Pharmacokinetics of ceftaroline in normal body weight and obese (classes I, II, and III) healthy adult subjects

Abstract

The pharmacokinetic profile of ceftaroline has not been well characterized in obese adults. The purpose of this study was to evaluate the pharmacokinetics of ceftaroline in 32 healthy adult volunteers aged 18 to 50 years in the normal, overweight, and obese body size ranges. Subjects were evenly assigned to 1 of 4 groups based on their body mass index (BMI) and total body weight (TBW) (ranges, 22.1 to 63.5 kg/m(2) and 50.1 to 179.5 kg, respectively). Subjects in the lower-TBW groups were matched by age, sex, race/ethnicity, and serum creatinine to the upper-BMI groups. Serial plasma and urine samples were collected over 12 h after the start of the infusion, and the concentrations of ceftaroline fosamil (prodrug), ceftaroline, and ceftaroline M-1 (inactive metabolite) were assayed. Noncompartmental and population pharmacokinetic analyses were used to evaluate the data. The mean plasma ceftaroline maximum concentration and area under the curve were ca. 30% lower in subjects with a BMI of ≥40 kg/m(2) compared to those <30 kg/m(2). A five-compartment pharmacokinetic model with zero-order infusion and first-order elimination optimally described the plasma concentration-time profiles of the prodrug and ceftaroline. Estimated creatinine clearance (eCLCR) and TBW best explained ceftaroline clearance and volume of distribution, respectively. Although lower ceftaroline plasma concentrations were observed in obese subjects, Monte Carlo simulations suggest the probability of target attainment is ≥90% when the MIC is ≤1 μg/ml irrespective of TBW or eCLCR. No dosage adjustment for ceftaroline appears to be necessary based on TBW alone in adults with comparable eCLCR. Confirmation of these findings in infected obese patients is necessary to validate these findings in healthy volunteers. (This study has been registered at ClinicalTrials.gov under registration no. NCT01648127.).

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Figures

FIG 1

Mean concentration-time profile of ceftaroline in plasma by body size group.

FIG 2

Final, five-compartment population pharmacokinetic model describing ceftaroline fosamil and ceftaroline pharmacokinetics in plasma. R0 represents the zero-order i.v. infusion. “X” represents the amount of drug in the respective compartment. “V” represents the volume of the respective compartment. k13, k12, k21, k34, k43, k35, and k53 represent microtransfer rate constants. CLT represents total body clearance. CMT, compartment. *fm represents the fraction of ceftaroline fosamil converted to ceftaroline and was assumed to be 1.

FIG 3

Scatter and linear fit plots of observed versus population predicted (A) and observed versus individual predicted (B) concentrations of ceftaroline fosamil in plasma and of observed versus population predicted (C) and observed versus individual predicted (D) concentrations of ceftaroline in plasma. Bold dashed lines are linear fits of the data. Solid lines are lines of identity.

FIG 4

Visual predictive checks of ceftaroline concentrations (log scale) in plasma stratified by body size group: normal to overweight (A), obese class I (B), obese class II (C), and obese class III (D). Shaded region indicates 90% prediction interval of ceftaroline concentration over time. Solid black line indicates median predicted ceftaroline concentration over time. Solid gray circles indicate observed ceftaroline concentrations over time.