ppi-0903 and Kidney-Failure--Chronic

For patients with normal renal function, the recommended ceftaroline fosamil dose is a 600 mg 1-h intravenous (i.v.) infusion every 12 h (q12h). In patients with a creatinine clearance of ≤30 mL/min, including those with end-stage renal disease (ESRD), the recommended dose is a 200 mg 1-h i.v. infusion q12h. This phase 1 study (NCT01664065) evaluated the pharmacokinetics, safety and tolerability of ceftaroline fosamil 200 mg 1-h i.v. infusion in patients with ESRD. Patients with ESRD (n=8) participated in two treatment periods (ceftaroline fosamil 200 mg administered pre- and post-haemodialysis) separated by >1 week. Healthy volunteers (n=7) received a single 600 mg dose of ceftaroline fosamil. Blood (pre- and post-haemodialysis) and dialysate samples were obtained for pharmacokinetic analysis. In patients with ESRD, the geometric mean [coefficient of variation (%CV)] plasma ceftaroline area under the plasma concentration-time curve from zero to infinity (AUC0-∞) following post-haemodialysis ceftaroline fosamil 200 mg infusion was 64.8 (38.9)μg·h/mL, similar to that in volunteers following a 600 mg infusion [62.7 (9.4)μg·h/mL]. Ceftaroline AUC0-∞ decreased by ca. 50% when infusion was initiated pre-haemodialysis. In the pre-haemodialysis treatment period, 80% of the ceftaroline fosamil dose was recovered in dialysate as ceftaroline (73%) and ceftaroline M-1 (7%). The frequency of adverse events was similar across patients with ESRD (pre- and post-haemodialysis) and volunteers (43%, 50% and 43% of subjects, respectively). Ceftaroline fosamil 200 mg 1-h i.v. infusion q12h, administered post-haemodialysis on dialysis days, is an appropriate dosage regimen for ESRD patients.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Area Under Curve; Ceftaroline; Cephalosporins; Drug Administration Schedule; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Half-Life; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Young Adult

Ceftaroline fosamil is a parenteral cephalosporin indicated for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Ceftaroline, the active component of ceftaroline fosamil, exhibits broad-spectrum bactericidal activity against gram-positive organisms, including methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae, as well as common gram-negative pathogens. The objective of the studies presented herein was to establish the pharmacokinetic profile of ceftaroline in healthy subjects and special populations of interest, such as elderly subjects, subjects with renal impairment, or subjects with end-stage renal disease on intermittent hemodialysis. The mean half-life of ceftaroline in healthy subjects was approximately 2.6 hours, and urinary excretion was the primary route of elimination. Ceftaroline Cmax and AUC values increased in proportion to dose increases within the range of 50-1000 mg, demonstrating an approximately linear pharmacokinetic profile following intravenous infusion. The pharmacokinetic parameters of ceftaroline were modestly altered in elderly subjects compared with younger adults, which was attributed to decreased renal function in elderly subjects. Ceftaroline pharmacokinetic parameters varied with different degrees of renal impairment, resulting in recommended dosage adjustments for patients with moderate to severe impairment. Ceftaroline fosamil was generally well tolerated regardless of age or severity of renal impairment.

Topics: Adolescent; Adult; Aged; Aging; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Cohort Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Half-Life; Humans; Infusions, Intravenous; Kidney; Kidney Failure, Chronic; Male; Prodrugs; Renal Dialysis; Renal Elimination; Renal Insufficiency; Severity of Illness Index; Young Adult

Topics: Administration, Intravenous; Aged; Bacteremia; Ceftaroline; Cephalosporins; Discitis; Drug Administration Schedule; Endocarditis; Humans; Kidney Failure, Chronic; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Renal Dialysis; Staphylococcal Infections