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Antimicrobial Agents and Chemotherapy, June 2004, p. 2061-2068, Vol. 48, No. 6
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.6.2061-2068.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Novel Pharmacokinetic-Pharmacodynamic Model for Prediction of Outcomes with an Extended-Release Formulation of Ciprofloxacin

Alison K. Meagher,1* Alan Forrest,1,2 Axel Dalhoff,3 Heino Stass,3 and Jerome J. Schentag1,2

CPL Associates, L.L.C., Amherst,1 The School of Pharmacy, State University of New York at Buffalo, Buffalo, New York,2 Bayer Healthcare, Wuppertal, Germany3

Received 21 July 2003/ Returned for modification 9 December 2003/ Accepted 10 February 2004

The pharmacokinetics of an extended-release (XR) formulation of ciprofloxacin has been compared to that of the immediate-release (IR) product in healthy volunteers. The only significant difference in pharmacokinetic parameters between the two formulations was seen in the rate constant of absorption, which was approximately 50% greater with the IR formulation. The geometric mean plasma ciprofloxacin concentrations were applied to an in vitro pharmacokinetic-pharmacodynamic model exposing three different clinical strains of Escherichia coli (MICs, 0.03, 0.5, and 2.0 mg/liter) to 24 h of simulated concentrations in plasma. A novel mathematical model was derived to describe the time course of bacterial CFU, including capacity-limited replication and first-order rate of bacterial clearance, and to model the effects of ciprofloxacin concentrations on these processes. A "mixture model" was employed which allowed as many as three bacterial subpopulations to describe the total bacterial load at any moment. Comparing the two formulations at equivalent daily doses, the rates and extents of bacterial killing were similar with the IR and XR formulations at MICs of 0.03 and 2.0 mg/liter. At an MIC of 0.5 mg/liter, however, the 1,000-mg/day XR formulation showed a moderate advantage in antibacterial effect: the area under the CFU-time curve was 45% higher for the IR regimen; the nadir log CFU and 24-h log CFU values for the IR regimen were 3.75 and 2.49, respectively; and those for XR were 4.54 and 3.13, respectively. The mathematical model explained the differences in bacterial killing rate for two regimens with identical AUC/MIC ratios.

* Corresponding author. Mailing address: Division of Infectious Diseases, Cognigen Corporation, 395 Youngs Rd., Buffalo, NY 14221. Phone: (716) 633-3463. Fax: (716) 633-7404. E-mail: alison.meagher{at}cognigencorp.com.

Antimicrobial Agents and Chemotherapy, June 2004, p. 2061-2068, Vol. 48, No. 6
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.6.2061-2068.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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