Date of Award

2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Department

Pharmaceutical Sciences

First Advisor

David Taft

Committee Chair and Members

David Taft, Chair

Grazia Stagni

Jaclyn Cusumano

Pooja Manchandani

Keywords

Bioavailability, Intra-abdominal infections, Oral antibiotics, PBPK modeling, Respiratory infections, RYGB

Abstract

Understanding the mechanisms that govern drug absorption and elimination is a critical component in pharmaceutical research and development, as the oral route remains the most common method of drug administration. The utilization of in silico physiologically based pharmacokinetic modeling and simulation (PBPK M&S) has enabled the extrapolation of modeling and simulation in special populations where concerns regarding alteration in overall drug exposure may arise, such as following gastrointestinal surgery. Roux-en-Y Gastric bypass (RYGB), or partial resection of the gastrointestinal tract, leads to multiple physiological alterations that affect drug absorption. The inability to generalize and predict changes in oral drug bioavailability (Foral) following gastric bypass surgery presents a considerable therapeutical challenge to clinicians. PBPK M&S is a widely used approach for predicting the bioavailability changes in different clinical scenarios. Infection post-surgery is the most common risk factor and should be monitored and treated with utmost care. There is limited literature assessing the bioavailability changes of oral antibiotics post-gastric bypass surgery. This thesis aimed to determine the impact of gastric bypass surgery on oral drug absorption and metabolism for antibiotics such as azithromycin, cefuroxime axetil, and metronidazole. This was accomplished by applying the PBPK M&S approach to identify and define essential intrinsic elements and parameters, model implementation, and validation within a general model development framework. The developed post gastric bypass surgery PBPK model provides a framework for investigating physiological mechanisms associated with changes in systemic drug exposure after oral administration, which may result from the interplay of disintegration, dissolution, absorption, and presystemic metabolism by the intestine and liver. The developed PBPK models of azithromycin, cefuroxime axetil, and metronidazole were used to evaluate the changes in antibiotic exposure in gastric bypass surgery patients after a solid and liquid formulation. The results from solid formulation bioavailability post gastric bypass surgery model simulations suggest that the current dosing regimen for azithromycin and cefuroxime axetil may not be sufficient for treating infections, and dose modifications might be necessary. At the same time, no significant changes were observed for metronidazole bioavailability post-surgery. The results from liquid formulations of these antibiotics suggest that the azithromycin suspension presents enhanced absorption and bioavailability than the tablet formulation. In contrast, the suspension of cefuroxime axetil followed the same trend as solid formulation. Overall, this thesis demonstrates the application of PBPK M&S in the extrapolation of oral drug exposure to special populations (e.g., RYGB). The PBPK approach shows oral bioavailability to provide clinicians with an evidence-based dose selection to prevent the risk of treatment failure due decreased drug exposure of oral antibiotics post gastric bypass surgery.

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