(M1030-10-68) Plasma Pharmacokinetics and Tissue Disposition of Cefoxitin in an Animal Model of Obesity

Purpose: The prevalence of obesity is rapidly increasing worldwide. There is a significant knowledge gap regarding appropriate dosing strategies in patients with obesity. Our previous research showed that the currently recommended dosing approach results in inadequate tissue concentrations in obese patients undergoing bariatric surgeries. The goal of the study was to investigate biodisposition of cefoxitin in a diet-induced obesity model in rats.

Methods: Male Long-Evans rats were randomized to receive either Teklad high-fat diets (HFD; Custom Diet TD.06414) or Teklad regular diets (2014S) from the age of 3 weeks. Total body weight (TBW) and body composition were monitored weekly. At the age of 26 weeks, the rats were dosed with a single intravenous dose of cefoxitin (50 mg/kg of TBW), followed by blood and tissues collection (brain, spinal cord, heart, liver, spleen, lungs, kidney, small intestines, abdominal fat tissues, subcutaneous fat tissues, skin and muscles) at different time points (5, 15, 30, 45, 60, 90 and 120 minutes after the dose administration). All the samples were analyzed by a validated LCMSMS method. The concentrations between lean and obese groups were compared using t-tests.

Results: Obesity was successfully induced using high-fat diet, and mean body size metrics of obese and control group at the time of cefoxitin dosing are shown in Table 1. A significant difference in concentration of cefoxitin was observed in the liver and spleen between lean and obese groups over several time points as shown in Figure 1. It is also noteworthy that the differences could be observed at early time points in plasma and tissues including lungs, kidney, spinal cord, abdominal fat, muscles, skin and small intestines while the separation was relatively subtle at the later time points.

Conclusion: Significant differences in cefoxitin biodisposition was found between lean and obese animals, especially during the initial disposition stage. A physiological-based pharmacokinetics modeling will be used to capture the data as the next step for this study. The study provided important insights into obesity-induced changes in pharmacokinetics. These differences should be further investigated in patients with obesity to improve efficacy and safety of pharmacotherapy.

References: Cefoxitin plasma and subcutaneous adipose tissue concentration in patients undergoing sleeve gastrectomy. Brunetti et al. 2016. Clin Ther. 38(1): 204–210.

Figure 1. Plasma and tissue concentrations of cefoxitin in lean and obese rats. T-tests were performed. * - a p < 0.05; ** - p < 0.01; *** - p < 0.001.

Table 1. Study groups.