P-1222. Oral Cephalexin Population Pharmacokinetics and Target Attainment Analysis in Infants 0-60 Days Old
Authors: Haynes Andrew , Wei Zixuan , Scheetz Marc H , Gonzalez Daniel , Messacar Kevin , Tang-Girdwood Sonya , Douglas N , Anderson Peter 
Published: January 2025

Abstract

Background
Transitioning from intravenous (IV) to oral (PO) antibiotics is uncommon practice in young infants due to a lack of pharmacokinetic (PK) or pharmacodynamic (PD) data to guide effective PO doses. Cephalexin is a promising PO treatment option against common neonatal pathogens, but rapid renal and intestinal maturation during the first months of life hinder extrapolation of dosing from older populations. In this study, we describe cephalexin’s PK in infants ≤ 60 days old and evaluate dosing regimens to achieve desired PD targets.

Methods
A prospective, single-center, open-label study was conducted to define cephalexin PK parameters in admitted infants 0-60 days old who were either receiving cephalexin clinically or were given a single oral study dose of cephalexin (25 mg/kg). Cephalexin plasma concentrations, quantified using liquid chromatography-mass spectrometry, were used for nonlinear mixed-effects modeling. Monte Carlo simulations were performed to assess the probability of various cephalexin dosing regimens to attain PD targets of free concentrations above the MIC (fT &gt; MIC) for 40% and 70% of the day for MICs up to 8 mg/L (assuming 15% protein binding).

Results
The final analysis included 114 cephalexin concentrations obtained from 27 infants [median age: 31 days (range 9-56), gestational age: 37 wks (range 31-41)]. The data were best described using a one-compartment PK model with first order absorption and an absorption lag time. The covariates included in the final PK model were weight on apparent volume of distribution and apparent clearance (CL/F) using standard allometric scaling, post-natal age on absorption rate, and eGFR on CL/F. Cephalexin doses were simulated in 8 cohorts of virtual infants in weekly intervals from 1-8 weeks old assigned normal weights-for-age and eGFRs based on reference values. Conventional cephalexin dosing (25 mg/kg/dose q6 hrs) achieved a 40% fT &gt; MIC PD target for every cohort and MIC range, and a 70% fT &gt; MIC target in the 1, 2, and 3-week-old cohorts. Higher dosing was needed to achieve 70% fT &gt; MIC in infants 4-8 weeks old.

Conclusion
Among infants ≤ 60 days, oral cephalexin can achieve high PD targets for efficacy against common neonatal pathogens with MIC ≤ 8 mg/L. These results provide dosing guidance to facilitate IV to PO transition in young infants.

Disclosures
Marc H. Scheetz, PharmD, MSc, Abbvie: Advisor/Consultant|Basilea: Advisor/Consultant|Cidara: Advisor/Consultant|DoseMe: Advisor/Consultant|Entasis: Advisor/Consultant|F2G: Advisor/Consultant|GSK: Advisor/Consultant|Lykos: Advisor/Consultant|Roche: Advisor/Consultant|Third Pole Therapeutics: Advisor/Consultant|Xelia: Advisor/Consultant Daniel Gonzalez, PharmD, PhD, Melinta Therapeutics, LLC: Advisor/Consultant|Nabriva Therapeutics plc: Grant/Research Support|Simulations Plus, Inc.: Advisor/Consultant Sonya Tang-Girdwood, MD, PhD, Kaizen Biosciences: Advisor/Consultant|Kaizen Biosciences: Grant/Research Support|Pfizer: Grant/Research Support Peter Anderson, PharmD, Gilead: Grant/Research Support