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Antimicrobial Agents and Chemotherapy, May 2004, p. 1713-1718, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1713-1718.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Use of Monte Carlo Simulations To Select Therapeutic Doses and Provisional Breakpoints of BAL9141

Johan W. Mouton,1* Anne Schmitt-Hoffmann,2 Stuart Shapiro,2 Norman Nashed,2 and Nieko C. Punt3

Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen,1 Medimatics, Maastricht, The Netherlands,3 Basilea Pharmaceutica AG, Basel, Switzerland2

Received 10 July 2003/ Returned for modification 9 December 2003/ Accepted 20 January 2004

BAL9141, a new antimicrobial agent belonging to the class of parenteral pyrrolidinone-3-ylidenemethyl cephalosporins, is active against most gram-positive microorganisms, including methicillin-resistant variants (methicillin-resistant Staphylococcus aureus [MRSA] and methicillin-resistant Staphylococcus epidermidis [MRSE]), as well as against penicillin-resistant pneumococci (PRP) and many gram-negative microorganisms. BAL9141 is administered as the prodrug BAL5788, which is rapidly converted to BAL9141 by plasma esterases. Pharmacokinetic (PK) data obtained in a previous multiple ascending dose study were used to fit a population PK model to using the NPEM2 program, yielding PK parameter estimates and its covariance matrix for BAL9141. These estimates and matrix were used to perform Monte Carlo simulations (MCSs) and obtain unbiased target attainment rates (TARs) for various time periods during which the concentration remains above the MIC (T>MIC). Assuming a T>MIC of 40%, TARs of 100% were reached with a dose of 500 mg/liter every 12 h for pathogens with MICs of 2 mg/liter and with a dose of 750 mg/liter every 12 h for pathogens with MICs of 4 mg/liter. Because MICs are <=2 mg/liter for most strains of MRSA, MRSE, and PRP (with some strains showing an MIC of 4 mg/liter), a dosing regimen of 750 mg every 12 h is proposed for clinical studies. The corresponding provisional breakpoint is S (susceptible) <= 4 mg/liter.

* Corresponding author. Mailing address: Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Ziekenhuis Nijmegen, Weg door Jonkerbos 100, 6532 sz Nijmegen, The Netherlands. Phone: 31 (0)24 365 7514. Fax: 31 (0)24 365 7516. E-mail: Mouton{at}cwz.nl.

Antimicrobial Agents and Chemotherapy, May 2004, p. 1713-1718, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1713-1718.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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