PBPK Modeling of Azithromycin Systemic Exposure in a Roux-en-Y Gastric Bypass Surgery Patient Population

Area of Science:

• Pharmacokinetics and drug metabolism
• Systems pharmacology
• Clinical pharmacology

Background:

• Roux-en-Y gastric bypass (RYGB) surgery can alter drug absorption and bioavailability.
• Azithromycin is commonly prescribed for community-acquired pneumonia.
• Understanding drug behavior post-RYGB is crucial for effective treatment.

Purpose of the Study:

• To evaluate the impact of RYGB surgery on azithromycin oral absorption and bioavailability using PBPK modeling.
• To simulate azithromycin systemic exposure in patients before and after RYGB surgery.
• To assess the potential clinical efficacy implications of altered azithromycin exposure post-RYGB.

Main Methods:

• Physiologically based pharmacokinetic (PBPK) modeling was performed using the Simcyp® Simulator.
• An RYGB patient population model was developed and verified with probe medications (atorvastatin, midazolam).
• Azithromycin PBPK models simulated systemic exposure for tablet and suspension formulations pre- and post-RYGB.

Main Results:

• PBPK modeling accurately captured observed changes in azithromycin systemic exposure post-RYGB.
• Simulations predicted a 30% reduction in steady-state AUC for azithromycin tablets post-surgery.
• The suspension formulation showed 1.5-fold higher relative bioavailability than the tablet formulation post-surgery.

Conclusions:

• RYGB surgery may decrease azithromycin bioavailability, particularly for tablet formulations.
• Altered azithromycin exposure post-RYGB could affect clinical efficacy against community-acquired pneumonia pathogens.
• PBPK modeling offers a valuable framework for optimizing drug therapy in post-RYGB patients.