Dataset Information

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.

SUBMITTER: Hornik CP

PROVIDER: S-EPMC5597447 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Hornik Christoph P CP Wu Huali H Edginton Andrea N AN Watt Kevin K Cohen-Wolkowiez Michael M Gonzalez Daniel D

Clinical pharmacokinetics 20171101 11

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 ...[more]

PMID: 28290120

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Project description:Background: Atezolizumab has been studied in multiple indications for both pediatric and adult patient populations. Generally, clinical studies enrolling pediatric patients may not collect sufficient pharmacokinetic data to characterize the drug exposure and disposition because of operational, ethical, and logistical challenges including burden to children and blood sample volume limitations. Therefore, mechanistic modeling and simulation may serve as a tool to predict and understand the drug exposure in pediatric patients. Objective: To use mechanistic physiologically-based pharmacokinetic (PBPK) modeling to predict atezolizumab exposure at a dose of 15 mg/kg (max 1,200 mg) in pediatric patients to support dose rationalization and label recommendations. Methods: A minimal mechanistic PBPK model was used which incorporated age-dependent changes in physiology and biochemistry that are related to atezolizumab disposition such as endogenous IgG concentration and lymph flow. The PBPK model was developed using both in vitro data and clinically observed data in adults and was verified across dose levels obtained from a phase I and multiple phase III studies in both pediatric patients and adults. The verified model was then used to generate PK predictions for pediatric and adult subjects ranging from 2- to 29-year-old. Results: Individualized verification in children and in adults showed that the simulated concentrations of atezolizumab were comparable (76% within two-fold and 90% within three-fold, respectively) to the observed data with no bias for either over- or under-prediction. Applying the verified model, the predicted exposure metrics including Cmin, Cmax, and AUCtau were consistent between pediatric and adult patients with a geometric mean of pediatric exposure metrics between 0.8- to 1.25-fold of the values in adults. Conclusion: The results show that a 15 mg/kg (max 1,200 mg) atezolizumab dose administered intravenously in pediatric patients provides comparable atezolizumab exposure to a dose of 1,200 mg in adults. This suggests that a dose of 15 mg/kg will provide adequate and effective atezolizumab exposure in pediatric patients from 2- to 18-year-old.

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Dataset Information

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

Publications

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

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