Physiologically Based Modeling of Cefoxitin, Cefazolin, and Piperacillin Pharmacokinetics in Obese and Lean Rats

The prevalence of obesity is rapidly increasing worldwide, however there is a notable gap in understanding how obesity affects the pharmacokinetics of drugs and how dosing should be adjusted in obese population. The goals of this work were to evaluate plasma pharmacokinetics and tissue disposition of piperacillin, cefazolin, and cefoxitin in a rat model of diet-induced obesity compared to a lean cohort. Male Long-Evans rats were fed high-fat or control diets for 23 weeks. Various measures of body size and composition were collected. The animals were administered a mixture containing 50 mg/kg cefoxitin, 50 mg/kg cefazolin, and 120 mg/kg piperacillin. Plasma and tissues were collected and analyzed using a validated LC-MS/MS method. Whole-body physiologically-based pharmacokinetic (PBPK) models were develop to capture the biodistribution of these drugs in lean and obese cohorts. Most plasma and tissue concentrations were comparable between lean and obese rats after dosing based on mg/kg of total body weight; however, in some tissues concentration was consistently higher in obese animals. PBPKs successfully captured biodistribution of three drugs and both cohorts; however, cohort-specific (lean or obese) parameters were required for liver (for cefoxitin and cefazolin) and spleen (for all three drugs) for capturing the data.The results support the necessity of using mg/kg dosing for obese rats to achieve drug exposure comparable to that of lean rats. In the future, these models could be extended to predict plasma pharmacokinetics and tissue disposition of cefoxitin, cefazolin, and piperacillin in humans by incorporating interspecies scaling approaches.