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

Abstract

In this investigation, PBPK modeling using the Simcyp^® Simulator was performed to evaluate whether Roux-en-Y gastric bypass (RYGB) surgery impacts the oral absorption and bioavailability of azithromycin. An RYGB surgery patient population was adapted from the published literature and verified using the same probe medications, atorvastatin and midazolam. Next, a PBPK model of azithromycin was constructed to simulate changes in systemic drug exposure after the administration of different oral formulations (tablet, suspension) to patients pre- and post-RYGB surgery using the developed and verified population model. Clinically observed changes in azithromycin systemic exposure post-surgery following oral administration (single-dose tablet formulation) were captured using PBPK modeling based on the comparison of model-predicted exposure metrics (C_max, AUC) to published clinical data. Model simulations predicted a 30% reduction in steady-state AUC after surgery for three- and five-day multiple dose regimens of an azithromycin tablet formulation. The relative bioavailability of a suspension formulation was 1.5-fold higher than the tablet formulation after multiple dosing. The changes in systemic exposure observed after surgery were used to evaluate the clinical efficacy of azithromycin against two of the most common pathogens causing community acquired pneumonia based on the corresponding AUC₂₄/MIC pharmacodynamic endpoint. The results suggest lower bioavailability of the tablet formulation post-surgery may impact clinical efficacy. Overall, the research demonstrates the potential of a PBPK modeling approach as a framework to optimize oral drug therapy in patients post-RYGB surgery.

Keywords: PBPK modeling; Roux-en-Y; azithromycin; pharmacokinetics.

Figure 1

Effect of RYBG surgery on GI anatomy. The upper part of the stomach is separated to form a pouch with a capacity of ≈ 30 mL. The small intestine is separated at the jejunum into a proximal biliopancreatic limb (≈40 cm, composed of the duodenum and proximal jejunum that remains in continuity with stomach) and a Roux limb (75–150 cm, beginning where jejunum is divided). The top of the Roux limb is surgically attached to the stomach pouch, and the bottom is attached to the biliopancreatic limb [7]. The illustration was obtained from [8].

Figure 2

Verification of the azithromycin PBPK model in a healthy volunteer population. Plasma concentration vs. time profiles were simulated for both single and multiple oral doses and overlayed with observed clinical data [41,42,43]. Included in each plot are the model-predicted mean curve and the 5th percentile and 95th percentiles. The open circles represent clinically observed data.

Figure 3

PBPK model-simulated concentration–time profiles for azithromycin in RYGB patients before (left panel) and after surgery (middle panel). Included in each plot are the model-predicted mean curve and the 5th percentile and 95th percentiles. The open circles represent clinically observed data [44]. The right panel compares the simulated mean profile pre- and post-surgery.