Use of Monte Carlo simulations to select therapeutic doses and provisional breakpoints of BAL9141.
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.
Mouton
Johan W
JW
Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands. Mouton@cwz.nl
Schmitt-Hoffmann
Anne
A
Shapiro
Stuart
S
Nashed
Norman
N
Punt
Nieko C
NC
D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D019540:Area Under Curve; D002511:Cephalosporins / Q000008:administration & dosage* / Q000627:therapeutic use*; D006801:Humans; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D009010:Monte Carlo Method
D000890:Anti-Infective Agents; D002511:Cephalosporins; C443755:ceftobiprole