Pharmacokinetic-Pharmacodynamic Analyses for Efficacy of Ceftaroline Fosamil in Patients with Community-Acquired Bacterial Pneumonia

Abstract

c Pharmacokinetic-pharmacodynamic (PK-PD) analyses for efficacy using phase III trial data from patients treated with a ceftaroline fosamil dosing regimen of 600 mg intravenously (i.v.) every 12 h (q12h) for 5 to 7 days for community-acquired bacterial pneumonia (CABP) were conducted. High clinical and microbiological success rates (84.7 and 86.3%, respectively) and percentages of time during the dosing interval that free-drug steady-state concentrations remained above the MIC (f%T>MIC) (98.4% had f%T>MIC values of >63.3) were observed among 124 microbiologically evaluable patients. As a result, significant PK-PD relationships could not be identified. These data provide support for the use of a ceftaroline fosamil dosing regimen of 600 mg i.v. q12h to treat patients with CABP. R esults of pharmacokinetic (PK)-pharmacodynamic (PD)analyses have increasingly been used to support drug development, both early in development to make decisions about dosing regimens and then in late-stage development to confirm these decisions (1). Such analyses were carried out for ceftaroline fosamil, a water-soluble prodrug of ceftaroline (2). Ceftaroline is a broad-spectrum cephalosporin with activity against pathogens commonly associated with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP), including methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae, respectively. Ceftaroline fosamil is approved by the FDA for the treatment of patients with ABSSSI and CABP and for similar such indications in Europe (3,4,5).By using data from ceftaroline-treated patients with ABSSSI enrolled in two phase II and two phase III studies, PK-PD efficacy analyses were carried out (2). The results of these analyses demonstrated a relationship between ceftaroline exposure, as measured by the percentage of time during the dosing interval that free-drug steady-state concentrations remained above the MIC (f%TϾMIC) and microbiological response. Given that a ceftaroline fosamil dosing regimen of 600 mg given intravenously (i.v.) every 12 h (q12h) provided exposures associated with the upper plateau of the PK-PD relationship identified for efficacy, these data provided support for the use of this dosing regimen for the treatment of patients with ABSSSI. The objective of the analyses described herein was to conduct similar such PK-PD analyses for efficacy by using data from two phase III studies of patients with CABP (ClinicalTrials.gov registration numbers NCT00621504 and NCT00509106) in which the efficacy and safety of a ceftaroline fosamil dosing regimen of 600 mg i.v. q12h were evaluated (6, 7).In each of the above-described phase III studies, patients received two consecutive infusions of 300 mg of ceftaroline fosamil i.v. q12h, each infused over 30 min for a total dose of 600 mg and a total infusion time of 60 min, with dose adjustments for patients with moderate renal impairment. The total duration of treatment was 5 to 7 days. Patients were eligible fo...

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

“…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.…”

“…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).…”

“…every 12 h as a 1-h infusion should provide adequate target exposure for the majority of clinical isolates of MSSA, S. pneumoniae, and non-ESBL-producing E. coli or Klebsiella spp. encountered in the United States (28)(29)(30). This regimen also appears to be relatively safe with no serious AEs reported in this study.…”

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To EvaluateIn VitroSusceptibility Test Interpretive Criteria for Ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae

“…Although PK-PD analyses have been conducted based on clinical data from ceftaroline fosamil-treated patients with ABSSSI and S. aureus at baseline or CABP and S. pneumoniae at baseline (20,21), the results of the analyses described herein were based on nonclinical f %TϾMIC targets for each of these organisms. While PK-PD analyses of patients with ABSSSI and S. aureus isolated at baseline, which were conducted using data from two phase 2 and two phase 3 studies, revealed significant relationships between microbiological response and f %TϾMIC evaluated continuously or categorically, there was a high degree of uncertainty around the identified PK-PD relationships (20).…”

New antibiotics against gram-positives: present and future indications

“…The cure rates in the ceftaroline arm for S. pneumoniae, penicillin-resistant S. pneumoniae and S. aureus were 85% (54 out of 63), 100% (4 out of 4) and 72% (18 out of 25) while in the ceftriaxone arm the rates were 69% (41 out of 59), 25% (1 out of 4) and 55% (15 out of 27), respectively. According to the PK-PD data obtained from microbiology evaluable population, the majority of patients (91.1%) had ƒ%T > MIC values ranging from 91.7 to 100 [44]. Recently, a similar study using ceftriaxone 2 g every 24 h has also shown the superiority of ceftaroline (84% versus 74%, 95% CI of the difference: 2.8-17) [45 ].…”