Abstract
BACKGROUND: Cefiderocol is a siderophore cephalosporin discovered by Shionogi & Co., Ltd., which exhibits potent efficacy against Gram-negative carbapenem-resistant bacteria. Pediatric clinical studies are planned. Cefiderocol is mainly renally eliminated. A 2-g infusion of cefiderocol over 3 hours, every 8 hours (q8h) is the recommended dose regimen in adults. In this study, dose regimens for pediatric subjects (birth to <18 years old) are proposed based on predictions of pharmacokinetics (PK) in pediatrics using data from adults to provide adequate exposure. METHODS: The PK model developed based on data in adults was modified for predicting PK in pediatrics. Total clearance and volume of distribution at steady state in pediatrics were scaled using allometric relationships developed for parenteral β-lactam antibiotics. The maturation factor of renal function was also incorporated into the model to predict PK in neonates and infants whose glomeruli are immature. The dose was selected to provide area under the concentration curve (AUC) comparable to adults. Monte-Carlo simulations were performed to calculate probability of target attainment (PTA) for 75% of fraction of time during which the free plasma concentrations exceed the minimum inhibitory concentration (MIC) over the dosing interval (fT(>MIC)) for age groups at the proposed doses against an MIC range from 0.25 to 16 µg/mL. RESULTS: The dose regimens for pediatrics were proposed based on age and body weight as shown in the table below. The dose of 60 mg/kg (maximum 2 g) q8h was selected as a standard dose. The dose for pediatrics aged <3 months was adjusted based on age. AUC predicted in pediatrics from birth to <18 years old for the proposed dose was comparable to that observed in adults. The proposed dose provided >90% PTA for 75% fT(>MIC) against MICs up to 4 µg/mL. CONCLUSION: The proposed dose regimens provide comparable (to adults) exposure in pediatric patients for target carbapenem-nonsusceptible pathogens, 98% of which are susceptible to cefiderocol at a MIC of ≤4 µg/mL. DISCLOSURES: All authors: No reported disclosures.