Pharmacy & Therapeutics - November 2008 - (Page 633)

DRUG FORECAST AUC of 102 mcg • hour mL. Protein binding is limited (16%) and is independent of the drug concentration; therefore, alterations in protein binding are unlikely to affect its overall activity.11 Ceftobiprole is neither an inhibitor of nor a substrate for the cytochrome P450 (CYP 450) system.11 Studies with cyclosporine have also demonstrated that ceftobiprole is neither an inhibitor of nor a substrate of the p-glycoprotein (PGP) transporter system. Based on combination studies with probenecid, ceftobiprole is eliminated by the kidneys as unchanged drug via glomerular filtration, not through active tubular secretion.11 The half-life of ceftobiprole is approximately three hours, with more than 80% of the active drug recovered in the urine within 12 hours after the administration. Although slight variations in the drug’s pharmacokinetic properties are apparent based on a patient’s sex, no dosing adjustments are necessary.11,21 Pharmacokinetic properties, in terms of race and optimal dosing for pediatric patients, have not been published. The pharmacokinetic parameters of ceftobiprole in patients with normal renal function and in those with mild, moderate, and severe renal impairment have been determined.11,19,20 Twenty male subjects with varying degrees of renal function were studied to determine the optimal dosing schedule for those patients with renal impairment for use in future clinical trials. Roos et al. determined that systemic exposure, as measured by the AUC concentration, was elevated in the patients with renal impairment. Renal impairment was defined as a creatinine clearance (CrCl) below 80 mL/ minute; normal clearance was defined as a CrCl above 80 mL/minute. Compared with subjects with normal renal function, patients with mild renal impairment (CrCl, 50 to 80 mL/minute) experienced an increase of 29% in the AUC concentration; patients with moderate renal impairment (CrCl, 30 to 50 mL/minute), an AUC increase of 250%; and patients with severe renal impairment (CrCl, below 30 mL/minute), an AUC increase of 330%. The half-life of ceftobiprole increased with decreasing renal function. The longest half-life occurred in patients with severe renal impairment (11 hours). As a result, dosage adjustment is necessary in patients with renal insufficiency. The in vitro and in vivo pharmacodynamics of ceftobiprole have been studied extensively and are similar to those of other beta-lactam antimicrobial drugs.20,22 The pharmacodynamic parameter most correlated with clinical efficacy of ceftobiprole is the percentage of time in which the free serum concentration (%fT) is above the MIC. Like other cephalo sporins, the optimal %fT above the MIC required for ceftobiprole to achieve a bacteriostatic effect is 30% of the dosing interval for staphylococci and 40% of the dosing interval for gram-negative bacilli, respectively. For maximal bactericidal activity, the %fT above the MIC should be at least 50% (staphylococci) and 60% (gram-negative bacilli) of the dosing interval. Using pharmacokinetic data from 150 subjects, Lodise et al. performed a Monte Carlo simulation to determine the probability of target attainment (PTA) of ceftobiprole against gram-positive and gramnegative pathogens.20 Several different dosing strategies, in vitro MIC data, and the four goals for target attainment, as just described, were used. When the investigators used 500 mg every 12 hours over one hour, they found no significant difference in the PTA for gram-positive isolates with MIC values of 1 mcg/mL or below, using a target for the PTA of 50% for bactericidal activity. Using the dosing scheme of 500 mg every eight hours and three dif ferent lengths of infusions (30 minutes, one hour, two hours), they determined that the twohour infusion improved the likelihood of target attainment for gram-positive and gram-negative organisms with an MIC of 2 mcg/mL or greater. For isolates with MIC values of 1 mcg/ mL or below, the infusion time had little effect on the PTA for a %fT above the MIC target of 40%, 50%, or 60%. The investigators did notice a decreased PTA for the two-hour dosing scheme against AmpC-producing gram-negative isolates and P. aeruginosa (MIC50 = 4), compared with isolates that were non–AmpCproducing gram-negative isolates, PTA (of 60%fT > MIC) 87.8%, 62%, and 94.1%, respectively. blind, phase 3 trials (STRAUSS 1 and 2) evaluated the clinical efficacy of ceftobiprole for hospitalized patients with complicated skin and skin structure infections (cSSSIs). The STRAUSS 1 Study24 CLINICAL EFFICACY Skin and Skin-Structure Infections23–26 Two randomized, multicenter, double- STRAUSS 1 compared ceftobiprole with vancomycin for the treatment of cSSSIs caused by documented or suspected gram-positive pathogens. Patients were considered eligible for enrollment if they were older than 18 years of age and had a cSSSI caused by gram-positive pathogens based on predefined criteria. Patients were classified according to infection type, and the investigators limited the percentage of patients with cellulitis to less than 20%. Patients with diabetic foot infections, infections from animal or human bites, or osteomyelitis were excluded. Patients were randomly assigned, in a 1:1 ratio, according to the type of infection (abscess, wound infections, or cellulitis) to receive either IV ceftobiprole 500 mg every 12 hours as a 60-minute infusion or IV vancomycin 1,000 mg every 12 hours as a 60-minute infusion for 7 to 14 days. The primary efficacy endpoint of this non-inferiority trial was a clinical cure rate at the test-of-cure (TOC) visit (7 to 14 days after the end of therapy). This outcome was assessed in the clinically evaluable and intent-to-treat (ITT) populations (Figures 1 and 2). The ITT population included all randomized patients. The clinically evaluable patients had a protocol-defined cSSSI, completed the TOC visit (6 to 14 days after therapy), and received 80% or more of the study drug course. Based on an expected clinical cure rate of 80%, ceftobiprole was considered non-inferior if the lower limit of the 95% confidence interval (CI) for the difference in clinical cure rate was –10% or more. The ITT analysis included a total of 784 patients, with 42% patients from the U.S.; 397 patients were randomly assigned to receive ceftobiprole, and 387 patients received vancomycin. The clinically evaluable population consisted of 559 patients with a clinical outcome evaluated at the TOC visit (282 in the ceftobiprole group, 277 in the vancomycin group). In the ITT population, there were no significant differences in demographics, Vol. 33 No. 11 • November 2008 • P&T® 633

Table of Contents Feed for the Digital Edition of Pharmacy & Therapeutics - November 2008

Pharmacy & Therapeutics - November 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Heparin-Induced Thrombocytopenia Medication Utilization Patterns and Hypertension-Related Expenditures among Patients Who Were Switched From Fixed-Dose to Free-Combination Antihypertensive Therapy European Society for Medical Oncology and Association for the Study of Bone and Mineral Research Pharmaceutical Approval Update

Pharmacy & Therapeutics - November 2008

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