Population Pharmacokinetics Of Piperacillin In Hospitalised Children

Background and Aims: Piperacillin is an anti-pseudomonal penicillin antibiotic that is commonly used in hospitalised children within the NHS (National Health Service). It is frequently prescribed in an off-label or unlicensed context, since in the UK it is only licensed for the treatment of neutropenia and complicated intra-abdominal infections in children under 12 years-of-age. Other common indications include the treatment of hospital-acquired pneumonia and septicaemia. There is, however, limited pharmacokinetic (PK) data to support current paediatric dosing regimens. The NAPPA study (Neonatal and Paediatric Pharmacokinetics of Antimicrobials Study) is an ongoing multicentre population-PK study employing opportunistic sampling strategies to study the PK of several penicillins during routine NHS care of children and neonates. This interim analysis aimed to investigate the piperacillin PK in the first cohort of participants.

Methods: Eligible children, administered intravenous piperacillin (in combination with the beta-lactamase inhibitor tazobactam) as standard-of-care, were enrolled at participating hospitals. The dosing regimen followed normal local NHS practice. Following informed consent, study blood samples (0.5mL) were obtained with routine blood tests or at recommended times. All plasma samples were frozen at -80 degrees Celsius and analysed in retrospect using high-performance liquid chromatography with tandem mass spectrometry. A population-PK model was fitted simultaneously to the measured drug concentration-time data using non-linear mixed-effects modelling software (NONMEM v7.3, Icon plc). The log-likelihood ratio was used to discriminate between nested structural models; the drop in model objective function value (OFV) was tested at the significance level corresponding to p<0.05. The study protocol was approved by the London Dulwich NRES Research Ethics Committee.

Results: For this interim analysis 41 evaluable samples were available from 17 study participants (59%female, age range: 1 month to 11.8 years). Using NONMEM v7.3, one- , two- and three-compartment models were tested, and the objective function values (OFVs) were compared. The OFVs were 437.139, 425.884 and 420.751, for the one-, two- and three-compartment models, respectively. A 2-compartment model was most suitable for these data. The final PK parameter estimates for the two-compartment model were: 0.96 L/h for clearance (CL) and 0.27 L for the central volume of distribution (Vd), 0.98 L/h for intercompartmental CL and 0.88 L for the volume of the peripheral compartment.

Conclusions: Based on interim data from the NAPPA study, a paediatric population PK model was developed for piperacillin. A 2-compartment structural model provided the best fit to these data. Future analysis will incorporate allometric scaling and a mathematical function that describes glomerular filtration maturation. In addition, covariate analysis will be undertaken, to investigate factors including weight and renal function, and the influence of concomitant medications on piperacillin pharmacokinetics in children. The final dataset will be used for model-based simulations to evaluate the suitability of different paediatric dosing regimens, in order to improve the evidence underpinning future dosing recommendations.