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

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.


Physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) prediction of i.v. drugs in adults and children. Predictions are expressed as ratios of predicted over observed of clearance values: mean of PBPK (blue filled squares) and PopPK (red open squares) with SD (bars). The dashed line represents the identity (predicted/observed ratio = 1); the gray shade represents the 0.5–2.0 ratio window. Literature sources are presented in Supplementary Material online. Observed data sources for avibactam, ceftazidime,28,S32 meropenem,S33 and vancomycin.42,S30 The bottom two labels in the meropenem infant groups indicate a study in children 3 months to 1 year old and the top two labels indicate a study in children 1–2 years old. The bottom two labels in the vancomycin infant groups indicate a study in children 2–4 months, and the top two labels indicate a study in children 2–7 months old.
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psp412101-fig-0002: Physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) prediction of i.v. drugs in adults and children. Predictions are expressed as ratios of predicted over observed of clearance values: mean of PBPK (blue filled squares) and PopPK (red open squares) with SD (bars). The dashed line represents the identity (predicted/observed ratio = 1); the gray shade represents the 0.5–2.0 ratio window. Literature sources are presented in Supplementary Material online. Observed data sources for avibactam, ceftazidime,28,S32 meropenem,S33 and vancomycin.42,S30 The bottom two labels in the meropenem infant groups indicate a study in children 3 months to 1 year old and the top two labels indicate a study in children 1–2 years old. The bottom two labels in the vancomycin infant groups indicate a study in children 2–4 months, and the top two labels indicate a study in children 2–7 months old.

Mentions: The developed PBPK models were first verified with clinical studies in adults to demonstrate that the models could reasonably predict drug exposure in adult populations before predictions in pediatrics. Using the same drug models validated in adults, pediatric PK was predicted with the same age range, male/female ratio, and dosing information, as in the actual clinical trials, which provided reasonable prediction for each drug in children across all age groups. For avibactam, ceftazidime, and meropenem via i.v. administration (Figure2), the predicted clearance values across all pediatric age groups were within 50% error. A larger prediction error was observed for vancomycin, in which the clearance ratios of all prediction were within a generally accepted twofold error range, except neonates at 0 to 1 week and infants 2–4 months (ratios were 4.39 and 2.39, respectively).


Predictive Performance of Physiologically Based Pharmacokinetic and Population Pharmacokinetic Modeling of Renally Cleared Drugs in Children
Physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) prediction of i.v. drugs in adults and children. Predictions are expressed as ratios of predicted over observed of clearance values: mean of PBPK (blue filled squares) and PopPK (red open squares) with SD (bars). The dashed line represents the identity (predicted/observed ratio = 1); the gray shade represents the 0.5–2.0 ratio window. Literature sources are presented in Supplementary Material online. Observed data sources for avibactam, ceftazidime,28,S32 meropenem,S33 and vancomycin.42,S30 The bottom two labels in the meropenem infant groups indicate a study in children 3 months to 1 year old and the top two labels indicate a study in children 1–2 years old. The bottom two labels in the vancomycin infant groups indicate a study in children 2–4 months, and the top two labels indicate a study in children 2–7 months old.
© Copyright Policy - creativeCommonsBy-nc
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5036422&req=5

psp412101-fig-0002: Physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) prediction of i.v. drugs in adults and children. Predictions are expressed as ratios of predicted over observed of clearance values: mean of PBPK (blue filled squares) and PopPK (red open squares) with SD (bars). The dashed line represents the identity (predicted/observed ratio = 1); the gray shade represents the 0.5–2.0 ratio window. Literature sources are presented in Supplementary Material online. Observed data sources for avibactam, ceftazidime,28,S32 meropenem,S33 and vancomycin.42,S30 The bottom two labels in the meropenem infant groups indicate a study in children 3 months to 1 year old and the top two labels indicate a study in children 1–2 years old. The bottom two labels in the vancomycin infant groups indicate a study in children 2–4 months, and the top two labels indicate a study in children 2–7 months old.
Mentions: The developed PBPK models were first verified with clinical studies in adults to demonstrate that the models could reasonably predict drug exposure in adult populations before predictions in pediatrics. Using the same drug models validated in adults, pediatric PK was predicted with the same age range, male/female ratio, and dosing information, as in the actual clinical trials, which provided reasonable prediction for each drug in children across all age groups. For avibactam, ceftazidime, and meropenem via i.v. administration (Figure2), the predicted clearance values across all pediatric age groups were within 50% error. A larger prediction error was observed for vancomycin, in which the clearance ratios of all prediction were within a generally accepted twofold error range, except neonates at 0 to 1 week and infants 2–4 months (ratios were 4.39 and 2.39, respectively).

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.