Charlotte Barker (1,2,3), Karin Kipper (1,4), Georgina Thompson (1,5), Min Kim (1,2), Mark Turner (6), Atholl Johnston (7), Mike Sharland (1,3), Joe Standing (2,1)
(1) Paediatric Infectious Diseases Research Group, Institute for Infection and Immunity, St George's University of London, London, UK (2) UCL Institute of Child Health, London, UK (3) St George's University Hospitals NHS Foundation Trust, London, UK (4) Institute of Chemistry, University of Tartu, Tartu, Estonia (5) University of Exeter, Exeter, UK (6) Department of Women's and Children's Health, University of Liverpool, Liverpool, UK (7) Clinical Pharmacology, Barts and The London School of Medicine and Dentistry, London, UK
Objectives: Developmental physiology and ontogeny are known to affect drug disposition in neonates and children. Thus improving our understanding of developmental pharmacology is an important component of paediatric dose optimization strategies. This analysis aimed to use interim data from NAPPA, a multicentre, multi-drug paediatric penicillin pharmacokinetic (PK) study [1], to inform a common maturation function (MF) from birth to adolescence for two drugs: benzylpenicillin and piperacillin.
Methods: Eligible participants were recruited at participating hospitals with informed consent. The antibiotic dosing regimen was as per standard care. Study blood samples (0.5mL each) were obtained with routine samples or at recommended times, then frozen and analysed in retrospect using high-performance liquid chromatography with tandem mass spectrometry. PK data from both penicillins were analysed simultaneously with a joint PK model implemented in non-linear mixed-effects modelling software (NONMEM v7.3, Icon plc), with a priori allometric weight scaling on both volume (Vd) and clearance (CL), and a shared postmenstrual age (PMA) driven MF on CL [2,3]. The importance sampling (IMP) estimation method was used to obtain the objective function value (OFV). The study had NRES Research Ethics Committee approval.
Results: For this analysis, interim NAPPA PK data were available for participants on benzylpenicillin (n=45) and piperacillin/tazobactam (n=29). The study population included 46 neonates (25 preterm), and 28 infants and children (up to 12 years-old). Using a joint one compartment population PK model, the combined data were analysed simultaneously and the optimization was completed with successful convergence. The OFV was 1522.3. The final parameter estimates were: 3.4 L/h/70 kg for benzylpenicillin CL and 11.4 L/70kg for Vd; 7.9 L/h/70 kg for piperacillin CL and 16.3 L/70kg for Vd, and for the common MF, the final parameter estimates were: 3.2 for the Hill coefficient and a PMA of 41.3 weeks for the maturation half-time (TM50).
Conclusions: Interim paediatric PK data from two penicillins were successfully analysed simultaneously using a joint model with a common MF. Allometric weight scaling with a sigmoidal MF was used as standardised parameterization to facilitate extrapolation and learning across drugs with similar PK [4]. Future work will include incorporating data from additional NAPPA study penicillins and retesting the model with the final dataset.
References:
[1] NAPPA: Neonatal and Paediatric Pharmacokinetics of Antimicrobials Study. EudraCT 2013-002366-40. https://clinicaltrials.gov/ct2/show/NCT01975493
[2] Holford N, Heo YA, Anderson B. A pharmacokinetic standard for babies and adults. J Pharm Sci 2013; 102: 2941-52.
[3] Anderson BJ, Holford NH. Understanding dosing: children are small adults, neonates are immature children. Arch Dis Child 2013; 98: 737-44.
[4] Germovsek E, Barker CIS, Standing JF. An Argument for Standardised Scaling: Comparison of Methods for Scaling Clearance in Children. PAGE poster presentation (PAGE 24 (2015) Abstr 3635). Abstracts of the Annual Meeting of the Population Approach Group in Europe. ISSN 1871-6032. Available at: www.page-meeting.org/?abstract=3635
Reference: PAGE 25 () Abstr 5803 [www.page-meeting.org/?abstract=5803]
Poster: Drug/Disease modeling - Paediatrics