Pharmacokinetics of Clavulanic Acid in the Pediatric Population: A Systematic Literature Review

BACKGROUND AND OBJECTIVE: Clavulanic acid is a commonly used β-lactam inhibitor in pediatrics for a variety of infections. Clear insight into its mode of action is lacking, however, and a target has not been identified. The dosing of clavulanic acid is currently based on that of the partner drug (amoxicillin or ticarcillin). Still, proper dosing of the compound is needed because clavulanic acid has been associated with adverse effects. In this systematic review, we aim to describe the current literature on the pharmacokinetics of clavulanic acid in the pediatric population METHODS: We performed a systematic search in MEDLINE, Embase.com, Cochrane Central, Google Scholar, and Web of Science. We included all published studies reporting pharmacokinetic data on clavulanic acid in neonates and children 0-18 years of age. RESULTS: The search resulted in 18 original studies that met the inclusion criteria. In general, the variation in drug exposure was large, which can be partly explained by differences in disease state, route of administration, or age. Unfortunately, the studies' limited background information hampered in-depth assessment of the observed variability. CONCLUSION: The pharmacokinetics of clavulanic acid in pediatric patients is highly variable, similar to reports in adults, but more pronounced. Significant knowledge gaps remain with regard to the population-specific explanation for this variability. Model-based pharmacokinetic studies that address both maturational and disease-specific changes in the pediatric population are therefore needed. Furthermore, additional pharmacodynamic studies are needed to define a clear target. The combined outcomes will eventually lead to pharmacokinetic-pharmacodynamic modeling of clavulanic acid and targeted exposure. CLINICAL TRIAL REGISTRATION: PROSPERO CRD42020137253.