Development of a Pediatric Physiologically-Based Pharmacokinetic Model of Clindamycin Using Opportunistic Pharmacokinetic Data

Christoph P. Hornik, Huali Wu, Andrea N. Edginton, Kevin Watt, Michael Cohen-Wolkowiez, Daniel Gonzalez

Research output: Contribution to journalArticle

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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.

LanguageEnglish (US)
Pages1343-1353
Number of pages11
JournalClinical Pharmacokinetics
Volume56
Issue number11
DOIs
StatePublished - Nov 1 2017

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Clindamycin
Pharmacokinetics
Pediatrics
Pharmaceutical Preparations
Methicillin-Resistant Staphylococcus aureus
Age Groups
Anti-Bacterial Agents

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Development of a Pediatric Physiologically-Based Pharmacokinetic Model of Clindamycin Using Opportunistic Pharmacokinetic Data. / Hornik, Christoph P.; Wu, Huali; Edginton, Andrea N.; Watt, Kevin; Cohen-Wolkowiez, Michael; Gonzalez, Daniel.

In: Clinical Pharmacokinetics, Vol. 56, No. 11, 01.11.2017, p. 1343-1353.

Research output: Contribution to journalArticle

Hornik, Christoph P. ; Wu, Huali ; Edginton, Andrea N. ; Watt, Kevin ; Cohen-Wolkowiez, Michael ; Gonzalez, Daniel. / Development of a Pediatric Physiologically-Based Pharmacokinetic Model of Clindamycin Using Opportunistic Pharmacokinetic Data. In: Clinical Pharmacokinetics. 2017 ; Vol. 56, No. 11. pp. 1343-1353
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