Nonlinear pharmacokinetics of piperacillin in healthy volunteers – implications for optimal dosage regimens

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Despite the clinical use of piperacillin for more than two decades, there are still contradictory reports whether or not the elimination of piperacillin is saturable at clinically relevant concentrations. • Two recent studies that applied population pharmacokinetic (PK) modelling found evidence for a saturable component of piperacillin elimination, whereas other published population PK analyses found non‐saturable elimination of piperacillin. • There is limited information on the between occasion variability of beta‐lactams (including piperacillin) and such data might be important to maximize the effectiveness by individualizing beta‐lactam dosage regimens. WHAT THIS STUDY ADDS • Saturable and non‐saturable components of renal elimination were identified for piperacillin and the unbound non‐saturable renal clearance of piperacillin was similar to the glomerular filtration rate. • Between occasion variability of clearance and volume of distribution at steady‐state of piperacillin was below 20% which indicated that the PK of piperacillin was predictable from one dosing interval to the next. • Monte Carlo simulation predicted 5 h infusions every 8 h and continuous infusion of piperacillin would be able to successfully treat infections by pathogens with a 2 to 4‐fold (5 to 8‐fold) higher MIC compared with 30 min infusions given every 6 h (every 8 h) at the same daily dose. 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 5 min 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 V max , and 49.7 mg l −1 for K m for the mixed‐order renal elimination. The BOV was 39% for V max , 117% for K m , and 8.5% for total clearance. A 30 min 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 .