Impact of obesity on cefazolin pharmacokinetics and optimal dosing for surgical prophylaxis in patients with obesity

Cefazolin, a first-generation cephalosporin, has been used for decades for surgical site infection prophylaxis as well as for treatment for a variety of infections. Little data is available on dosing in obese individuals or those weighing ≥ 120 kg. The objectives of this analysis were to obtain a better understanding of cefazolin in these patients by conducting a literature search to gather available information on the safety and pharmacokinetics (PK) of high doses of cefazolin in obese individuals. Additionally, a previously-developed population PK model was assessed using the data from patients enrolled in a Phase 1 study who weighed ≥ 120 kg. Model-based simulations were also conducted to confirm the appropriateness of a 3 g dose in those weighing ≥ 120 kg. The literature search revealed that cefazolin was well-tolerated at high doses, and that patients weighing ≥ 120 kg demonstrated PK differences in protein binding, clearance, and volumes of distribution compared to those < 120 kg. The previously-developed 2-compartment population PK model required no refinements and provided a robust fit to the data. The model-based simulations indicate that a 3 g dose in patients weighing ≥ 120 kg provides more consistent exposure than a 2 g dose relative to observed and simulated normal weight (60–120 kg) patients administered 2 g. These results suggest that a 3 g dose, recently approved by the FDA, is more appropriate than the FDA-approved 2 g dose for surgical prophylaxis in patients with body weight ≥ 120 kg in both adults and children aged 10 to 17 years.