title: Development of a Pediatric Physiologically-Based Pharmacokinetic Model of Clindamycin Using Opportunistic Pharmacokinetic Data.
abstract: Physiologically-based pharmacokinetic (PBPK) modeling is a powerful tool used to characterize maturational changes in drug disposition to inform dosing across childhood; however, its use is limited in pediatric drug development. Access to pediatric pharmacokinetic data is a barrier to widespread application of this model, which impedes its development and optimization. To support the development of a pediatric PBPK model, we sought to leverage opportunistically-collected plasma concentrations of the commonly used antibiotic clindamycin. The pediatric PBPK model was optimized following development of an adult PBPK model that adequately described literature data. We evaluated the predictability of the pediatric population PBPK model across four age groups and found that 63-93% of the observed data were captured within the 90% prediction interval of the model. We then used the pediatric PBPK model to optimize intravenous clindamycin dosing for a future prospective validation trial. The optimal dosing proposed by this model was 9 mg/kg/dose in children ≤5 months of age, 12 mg/kg/dose in children >5 months-6 years of age, and 10 mg/kg/dose in children 6-18 years of age, all administered every 8 h. The simulated exposures achieved with the dosing regimen proposed were comparable with adult plasma and tissue exposures for the treatment of community-acquired methicillin-resistant Staphylococcus aureus infections. Our model demonstrated the feasibility of using opportunistic pediatric data to develop pediatric PBPK models, extending the reach of this powerful modeling tool and potentially transforming the pediatric drug development field.
authors.affiliation: Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA. christoph.hornik@duke.edu.|Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA. christoph.hornik@duke.edu.
authors.forename: Christoph P
authors.initials: CP
authors.lastname: Hornik
authors.affiliation: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Huali
authors.initials: H
authors.lastname: Wu
authors.affiliation: School of Pharmacy, University of Waterloo, Waterloo, ON, Canada.
authors.forename: Andrea N
authors.initials: AN
authors.lastname: Edginton
authors.affiliation: Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.|Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Watt
authors.affiliation: Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.|Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Cohen-Wolkowiez
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gonzalez
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002981:Clindamycin / Q000097:blood / Q000493:pharmacokinetics*; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods; D054796:Drug Dosage Calculations; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008954:Models, Biological; D010372:Pediatrics / Q000379:methods*
chemical_list: D002981:Clindamycin