A pooled population pharmacokinetic study of oral and intravenous clavulanic acid in neonates
Stef Schouwenburg (1, 2), Fleur Keij (3, 4), Tim Preijers (1, 2), Karel Allegaert (1, 5), Gerdien Tramper-Stranders (3), Birgit Koch (1, 2)
(1) Department of Hospital Pharmacy, Erasmus University Medical Centre, Rotterdam, the Netherlands, (2) Rotterdam Clinical Pharmacometrics Group, Erasmus University Medical Centre, Rotterdam, the Netherlands, (3) Department of Paediatrics, Division of Neonatology, Erasmus University Medical Centre-Sophia Children’s Hospital, Rotterdam, The Netherlands, (4) Department of Pediatrics, Franciscus Gasthuis & Vlietland, Rotterdam, Netherlands, (5) Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
Introduction/Objectives: Infectious diseases are a major cause of childhood morbidity and mortality. Therefore, antibiotics are among the most commonly prescribed drugs for (pre-)term neonates. Beta-lactam antibiotics specifically are effective against bacterial infections through inhibiting cell wall synthesis. However, bacteria can develop resistance for beta-lactam antibiotics by producing beta-lactamase, an enzyme that inactivates the bacteriostatic effects and causes antibiotic degradation. To counter this effect, clavulanic acid, a beta-lactamase inhibitor, is often co-administered with amoxicillin or ticarcillin. Current dosing strategies focus mainly on the beta-lactam antibiotic component, with little attention paid to the clavulanic acid specific dosing regimens as no pharmacodynamic target for clavulanic acid is available yet. Currently, there is a lack of population-based studies to elucidate the pharmacokinetic properties of clavulanic acid in (pre-)term neonates.
To describe clavulanic acid disposition following oral and intravenous administration in (pre-) term neonates. Additionally, the influence of covariates on clavulanic acid disposition and pharmacokinetic parameters will be assessed.
Methods: In this pooled population pharmacokinetic study two datasets from Rotterdam, the Netherlands (amoxicillin/clavulanic acid 4:1) (1) and Durham, United States (ticarcillin/clavulanic acid 30:1) (2) were combined. The complete cohort consisted of 60 (15 intravenous, 45 oral) (pre-)term neonates with a median (range) gestational age of 39.4 weeks (23 – 41.7), postnatal age of 40 days (6 – 44), and bodyweight of 3.4 kilograms (0.6 – 4.5). In total, 158 clavulanic acid blood concentrations (76 intravenous and 82 oral) were available for analysis. Postnatal age, gestational age, sex, and weight were tested in the model as covariates to explain the observed variability in pharmacokinetic parameters between patients. Data analysis was performed using nonlinear mixed-effects modeling with NONMEM v7.5 (ICON Development Solutions, Ellicott City, MD, USA). Simulations were performed using Markov Chain Monte Carlo methods.
Results: A one-compartment model with an additive residual error best described clavulanic acid pharmacokinetics. For a typical patient, the population estimates were 0.2 L/h/kg for clearance, 0.3 L for the volume of distribution and 14% for bioavailability. Clavulanic acid is absorbed with an estimated population absorption coefficient of 0.4 h-1. Inter-individual variability for clearance was estimated and resulted in an unexplained variability of 65.4% and shrinkage of 15%. Allometric scaling as well as other morphometric relationships were tested, but were not able to improve model fit. Incorporation of the covariates on clavulanic acid clearance did not further explain any variability. The percentage of free time above the minimal inhibitor concentration was simulated as a theoretical target for clavulanic acid pharmacodynamics.
Conclusions: This study described the first population pharmacokinetic analysis for oral and intravenous clavulanic acid in (pre-)term neonates. It was demonstrated that clavulanic acid bioavailability is lower in neonates compared with adults (14% vs. 60%, respectively) (3). In order to further optimize clavulanic acid dosing regimens, future research should focus on a pharmacodynamic target to ensure treatment efficacy.
References:
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