Charlotte I.S. Barker (1,2), Iblal Rakha (2), Karin Kipper (1), Mark A. Turner (3), Mike Sharland (1), Joseph F. Standing (2)
(1) Paediatric Infectious Diseases Research Group, St George’s, University of London, (2) UCL Institute of Child Health, (3) Department of Women's and Children's Health, University of Liverpool
Objectives: Penicillin G remains widely used in neonates and, with gentamicin, it forms the mainstay of standard treatment for early onset sepsis in the UK. Despite widespread usage, the pharmacokinetic/pharmacodynamic (PK/PD) data to support current neonatal dosing regimens are limited. NAPPA is a population-PK study utilizing opportunistic sampling strategies to study the PK of penicillins during routine care of neonates/children. This interim analysis aimed to investigate the population PK of penicillin G in the first cohort of neonatal participants.
Methods: Eligible neonates, receiving intravenous penicillin G as part of routine care, were recruited at participating sites. The dosing regimen was as per normal local NHS (National Health Service) practice. After informed consent was obtained, study blood samples (0.5mL each) were obtained by clinical staff at the time of routine blood tests or blood gases. Samples were frozen at -80 degrees Celsius and analysed retrospectively. The plasma samples were analysed 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 study protocol was approved by an NRES Research Ethics Committee.
Results: For the interim analysis, 102 evaluable samples were available from 45 neonates (22 term; 23 preterm). Using NONMEM v7.3, one-, two- and three-compartment models were tested, using FOCE-I method, and the objective function values were compared. A two-compartment model was most suitable for these data; the final parameter estimates were 0.10 L/h for clearance (CL) and 0.34 L for central volume of distribution, 0.03 L/h for intercompartmental CL and 0.72 L for volume of the peripheral compartment.
Conclusions: In conclusion, a population PK model was developed based on interim neonatal penicillin G data. A two-compartment model resulted in the best fit to the data. Future work will include the addition of allometric scaling and a function describing the maturation of the glomerular filtration rate. Covariate analysis will also be performed, to assess factors including birth weight, gestational age, and renal function.
Reference: PAGE 24 (2015) Abstr 3634 [www.page-meeting.org/?abstract=3634]
Poster: Drug/Disease modeling - Paediatrics