Simulation-based evaluation of the impact of dose fractionation study design on antibiotic PKPD analyses.

Objectives: To evaluate the impact of antibiotic dose fractionation study design on pharmacokinetic/pharmacodynamic (PK/PD) indices and PKPD model estimation.

Methods: PKPD models for meropenem and polymyxin B (PMB) were applied to (i) simulate various dose fractionation studies in mice to derive PK/PD indices and efficacy targets and (ii) perform stochastic simulations and estimations evaluating which efficacy assessment times, in addition to 24 h, would improve the estimation of drug effect parameters.

Results: The R ² values of PK/PD indices were primarily influenced by reductions of the dosing intervals for meropenem and by decreases of the lowest total daily dose for PMB. For certain study designs (e.g. frequent administration of higher meropenem doses), R ² values for fT > MIC and fAUC/MIC were similar. Efficacy target magnitudes were also sensitive to the selected doses. Additional efficacy assessment times improved parameter accuracy (e.g. 40% reduction in relative root mean squared error of PMB effect slope). The model parameter accuracy was more affected by the selection of time points for meropenem, which included resistance, than for PMB. Efficacy measurements in the first hours after treatment start (e.g. 2 and 6 h), in addition to 24 h, were essential for resistance characterization.

Conclusions: The choice of doses and fractionations impacted PK/PD index selection and efficacy target magnitude. Depending on the antibiotic, the dose or fractionation selection appeared to be the most critical. Early treatment efficacy measurements were beneficial to PKPD model-based analyses, particularly to describe resistance processes.