Pharmacokinetic/pharmacodynamic (PK/PD) evaluation of a once-daily treatment using ciprofloxacin in an extended-release dosage form.

OBJECTIVE

To evaluate the suitability of a once-a-day dosing regimen of ciprofloxacin using a new extended-release dosage form based on PK/PD principles.

METHODS

Ciprofloxacin's serum concentrations were measured after administration of 500 mg immediate-release twice-daily, and 1,000 mg extended-release once-daily to 19 healthy volunteers. Pharmacokinetic parameters were determined using non-compartmental and compartmental data analysis. Measured serum concentration profiles were linked to ciprofloxacin's effect against Escherichia coli (MIC 0.013 mg/l) from in vitro kill curve studies where the pharmacokinetics of ciprofloxacin were simulated and change in number of bacteria (CFU/ml) versus time was monitored. Resulting parameters were used to compare expected kill curves for the two dosing regimens based on measured ciprofloxacin concentrations.

RESULTS

Fitting the data using an appropriate PK/PD model resulted in a set of mean pharmacodynamic parameters (bacterial growth rate constant, k0, maximum kill rate constant, Kmax, and EC50). The model included a novel term to account for a change in kill rate after approximately 4 h when Kmax decreased in concentration-dependent matter. The model allowed excellent curve fits of all ciprofloxacin concentrations investigated. Comparison of expected kill curves with the immediate-release versus extended-release treatments showed similar outcome. Both treatments resulted in a decrease in CFU/ml > 5 log units over 24 h.

CONCLUSION

Results indicate that once-a-day dosing of equal total daily doses with the new and more compliance-friendly extended-release dosing form will be therapeutically equivalent to once-a-day dosing with traditional immediate-release dosage forms for treatment of infections with this microorganism.