Introduction
Piperacillin
is a moderately bound, broad-spectrum beta-lactam antibiotic commonly
prescribed in intensive care units (ICU) to treat severe infections. The
pharmacokinetic/pharmacodynamic (PK/PD) parameter linked to piperacillin
antibacterial activity is defined by the time (T) during which the
unbound drug concentration (f ) remains above the minimum
inhibitory concentration (MIC) of the pathogen of interest (f T
> MIC) [1]. As a result, piperacillin unbound
concentration is required to assess target attainment. This value is
obtained with two methods; by either directly measuring the unbound
concentration of piperacillin with a validated bioanalytical method; or
by firstly measuring the total concentration to afterwards apply a
theoretical unbound fraction value to this concentration to obtain the
unbound concentration. The latter is often performed with a value of
70%, the typically assumed unbound fraction in healthy subjects
[2-8]. However, some studies have used other values to reflect
current findings of piperacillin unbound fractions in ICU patients, as
it may vary considerably within this population [7-9].
In our previous work, we noticed that the application of an unbound
fraction could alter the predictive performance of a population
pharmacokinetic (popPK) model evaluated with an independent dataset
[10]. In summary, the independent dataset contained total
piperacillin concentrations, whereas the model in question, developed by
Klastrup et al., used unbound piperacillin concentrations during the
development phase [11]. When calculating the predictive performance
of the model with both total and unbound concentrations – retrieved by
applying a factor of 70% - the latter concluded in favor of the
validity of the model, whereas the model was considered unfit for the
studied population when using total concentrations. This indicates that
a model may perhaps be inappropriately suitable or unsuitable depending
on the unbound fraction applied on a dataset in this type of evaluation.
No study has clearly shown whether variations in unbound fraction had an
impact on dosing recommendations for piperacillin, nor how it impacted
the validity of a popPK model. Additionally, Roberts et al. have stated
that more modeling-based research is required to determine whether
dosing adjustments would be warranted for drugs that are affected by
altered protein binding [12]. The aim of this study was therefore to
investigate these potential impacts through simulations by using a
previously validated popPK model developed by Klastrup et al. [11].