Inhibition of flucloxacillin tubular renal secretion by piperacillin

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Most β‐lactams are excreted by filtration and to a greater extent by tubular secretion, which is a capacity‐limited saturable pathway. • Pharmacokinetic interactions between co‐administered β‐lactams have been frequently reported; however, their mechanism and possible clinical benefits are not well defined. • We are not aware of the interaction between piperacillin and flucloxacillin being reported in the literature. WHAT THIS STUDY ADDS • Piperacillin inhibits the renal and nonrenal elimination of flucloxacillin to a clinically significant extent, but not vice versa. • Modelling suggests that the mechanism for the decrease of renal clearance of flucloxacillin is probably competitive inhibition of renal tubular secretion by piperacillin. • Piperacillin has a 15‐times higher affinity for the renal transporter than flucloxacillin based on the molar ratio. AIMS To explore the extent, time course, site(s), mechanism and possible clinical relevance of the pharmacokinetic (PK) interaction between piperacillin and flucloxacillin. METHODS A single‐dose, randomized, six‐way crossover study in 10 healthy volunteers where all subjects received all of the following as 5‐min intravenous infusions: (i) 1.5 g piperacillin, (ii) 0.5 g flucloxacillin, (iii) 1.5 g piperacillin + 0.5 g flucloxacillin, (iv) 3 g piperacillin, (v) 1 g flucloxacillin, and (vi) 3 g piperacillin + 1 g flucloxacillin. Drug concentrations in plasma and urine were determined by high‐performance liquid chromatography. WinNonlin® was used for PK modelling and statistics. RESULTS Piperacillin significantly decreased the renal clearance of flucloxacillin from 5.44 to 2.29 l h−1 (medians, P < 0.01) and the nonrenal clearance of flucloxacillin from 2.67 to 1.80 l h−1 (P < 0.01). The renal clearance of flucloxacillin was reduced to 45% (point estimate, 90% confidence interval 40 to 50%) and the nonrenal clearance to 66% (59, 73). The extent of interaction was larger at the higher doses. Competitive inhibition of tubular secretion by piperacillin was identified as the most likely mechanism for the decreased renal clearance of flucloxacillin. Piperacillin had a 15‐times higher affinity for the renal transporter than flucloxacillin based on the molar ratio. Piperacillin PK was only slightly affected by flucloxacillin. CONCLUSIONS Piperacillin inhibits renal and nonrenal elimination of flucloxacillin. This interaction seems clinically significant, as total clearance was reduced by a factor of 1.5 for the lower and 2.1 for the higher doses. PK interactions, especially with piperacillin, are likely to occur also with other β‐lactam combinations and might be useful to improve the effectiveness of antibacterial treatment.

Simultaneous determination of seven β-lactam antibiotics in human plasma for therapeutic drug monitoring and pharmacokinetic studies

“…The LLOQs are sufficiently lower than expected trough concentration or real plasma levels [61][62][63][64][65][66] and therefore the method can accurately determination concentrations in the expected low ranges. Concentrations above the upper limit of quantification can be diluted with blank drug free plasma as needed to put the concentration in the range of the calibration curve.…”

Mechanistic Models Describing Active Renal Reabsorption and Secretion: A Simulation-Based Study

“…Model R2 represents a more physiological model of the kidney with renal blood flow, glomerular filtration from the kidney compartment, proximal and distal tubule compartments, and a urine compartment (17). Model S1 is a one-compartment model with linear and saturable clearance processes described by glomerular filtration and active tubular secretion, as well as linear nonrenal clearance (18). Model S2 is a mechanistic semiphysiological model, incorporating renal blood flow from the central compartment to the kidneys.…”

“…1) were selected for analysis based on the available models within the literature (16)(17)(18)(19). The differential equations for the structural models are listed in the supplemental data.…”

“…In our evaluation, we used four published mechanistic models with varying degrees of complexity describing active renal reabsorption (16,17) and active renal secretion (18,19). These mechanistic models include specific transport kinetic parameters that are driven by a physiologically relevant drug concentration (plasma/blood or tubular lumen) as opposed to evaluating renal clearance as a singular parameter.…”

Frequency of Acute Kidney Injury Caused by Tazobactam/Piperacillin in Patients with Pneumonia and Chronic Kidney Disease: A Retrospective Observational Study

“…18) Furthermore, PIPC inhibits OATs. Landersdorfer et al 19) has found that when 3.0 g of PIPC was administered alone, PIPC clearance was smaller than when 1.5 g of PIPC was administered.…”