Stef Schouwenburg(1)*, Fleur Keij(2, 3)*, René F. Kornelisse(2), Tim Preijers(1), Fatima Mir(4), Pieter Degraeuwe(5), Leo Stolk(5), Sandra Kenter(2), Irwin K. M. Reiss(2, 3), Karel Allegeart(1, 6), Gedrien A. Tramper-Stranders(2), Birgit C. P. Koch(1), Robert B. Flint(1, 2)
(1) Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, Netherlands (2) Department of Pediatrics, Division of Neonatology, Erasmus University Medical Centre-Sophia Children’s Hospital, Rotterdam, Netherlands (3) Department of Pediatrics, Franciscus Gasthuis & Vlietland, Rotterdam, Netherlands (4) Section of Pediatric Infectious Disease, Pediatrics and Child Health,, The Aga Khan University, Karachi, Pakistan (5) Department of Clinical Pharmacy, University Hospital of Maastricht, Maastricht, Netherlands (6) Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium *contributed equally
Introduction/Objectives: In neonates, use of oral antibiotics is limited due to lacking evidence on pharmacokinetics (PK) and adequate exposure after administration. Amoxicillin/clavulanic acid covers most causative pathogens of early-onset neonatal sepsis. Adequacy of treatment depends on time (T) the free drug concentration (fC) exceeds the minimal inhibitory concentration (MIC) of pathogen (fT>MIC). Adequate target attainment ensures bacteriostatic effects, whereas suboptimal dosing induces antibiotic resistance. Target percentages reported in literature vary from 30% fT>MIC up to 100% fT>4xMIC varying based on the etiology and severity of infection and cut-offs are population specific. For neonates, the desired goal in literature is 40-50% of time. Our aim was to describe oral amoxicillin PK in neonates, including bioavailability. Our second aim was to evaluate pharmacodynamics (PD) based on target attainment and to provide dosing recommendations.
Methods: For this study we combined three datasets on 261 newborns with a median (range) gestational age of 35.8 weeks (24.9 – 42.4), postnatal age of 6.8 days (0 – 55) and bodyweight of 2.6 kg (0.5 – 5). In total 938 plasma samples were used upon 79 oral and 182 intravenous treatments (1-3). NONMEM 7.4 was used for population PK modeling. A target of 50% fT>MIC with an MIC of 8 mg/L (to cover Gram-negatives such as E. coli) was used to provide dosing recommendations.
Results: A one-compartment model with a priori allometric scaling on V and Cl best described amoxicillin PK. An additional non-linear influence of postnatal age and gestational age on amoxicillin clearance was identified. For a typical patient the population estimates were 0.046 L/h/kg (IIV 26.7%) for clearance, 0.61 L for the volume of distribution and 87% bioavailability. Clearance (L/hour/kg) at a postnatal age of 5 days was 2.6-fold and 4.7-fold higher in case of a gestational age of 32 – 37 and >37 weeks, respectively, compared with 24 – 32 weeks. Dosing simulations for a typical patient indicated that the lowest dosage to achieve 50% fT>MIC was 50 mg/kg/day (MIC 8 mg/L).
Conclusions: This first population PK description of oral amoxicillin in (pre-)term neonates. We showed that oral amoxicillin is well absorbed. Moreover, we provided guidance to further optimize dosing regimens in neonates with bacterial infections. Current oral dosing regimens lead to adequate exposure and may even be reduced and/or administered twice daily.
References:
[1] Keij FM, Kornelisse RF, Hartwig NG, Mauff K, Poley MJ, Allegaert K, et al. RAIN study: a protocol for a randomised controlled trial evaluating efficacy, safety and cost-effectiveness of intravenous-to-oral antibiotic switch therapy in neonates with a probable bacterial infection. BMJ Open. 2019;9(7):e026688. [2] Pullen J, Stolk LM, Nieman FH, Degraeuwe PL, van Tiel FH, Zimmermann LJ. Population pharmacokinetics and dosing of amoxicillin in (pre)term neonates. Ther Drug Monit. 2006;28(2):226-31. [3] Mir F, Pearce RE, Baig-Ansari N, Qazi S, Barrett JS, Abdel-Rahman S, et al. Serum amoxicillin levels in young infants (0–59 days) with sepsis treated with oral amoxicillin. Archives of Disease in Childhood. 2020;105(12):1208-14.
Reference: PAGE 30 (2022) Abstr 9987 [www.page-meeting.org/?abstract=9987]
Poster: Drug/Disease Modelling - Infection