Application of patient population-derived pharmacokinetic-pharmacodynamic relationships to tigecycline breakpoint determination for staphylococci and streptococci.

Correctly determined susceptibility breakpoints are important to both the individual patient and to society at large. A previously derived patient population pharmacokinetic model and Monte Carlo simulation (9999 patients) were used to create a likelihood distribution of tigecycline exposure, as measured by the area under the concentration-time curve at 24 h (AUC(24)). Each resultant AUC(24) value was paired with a clinically relevant fixed MIC value ranging from 0.

Use of a clinically derived exposure-response relationship to evaluate potential tigecycline-Enterobacteriaceae susceptibility breakpoints.

Potential tigecycline-Enterobacteriaceae susceptibility breakpoints were evaluated using 2 approaches, which differed in the nature of the probabilities assessed by MIC value. Using a previously derived tigecycline population pharmacokinetic model and Monte Carlo simulation, a probability density function of steady-state area under the concentration-time curve for 24 h (AUC(SS(0-24))) values for 9999 patients was generated. AUC(SS(0-24)) values were divided by clinically relevant fixed MIC values to derive AUC(SS(0-24))/MIC ratios, which were used to calculate the clinical response expectation by MIC value based upon a logistic regression model for efficacy (1st approach).

Challenges in the transition to model-based development.

Practitioners of the art and science of pharmacometrics are well aware of the considerable effort required to successfully complete modeling and simulation activities for drug development programs. This is particularly true because of the current, ad hoc implementation wherein modeling and simulation activities are piggybacked onto traditional development programs. This effort, coupled with the failure to explicitly design development programs around modeling and simulation, will continue to be an important obstacle to the successful transition to model-based drug development.

Use of pharmacokinetic-pharmacodynamic target attainment analyses to support phase 2 and 3 dosing strategies for doripenem.

A doripenem population pharmacokinetic model and Monte Carlo simulations were utilized for dose regimen decision support for future clinical development. Simulation results predict that 500 mg of doripenem administered over 1 h every 8 h would be effective against bacterial strains with MICs less than 2 microg/ml and that less susceptible strains could be treated with prolonged infusions.

Gatifloxacin and the elderly: pharmacokinetic-pharmacodynamic rationale for a potential age-related dose reduction.

Objectives: Recently, anecdotal reports via the FDA's MedWatch reporting system have documented rare but serious hyperglycaemia in elderly patients receiving gatifloxacin. One possible factor contributing to these events may be gatifloxacin overexposure, resulting from age-related decreases in renal function in elderly patients predisposed to glycaemic alterations. These analyses examine gatifloxacin exposure in 10 patients with severe hyperglycaemia, provide a pharmacokinetic-pharmacodynamic (PK-PD) rationale for a potential age-related dose reduction to avoid high exposures, and evaluate the likely impact of such a dose reduction on clinical efficacy in this specific patient population.