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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.


Workflow of the development of physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) models and prediction of pharmacokinetic (PK) in pediatrics for drugs primarily eliminated by the kidneys. CRCL, creatinine clearance; WT, body weight.
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psp412101-fig-0001: Workflow of the development of physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) models and prediction of pharmacokinetic (PK) in pediatrics for drugs primarily eliminated by the kidneys. CRCL, creatinine clearance; WT, body weight.

Mentions: The main objective of this study was to systematically characterize the pediatric predictive performance of both PBPK and PopPK approaches for drugs predominantly eliminated via kidney. By considering physiologic changes (multiple for PBPK described by Johnson et al.7 and body weight for PopPK) and renal function maturation (both approaches) in pediatrics, predictions of drug exposure by both approaches were compared with clinical observations conducted in infants, children, and adolescents. The work flow is illustrated in Figure1. The PBPK model of each drug was built and optimized using published adult clinical PK data. The accuracy of pediatric exposure was evaluated by comparing simulated concentrationā€time profiles with observed clinical PK results in children at respective age groups for each drug. Simulations using structural models developed in adults with plausible combinations of covariates were performed to assess the predictive performance of PopPK modeling in children.


Predictive Performance of Physiologically Based Pharmacokinetic and Population Pharmacokinetic Modeling of Renally Cleared Drugs in Children
Workflow of the development of physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) models and prediction of pharmacokinetic (PK) in pediatrics for drugs primarily eliminated by the kidneys. CRCL, creatinine clearance; WT, body weight.
© Copyright Policy - creativeCommonsBy-nc
Related In: Results  -  Collection

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

psp412101-fig-0001: Workflow of the development of physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) models and prediction of pharmacokinetic (PK) in pediatrics for drugs primarily eliminated by the kidneys. CRCL, creatinine clearance; WT, body weight.
Mentions: The main objective of this study was to systematically characterize the pediatric predictive performance of both PBPK and PopPK approaches for drugs predominantly eliminated via kidney. By considering physiologic changes (multiple for PBPK described by Johnson et al.7 and body weight for PopPK) and renal function maturation (both approaches) in pediatrics, predictions of drug exposure by both approaches were compared with clinical observations conducted in infants, children, and adolescents. The work flow is illustrated in Figure1. The PBPK model of each drug was built and optimized using published adult clinical PK data. The accuracy of pediatric exposure was evaluated by comparing simulated concentrationā€time profiles with observed clinical PK results in children at respective age groups for each drug. Simulations using structural models developed in adults with plausible combinations of covariates were performed to assess the predictive performance of PopPK modeling 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.