Jennie van Dyk (1) on behalf of the PediCAP trial team
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa
Objectives:
Amoxicillin alone or in combination with clavulanate (co-amoxiclav) is a widely prescribed antibiotic in paediatric infectious disease [1]. Its use in children with severe community acquired pneumonia (CAP) was investigated in the PediCAP trial (ISRCTN63115131). PediCAP is an open-label randomised controlled trial evaluating the impact of oral step-down to amoxicillin or co-amoxiclav on effectiveness, safety, and selection of antibiotic resistance in severe childhood CAP. Amoxicillin and co-amoxiclav 7:1 dispersible tablets (PediCAP-A, main trial), and co-amoxiclav 4:1 and 14:1 dispersible tablets (PediCAP-B, parallel phase II trial) were assessed. Pharmacokinetic (PK) data of oral amoxicillin and clavulanate in children are limited, especially in the context of lower middle-income countries. A suspension formula is ideal for paediatric use but necessitates refrigeration due to its instability, posing challenges in resource-limited settings. Dispersible tablets offer stability benefits but lacks investigation in paediatric populations [2]. This study aims to characterize the population PK of dispersible co-amoxiclav 7:1, 4:1, and 14:1 tablets in children with CAP enrolled in the PediCAP trial and evaluate clavulanate dose proportionality across dosing ratio formulations.
Methods:
PediCAP recruited Mozambican, South African, Ugandan, Zambian, and Zimbabwean children between 2 months and 6 years hospitalized with severe CAP. All children received at least 24 hours of intravenous antibiotic treatment prior to switching to oral co-amoxiclav dispersible tablets at the clinical discretion of the treating physician. Co-amoxiclav [JVD1] dosing was based on previous exposure findings in adults and children. Dose regimen accounted for allometry and maturation. Children were randomised to receive a twice-daily weight-banded dose of approximately 200 (3 – <6 kg), 400 (6 – <10kg), 500 (10 – <14kg), 800 (14 – <20 kg), 1000 (20 – <25 kg), and 1600 (25 – <35 kg) mg amoxicillin in 7:1, 4:1, and 14:1 formulation with clavulanate. Five blood samples were obtained over a six-hour period immediately prior to and following administration of dispersible co-amoxiclav. Amoxicillin and clavulanate were quantified by HPLC-MS/MS with a limit of detection (LOD) 0.05 ug/mL and 0.005 ug/mL, respectively. Concentration-time data was analysed using nonlinear mixed effects modelling in NONMEM (v.7.5.1) with FOCE-I parameter estimation and statistical and graphical analysis was performed in R (v.4.3.1). Allometry was applied to clearance and volume parameters. The effect of age, creatinine clearance, co-amoxiclav formulation and food was tested on model parameters. Data below the LOD were imputed to LOD/2 (M6 method) with extra additive error component of 50% LOD for the imputed data. Model fit was assessed with individual plots, goodness-of-fit and visual predictive checks (VPC).
Results:
Data was available from 83 children, with a total of 376 observations for each drug. Children included in this study had a median (range) weight of 8.3 (4.0–22) kg, age 11.1 (2.22–60.6) months and weight-for-age z-score -1.18 (-5.61–3.09). A two-compartment transit model with first-order elimination best described amoxicillin and clavulanate disposition, and allometry was described using total body weight normalised to 8 kg. The estimated typical clearance of amoxicillin was 9.56 L/h (BSV: 35.2%) and for clavulanate 4.95 L/h (BSV: 24%). Adding a maturation factor to clearance improved the model fit. A VPC indicated that a linear model fit clavulanate data well across the 4:1, 7:1, and 14:1 formulation.
Conclusions:
Proposed co-amoxiclav dosing using allometry and maturation achieved balanced exposures across all weight bands. Clavulanate exhibited dose linearity across 7:1, 4:1 and 14:1 co-amoxiclav formulations. We observed higher apparent clearance of amoxicillin than previously reported in hospitalised children receiving intravenous amoxicillin [3], which should be investigated. Clavulanate clearance observed in this study is comparable to that reported in healthy adult volunteers receiving oral clavulanate [4]. This study provides a population PK analysis of twice-daily co-amoxiclav dispersible tablets in African children with severe CAP, a population and drug that has been understudied up to this date.
References:
[1] A. Huttner et al., “Oral amoxicillin and amoxicillin–clavulanic acid: properties, indications and usage,” Clinical Microbiology and Infection, vol. 26, no. 7. Elsevier B.V., pp. 871–879, Jul. 01, 2020. doi: 10.1016/j.cmi.2019.11.028.[2] N. Peace, O. Olubukola, and A. Moshood, “Stability of reconstituted amoxicillin clavulanate potassium under simulated in-home storage conditions,” J Appl Pharm Sci, vol. 02, no. 01, pp. 28–31, 2012.
[3] C. I. S. Barker et al., “The Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA): investigating amoxicillin, benzylpenicillin, flucloxacillin and piperacillin pharmacokinetics from birth to adolescence,” Journal of Antimicrobial Chemotherapy, vol. 78, no. 9, pp. 2148–2161, Sep. 2023, doi: 10.1093/jac/dkad196.
[4] F. de Velde, B. C. M. de Winter, B. C. P. Koch, T. Van Gelder, and J. W. Mouton, “Highly variable absorption of clavulanic acid during the day: A population pharmacokinetic analysis,” Journal of Antimicrobial Chemotherapy, vol. 73, no. 2, pp. 469–476, 2018, doi: 10.1093/JAC/DKX376.
Reference: PAGE 32 (2024) Abstr 11020 [www.page-meeting.org/?abstract=11020]
Poster: Drug/Disease Modelling - Paediatrics