Characterizing Absorption Kinetics of Oral Antibiotics in Young Infants to Enhance Precision Dosing - PROPOSAL SUMMARY (ABSTRACT): This K23 Career Development Award application addresses the unmet need for safe and effective oral (PO) antibiotic dosing in neonates and young infants. Transitioning from intravenous (IV) to PO antibiotics is standard practice for serious pediatric infections, offering similar clinical outcomes with shorter hospital stays, fewer side effects, and reduced costs. However, neonates and young infants are often excluded due to their vulnerability to serious infections, a lack of pharmacokinetic (PK) and pharmacodynamic (PD) data, and high inter-individual variability (IIV) in drug absorption, all of which complicate optimal dosing. This proposal aims to address these challenges by leveraging PK/PD approaches to optimize PO dosing of amoxicillin and linezolid, two antibiotics that are well absorbed and effective against common neonatal pathogens but remain underutilized due to limited data characterizing their absorption and disposition in this population. The central hypothesis is that covariate-based dosing, considering patient-specific factors such as post-natal age and gestational age, will improve PD target attainment compared to standard weight-based dosing. The proposed research integrates population PK (popPK) modeling, physiologically-based PK (PBPK) modeling, and in vitro metabolism studies to optimize PO antibiotic dosing strategies. Aim 1 will use existing data to develop popPK and PBPK models for amoxicillin, identifying covariates to support covariate-informed dosing strategies, and will extend this work by developing a model-informed precision dosing (MIPD) framework in MwPharm++, providing a foundation for a future R01 application focused on implementation. Aim 2 will develop a preliminary PBPK model to predict PO linezolid PK in young infants by combining published PK data with in vitro microsomal stability assays that will define neonatal linezolid metabolism. Aim 3 will validate the PBPK model through a prospective, optimally-designed clinical study in young infants, refine covariate-based dosing strategies, and identify patient-specific factors driving absorption variability. Completing these aims is feasible and will address the critical need for personalized PO dosing regimens in this vulnerable population. This research reflects Dr. Haynes’s commitment to improving outcomes for infants with bacterial infections and aligns with his career goal of becoming an independent clinician-scientist specializing in pharmacometrics and pediatric clinical trials. To support this goal, this proposal outlines a four-year mentored career development plan encompassing didactic and experiential training in advanced PK modeling, simulation, MIPD, clinical trial design, and laboratory techniques, which is a natural extension from his K12 Clinical Pharmacology Career Development Award. Dr. Haynes has assembled a multidisciplinary mentorship team led by Peter Anderson, PharmD, and Kevin Messacar, MD, PhD, with additional support from a diverse and accomplished group of co- mentors and advisors, ensuring the resources and guidance needed to advance his long-term objective of improving personalized PO antibiotic dosing strategies across pediatrics.
