Single-Dose Pharmacokinetics and Safety of a Novel Broad-Spectrum Cephalosporin (BAL5788) in Healthy Volunteers

Abstract

BAL5788 is the water-soluble prodrug of BAL9141, a novel broad-spectrum cephalosporin with potent bactericidal activities against methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae. We investigated the safety and pharmacokinetics of BAL5788 in a double-blind, single-ascending-dose study with 40 healthy male subjects. The subjects were randomized to receive placebo (n ‫؍‬ 2 subjects per dose) or BAL5788 (n ‫؍‬ 6 subjects per dose) as a 200-ml intravenous infusion over 30 min. The BAL5788 doses used were 125, 250, 500, 750, and 1,000 mg (BAL9141 equivalents). All doses were well tolerated, with no severe or serious adverse events (AEs). The most frequent AE was taste disturbance. No electrocardiographic abnormalities and no trends or clinically significant changes in laboratory parameters or vital signs were observed. The maximum concentration of drug in serum and the area under the concentrationtime curve for BAL9141 were dose proportional over the dosing range. The elimination half-life of BAL9141 was about 3 h. The volume of distribution at steady state was equal to the volume of the adult extracellular water compartment, and the rate of renal clearance of free drug corresponded to the normal glomerular filtration rate for adults. More than 70% of the administered dose was excreted as BAL9141 in the urine, and almost no prodrug was detected. After the infusion of 750 mg, the mean plasma BAL9141 concentrations exceeded the MIC at which 100% of MRSA isolates are inhibited (4 g/ml) for approximately 7 h, or 58% of a 12-h dosing interval. These results indicate that infusions of 750 mg twice a day should be adequate for the treatment of infections caused by MRSA.

Emerging agents to combat complicated and resistant infections: focus on ceftobiprole

“…50 Ceftobiprole is predominantly eliminated in the urine. 44 The highest urine drug concentrations are observed within 2 hours after the start of the infusion, and urine concentrations correlate with dose. Glomerular filtration of the active metabolite appears to be predominantly responsible for removal of free drug from the systemic circulation.…”

“…The clearance (4.1-5.1 L/h), volume of distribution (18-20 L), and half-life in the post-distribution phase (3 hours) remained constant over the dose range. 44 Results of a multiple-dose study indicate that ceftobiprole has stable pharmacokinetic properties over an 8-day course of dosing, with low intersubject variability. 45 Overall results agreed with data reported by the same group in a single ascending-dose study.…”

“…In the Schmitt-Hoffmann studies, 44,45 8 subjects dosed with ceftobiprole experienced 10 adverse effects. Of these, 7 were reported as mild taste disturbances, described by subjects as a caramel-like taste experienced during the infusion period (attributed to conversion of the prodrug to ceftobiprole plus diacetyl, the latter being a natural product which has a caramel-like taste).…”

“…46,47 In a single-dose study performed following infusion of ceftobiprole medocaril at 500 and 1000 mg, total concentrations were above the MIC of 4 Bacteroides for 5 to 7 hours, corresponding to a T  MIC of 42% to 58% of a 12-hour interval, assuming twice-daily dosing, for 500 and 1000 mg, respectively. 44 For ceftobiprole medocaril 500 mg every 12 hours, the probabilities of achieving 30% and 50% T  MIC exceeded 90% for MIC values of 2 mcg/ml and 1 µg/mL, respectively. And for ceftobiprole medocaril 500 mg every 8 hours, the probabilities of achieving 40 and 60% T  MIC exceeded 90% for MIC values of 4 µg/mL and 2 µg/mL, respectively.…”

“…Glomerular filtration of the active metabolite appears to be predominantly responsible for removal of free drug from the systemic circulation. 44 Lodise et al 48 analyzed a total of 150 Phase I/II subjects in order to determine the optimal renal dose adjustment for intravenous ceftobiprole medocaril. Ceftobiprole medocaril 500 mg intravenously every 12 hours was determined to be the most appropriate …”