title: 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.).
authors.affiliation: College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Julie Ann
authors.initials: JA
authors.lastname: Justo
authors.affiliation: College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Stockton M
authors.initials: SM
authors.lastname: Mayer
authors.affiliation: Albany College of Pharmacy and Health Sciences, Albany, New York, USA.
authors.forename: Manjunath P
authors.initials: MP
authors.lastname: Pai
authors.affiliation: College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Melinda M
authors.initials: MM
authors.lastname: Soriano
authors.affiliation: College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Larry H
authors.initials: LH
authors.lastname: Danziger
authors.affiliation: College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Novak
authors.affiliation: College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA kar@uic.edu.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Rodvold
mesh_terms: D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D015992:Body Mass Index; D001835:Body Weight; D002511:Cephalosporins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003198:Computer Simulation; D003404:Creatinine / Q000097:blood; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D009010:Monte Carlo Method; D009765:Obesity / Q000378:metabolism*; D009767:Obesity, Morbid / Q000378:metabolism; D011355:Prodrugs / Q000493:pharmacokinetics; D011446:Prospective Studies; D055815:Young Adult; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D003404:Creatinine; D011355:Prodrugs; D000097583:Ceftaroline