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Antimicrobial Agents and Chemotherapy, July 2004, p. 2570-2575, Vol. 48, No. 7
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.7.2570-2575.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Anne Schmitt-Hoffmann,1* Brigitte Roos,1 Michael Schleimer,1 Jill Sauer,1 Anthony Man,1 Norman Nashed,1 Thomas Brown,1 Antonio Perez,1 Erhard Weidekamm,1 and Péter Kovács2

Basilea Pharmaceutica Ltd., Basel, Switzerland,1 1st Department of Medicine and Department of Clinical Pharmacology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary2

Received 30 April 2003/ Returned for modification 22 December 2003/ Accepted 4 March 2004

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 concentration-time 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 µg/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.

* Corresponding author. Mailing address: Basilea Pharmaceutica Ltd., P.O. Box 3255, Basel 4002, Switzerland. Phone: 41 61 606 1379. Fax: 41 61 606 1378. E-mail: schmita{at}basileapharma.com.

Antimicrobial Agents and Chemotherapy, July 2004, p. 2570-2575, Vol. 48, No. 7
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.7.2570-2575.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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