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Predictive Performance of Physiologically Based Pharmacokinetic and Population Pharmacokinetic Modeling of Renally Cleared Drugs in Children

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ABSTRACT

Predictive performance of physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) models of drugs predominantly eliminated through kidney in the pediatric population was evaluated. After optimization using adult clinical data, the verified PBPK models can predict 33 of 34 drug clearance within twofold of the observed values in children 1 month and older. More specifically, 10 of 11 of predicted clearance values were within 1.5‐fold of those observed in children between 1 month and 2 years old. The PopPK approach also predicted 19 of 21 drug clearance within twofold of the observed values in children. In summary, our analysis demonstrated both PBPK and PopPK adult models, after verification with additional adult pharmacokinetic (PK) studies and incorporation of known ontogeny of renal filtration, could be applied for dosing regimen recommendation in children 1 month and older for renally eliminated drugs in a first‐in‐pediatric study.

No MeSH data available.


Overall predictivity of physiologically based pharmacokinetic (PBPK) models. Filled circles represent mean ratios of PBPK predicted clearance over observed clearance of all drugs in children 1 month to 18 years old. Blue dashed lines and red dotted lines represent the 1.5‐fold and twofold error.
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psp412101-fig-0006: Overall predictivity of physiologically based pharmacokinetic (PBPK) models. Filled circles represent mean ratios of PBPK predicted clearance over observed clearance of all drugs in children 1 month to 18 years old. Blue dashed lines and red dotted lines represent the 1.5‐fold and twofold error.

Mentions: The ratios of predicted over observed mean clearance values from all nine drugs were also plotted across all age groups (except neonates) in Figure6. Collectively, 33 of 34 predictions were within the 0.5–2.0 range (twofold error); and 31 of 34 predictions were within the 0.67–1.5 range (50% error). Eleven clinical studies were available in infants between 1 month and 2 years old and 10 of 11 of the predicted clearance were within 50% error of observed values. The ratios of predicted over observed mean clearance for all these studies in adults (verification datasets) and children across all age groups can be found in Supplementary Table S5.


Predictive Performance of Physiologically Based Pharmacokinetic and Population Pharmacokinetic Modeling of Renally Cleared Drugs in Children
Overall predictivity of physiologically based pharmacokinetic (PBPK) models. Filled circles represent mean ratios of PBPK predicted clearance over observed clearance of all drugs in children 1 month to 18 years old. Blue dashed lines and red dotted lines represent the 1.5‐fold and twofold error.
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Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC5036422&req=5

psp412101-fig-0006: Overall predictivity of physiologically based pharmacokinetic (PBPK) models. Filled circles represent mean ratios of PBPK predicted clearance over observed clearance of all drugs in children 1 month to 18 years old. Blue dashed lines and red dotted lines represent the 1.5‐fold and twofold error.
Mentions: The ratios of predicted over observed mean clearance values from all nine drugs were also plotted across all age groups (except neonates) in Figure6. Collectively, 33 of 34 predictions were within the 0.5–2.0 range (twofold error); and 31 of 34 predictions were within the 0.67–1.5 range (50% error). Eleven clinical studies were available in infants between 1 month and 2 years old and 10 of 11 of the predicted clearance were within 50% error of observed values. The ratios of predicted over observed mean clearance for all these studies in adults (verification datasets) and children across all age groups can be found in Supplementary Table S5.

View Article: PubMed Central - PubMed

ABSTRACT

Predictive performance of physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) models of drugs predominantly eliminated through kidney in the pediatric population was evaluated. After optimization using adult clinical data, the verified PBPK models can predict 33 of 34 drug clearance within twofold of the observed values in children 1 month and older. More specifically, 10 of 11 of predicted clearance values were within 1.5‐fold of those observed in children between 1 month and 2 years old. The PopPK approach also predicted 19 of 21 drug clearance within twofold of the observed values in children. In summary, our analysis demonstrated both PBPK and PopPK adult models, after verification with additional adult pharmacokinetic (PK) studies and incorporation of known ontogeny of renal filtration, could be applied for dosing regimen recommendation in children 1 month and older for renally eliminated drugs in a first‐in‐pediatric study.

No MeSH data available.