro In Vivo Relationship for Budesonide Delayed Release Oral Drug Product

Purpose: Budesonide is a corticosteroid used in the treatment of inflammatory bowel diseases (IBD) exerting potent local effects in the gastrointestinal (GI) tract (1). Budesonide undergoes extensive intestinal metabolism which contributes to its low bioavailability (~9%) (2). Due to its quick absorption from the GI tract and its metabolism in the gut wall, controlled-release formulations have been developed to target the release of the drug to the pertinent GI segments. An example is Entercort®, a multi-particulate delayed-release (DR) budesonide drug product designed to release budesonide to the terminal ileum segment. Developing DR formulations can be challenging due to the numerous layers of complexity related to the in vivo behavior of such formulations, rendering it difficult to predict their in vivo behavior (3). The purpose of this study was to develop an oral absorption physiologically based pharmacokinetic (PBPK) model/physiologically based biopharmaceutics model (PBBM) for budesonide, to predict the clinical exposure of Entercort®. Subsequently, the PBPK/PBBM model was used to validate in vitro to in vivo relationships (IVIVR) to assess the bio-relevance of different in vitro dissolution methods.

Methods: A mechanistic PBPK/PBBM model for budesonide was built using GastroPlus® v.9.8.2 (beta version of extended ACAT model). Its physicochemical and biopharmaceutical properties were either obtained from literature (4–7); or predicted from budesonide chemical structure using the ADMET Predictor® module. Published in vitro CYP3A4 kinetics parameters (8) were converted to in vivo values and then optimized using intravenous (IV) (9–11) and oral (PO) immediate-release (12–14) pharmacokinetic (PK) data. Since Entercort® is designed to act in the late parts of the GI tract, an extended GI absorption model, including additional large intestine segments (transverse colon, descending colon, sigmoid colon, and rectum) was selected. Entercort® dissolution profiles were obtained from literature or measured in vitro. Two dissolution methods were used to measure the in vivo dissolution: single phase USP-II with biorelevant media (Fasted-State Simulated Intestinal Fluid-Version 2 (FaSSIF-V2) and Fasted-State Simulated Colonic Fluid (FaSSCoF), and USP-IV with sequential media change (Fasted-State Simulated Gastric Fluid (FaSSGF) - > FaSSIF v2 - > FaSSCoF)). All the results obtained using these dissolution methods were used to validate IVIVRs using the PBPK/PBBM model. External validation was performed using data from eight PK studies in healthy subjects (12,14–20).

Results: The developed PBPK model for budesonide adequately described the plasma PK profile following IV and PO in healthy subjects (Figure 1). The validated disposition parameters, such as clearance and volume of distribution, were then used in the PBPK/PBBM model to predict the plasma PK profile of budesonide following Entercort® administrations. The use of in vitro USP II FaSSIF v2 dissolution data resulted in prediction of higher Cmax and earlier Tmax than observed data (Cmax ratio of predicted vs. observed range: 1.31 – 1.99; AUC_0-inf ratio of predicted vs. observed range: 0.57 - 0.97). The use of USP II FaSSCoF dissolution data resulted in an underprediction of Cmax as well as overall misprediction of the PK profile shape (Cmax ratio of predicted vs. observed range: 0.53 – 0.82; AUC_0-inf ratio of predicted vs. observed range: 0.77-1.62). Hence, using directly in vitro dissolution data obtained using a USP II apparatus did not allow IVIVR validation. In contrast, the PBPK/PBBM model, informed by in vitro dissolution data obtained using a USP IV with sequential media change, generally well described the PK accordingly (Figure 2), i.e., it was more biopredictive (Cmax ratio of predicted vs. observed range: 0.87 – 1.33; AUC_0-inf ratio of predicted vs. observed range: 0.80 – 1.56).

Conclusion: An IVIVR of Entercort® was validated utilizing USP IV with sequential media change dissolution data. It resulted in the reasonable prediction of budesonide PK profiles from the different clinical PK studies and seems to be biopredictive. The PBPK-PBBM approach presented herein can be used for assessing the bio-relevance of different in vitro dissolution methods for DR formulations and can serve as an aid in new and generic drug development.

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Acknowledgements: The project was funded by a contract from the U.S. Food and Drug Administration (Contract # 1U01FD007660). The views expressed here do not reflect the official policies of the U.S. FDA or the Department of Health and Human Services, nor does any mention of trade names imply endorsement by the U.S. Government.

Figure 1: Prediction of mean systemic budesonide concentration in healthy subjects after (A) intravenous administration and (B) immediate release administration

Figure 2: Prediction of mean systemic budesonide concentration in healthy subjects after Entercort® administration (eight studies)