Population pharmacokinetics of ceftaroline in patients with acute bacterial skin and skin structure infections or community‐acquired bacterial pneumonia

Abstract

Ceftaroline, the active form of ceftaroline fosamil, is a broad-spectrum cephalosporin antibiotic. A population pharmacokinetic (PPK) model for ceftaroline was developed in NONMEM® using data from 185 healthy subjects and 92 patients with acute bacterial skin and skin structure infection (ABSSSI). Data from 128 patients with community-acquired bacterial pneumonia (CABP) were used for external model validation. Healthy subjects received 50-2,000 mg ceftaroline fosamil via intravenous (IV) infusion over 1 hour or intramuscular (IM) injection q12h or q24h. ABSSSI and CABP patients received 600 mg of ceftaroline fosamil IV over 1 hour q12h. A three-compartment model with zero-order IV or parallel first-order IM input and first-order elimination described ceftaroline fosamil PK. A two-compartment model with first-order conversion of prodrug to ceftaroline and parallel linear and saturable elimination described ceftaroline PK. Creatinine clearance was the primary determinant of ceftaroline exposure. Good agreement between the observed data and both population (r(2) = 0.93) and individual post-hoc (r(2) = 0.98) predictions suggests the PPK model can adequately approximate ceftaroline PK using covariate information. Such a PPK model can evaluate dose adjustments for patients with renal impairment and generate ceftaroline exposures for use in pharmacokinetic-pharmacodynamic assessments of efficacy in patients with ABSSSI or CABP.

Pharmacokinetics of Ceftaroline in Normal Body Weight and Obese (Classes I, II, and III) Healthy Adult Subjects

“…Similar power relationships between body size descriptors and the volume of distribution of ceftaroline (TBW with ␤ ϭ 0.46; BSA with ␤ ϭ 1.35) have been reported in previous POP-PK analyses based on earlier clinical trial data sets (27,31). The inclusion of this covariate in the present model is likely due to the wide, stratified distribution of body size descriptors in our study.…”

“…First, the study here enrolled healthy subjects who typically exhibit decreased pharmacokinetic variability and lower CL T levels compared to infected patients. Previous POP-PK models suggest that subjects in ceftaroline phase 2/3 studies had a 35% higher mean CL T than those in phase 1 studies (27)(28)(29)(30). Given this background, obese class III adults who are acutely infected may theoretically have a higher CL T than that predicted by our model.…”

“…In the previous model, the major determinant of variability in ceftaroline pharmacokinetics and the only covariate requiring dosage adjustment was eCL CR (27). Although the present POP-PK model utilized a linear relationship, the initial log-log regression of eCL CR on CL T estimated a ␤-exponent of 0.398 and the model from Van Wart et al estimated ␤-exponents of 0.441 and 0.343 for intrinsic and linear CL, respectively.…”

“…This final POP-PK model was relatively similar to a previously published POP-PK model developed with ceftaroline pharmacokinetic data from clinical trials, albeit with some notable differences (27)(28)(29)(30). The previous model utilized three and two compartments for ceftaroline fosamil and ceftaroline, respectively; parallel linear and Michaelis-Menten elimination pathways for ceftaroline; and additional covariates (age, gender, and phase 2/3 patient status).…”

Single- and Multiple-Dose Study To Determine the Safety, Tolerability, and Pharmacokinetics of Ceftaroline Fosamil in Combination with Avibactam in Healthy Subjects

“…In addition, in vitro studies demonstrated that ceftaroline does not inhibit or induce major CYP450 isoenzymes. Population pharmacokinetic analysis did not identify any clinically relevant differences in ceftaroline exposure in patients with ABSSSI or CABP who were taking concomitant medications that are known inhibitors, inducers, or substrates of the cytochrome P450 system; anionic or cationic drugs known to undergo active renal secretion; and vasodilator or vasoconstrictor drugs that may alter renal blood flow (5). Thus, the overall drug-drug interaction potential for ceftaroline can be considered to be low.…”