Aims: (i) To describe the first-order and mixed-order elimination pathways of piperacillin, (ii) to determine the between occasion variability (BOV) of pharmacokinetic parameters and (iii) to propose optimized dosage regimens. Methods: We performed a five-period replicate dose study in four healthy volunteers. Each subject received 4 g piperacillin as a single 5min intravenous infusion in each study period. Drug analysis was performed by HPLC. We used NONMEM and S-ADAPT for population pharmacokinetic analysis and Monte Carlo simulation to predict the probability of target attainment (PTA) with a target time of non-protein bound concentration above MIC >50% of the dosing interval. Results: A model with first-order nonrenal elimination and parallel first-order and mixed-order renal elimination had the best predictive performance. For a 70 kg subject we estimated 4.40 l h-1 for nonrenal clearance, 5.70 l h-1 for first-order renal clearance, 170 mg h-1 for Vmax, and 49.7 mg l-1 for Km for the mixed-order renal elimination. The BOV was 39% for Vmax, 117% for Km, and 8.5% for total clearance. A 30min infusion of 4 g every 6 h achieved robust (≥90%) PTAs for MICs ≤12 mg l-1. As an alternative mode of administration, a 5 h infusion of 6 g every 8 h achieved robust PTAs for MICs ≤48 mg l-1. Conclusions: Part of the renal elimination of piperacillin is saturable at clinically used doses. The BOV of total clearance and volume of distribution were low. Prolonged infusions achieved better PTAs compared with shorter infusions at similar daily doses. This benefit was most pronounced for MICs between 12 and 48 mg l-1.
- Healthy volunteers
- Monte Carlo simulation
- Piperacillin population pharmacokinetics/pharmacodynamics
- Saturable elimination
- Within subject variability/between occasion variability