Pharmacokinetics of Ceftaroline in Normal and Obese Subjects

The effect of obesity on the pharmacokinetics of ceftaroline (CPT) is currently unclear. This was a Phase I, open-label pharmacokinetic (PK) study performed in 32 healthy adult volunteers aged 18-50 years each receiving a single dose of ceftaroline fosamil (CPTF) 600 mg IV over 1 hour. Subjects were evenly assigned to 1 of 4 groups based on their body mass index (BMI) and total body weight (TBW) (range 22.1-63.5 kg/m2 and 50.1-179.5 kg, respectively). Subjects in the lower TBW groups were matched by age, sex, race/ethnicity, and serum creatinine to subjects in the upper TBW groups. Serial plasma and urine samples were collected over 12 hours following the start of the CPTF infusion and concentrations of CPT, CPTF, and ceftaroline M-1 were assayed. PK analysis was performed using noncompartmental and population PK methodology. A 5-compartment model with zero-order infusion and linear elimination best described CPTF and CPT PK. Significant covariates were estimated creatinine clearance (eCLCR) for CPT total body clearance and TBW for CPT central volume of distribution. Monte Carlo simulations suggest the probability of target attainment (PTA) is ≥ 90% when the MIC is ≤ 1 µg/mL, irrespective of TBW or eCLCR (target of 40% fT>MIC). However, the PTA is up to 49% lower in simulated subjects with augmented renal clearance (eCLCR ≥ 120 mL/min) compared to those with mild renal impairment (eCLCR 50-79.9 mL/min) when the MIC is 2 µg/mL. No dosage adjustment for CPT appears necessary based on TBW alone in healthy subjects with comparable renal function. CPT dosage adjustment may be necessary for cases with eCLCR ≥ 120 mL/min and less susceptible pathogens.