1321. Population Pharmacokinetic (PK) and Pharmacokinetic/Pharmacodynamic (PK/PD) Target Attainment Analyses for Dalbavancin in Pediatric Patients

Abstract

BackgroundDalbavancin is a lipoglycopeptide approved for treating adults with acute bacterial skin and skin structure infections (ABSSSI). It has a terminal half-life of >14 days, which allows for administration as a single-dose regimen. Pediatric studies for dalbavancin include three phase 1 studies and a phase 3 study in patients from birth to 17 years with ABSSSI or neonatal sepsis.MethodsA population PK model was developed using 1124 concentrations from 211 pediatric patients. Allometric scaling of clearance, and volume parameters was included with exponents fixed at 0.75 and 1, respectively. Based on exploratory analysis and prior knowledge, serum albumin was included as a covariate on all PK parameters, and creatinine clearance or estimated glomerular filtration rate (eGFR) was included as a covariate on clearance. eGFR for patients < 2 years accounted for renal maturation. Additional covariates were assessed by stepwise covariate modeling (SCM). The final model was qualified by visual predictive checks (VPCs) and bootstrapping and was used to simulate 1000 PK profiles for various pediatric age groups, ranging from preterm neonates to adolescents. PK/PD target attainment (PTA) was calculated for targets associated with stasis, 1-log kill, and 2-log kill of Staphylococcus aureus in the murine thigh infection model.ResultsDalbavancin PK was well-characterized by a 3-compartment model. SCM did not find any significant covariates besides albumin, weight, and renal function. VPCs demonstrated that the final model has good predictive performance across the full age range. Simulations showed that single-dose regimens of 22.5 mg/kg for patients < 6 years and 18 mg/kg for patients 6 to < 18 years resulted in PTA ≥94% for MICs up to 2 mg/L for the stasis target and up to 0.5 mg/L for the 2-log kill target. PTA for pediatric patients was similar to adults, and exposures (AUCs) were contained within the range for adults administered 1500 mg.ConclusionDalbavancin PK in pediatric patients was well-characterized by a 3-compartment model with allometric scaling of clearance and volume and with albumin and renal function included as covariates. Simulations with the final model demonstrate adequate PTA across the entire age range for the regimens used in the phase 3 pediatric study.DisclosuresTimothy J. Carrothers, ScD, AbbVie (Employee) H. Maxime Lagraauw, PhD, qPharmetra (Employee) Lars Lindbom, PhD, qPharmetra (Employee) Todd Riccobene, PhD, AbbVie (Employee)