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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.


Physiologically based pharmacokinetic (PBPK) modeling performance of oral drugs in adults and children. Predictions are expressed as ratios of predicted over observed of area under the curve (AUC) and peak plasma concentration (Cmax) values: mean AUC (blue triangles) and Cmax (red circles) with SD (bars). The dashed line represents the identity (predicted/observed ratio = 1), and the gray shade represents the 0.5–2.0 ratio window. Some literature sources are presented in the Supplementary Material online. Observed data sources for ceftibuten,S4,S34,S35 cetirizine,S11,S36,S38 levocetirizine,S8,S39,S40 pregabalin,S18,S41 and sotalol.S23,S42 The bottom two labels in the cetirizine young children groups indicate a study in children 2–4 years old and the bottom two labels indicate a study in children 2–6 years old.
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psp412101-fig-0003: Physiologically based pharmacokinetic (PBPK) modeling performance of oral drugs in adults and children. Predictions are expressed as ratios of predicted over observed of area under the curve (AUC) and peak plasma concentration (Cmax) values: mean AUC (blue triangles) and Cmax (red circles) with SD (bars). The dashed line represents the identity (predicted/observed ratio = 1), and the gray shade represents the 0.5–2.0 ratio window. Some literature sources are presented in the Supplementary Material online. Observed data sources for ceftibuten,S4,S34,S35 cetirizine,S11,S36,S38 levocetirizine,S8,S39,S40 pregabalin,S18,S41 and sotalol.S23,S42 The bottom two labels in the cetirizine young children groups indicate a study in children 2–4 years old and the bottom two labels indicate a study in children 2–6 years old.

Mentions: The predicted AUC and Cmax for five orally administrated drugs compared with those observed clinically are shown in Figure3. The exposure values of these drugs were reasonably predicted for all age groups, and the ratios of predicted over observed AUC or Cmax values mostly fall in the range of 0.67 and 1.5 (50% error). There were slightly larger errors in Cmax for cetirizine in infants 0.5–2 years (ratio of 1.56) and Cmax for sotalol in those younger than 1 month (ratio of 1.51). The predicted concentration‐time profiles of pregabalin overlaid with observed exposure in adults and all pediatric age groups are presented in Figure4a. Clinical observed plasma concentrations evenly distributed along with the model predicted profile and most observations were within the 5th percentile and 95th percentile of the prediction. The predicted concentration‐time profiles overlaid with observed exposure for other drugs can be found in Supplementary Figures S1–S8. The plots indicated that the developed PBPK models can reasonably predict the exposure for these renal eliminated drugs in children down to the age of 1 month (Supplementary Table S5). About 70% of administered meropenem is eliminated unchanged through the kidneys and 30% of meropenem is metabolized by renal dehydropeptidase‐1 (DHP‐1). Two PBPK models were constructed to assess the ontogeny of DHP‐I for 3‐month to 2‐year‐old infants. Model 1 (final model presented in Figure1) assumes DHP‐1 had a similar maturation profile as GFR, whereas model 2 assumes full maturation at birth for this nonrenal elimination pathway. The median prediction trends of clearance values by two models were compared with those observed in infants 3 months to 2 years old (Figure5). Without consideration of the maturation of DHP‐1, model 2 overpredicted meropenem clearance in infants. The mean ratios of predicted over observed clearance of meropenem in infants from 3 months to 1 year and 1 to 2 years were 1.23 and 1.02, respectively, by using the model 1 approach.


Predictive Performance of Physiologically Based Pharmacokinetic and Population Pharmacokinetic Modeling of Renally Cleared Drugs in Children
Physiologically based pharmacokinetic (PBPK) modeling performance of oral drugs in adults and children. Predictions are expressed as ratios of predicted over observed of area under the curve (AUC) and peak plasma concentration (Cmax) values: mean AUC (blue triangles) and Cmax (red circles) with SD (bars). The dashed line represents the identity (predicted/observed ratio = 1), and the gray shade represents the 0.5–2.0 ratio window. Some literature sources are presented in the Supplementary Material online. Observed data sources for ceftibuten,S4,S34,S35 cetirizine,S11,S36,S38 levocetirizine,S8,S39,S40 pregabalin,S18,S41 and sotalol.S23,S42 The bottom two labels in the cetirizine young children groups indicate a study in children 2–4 years old and the bottom two labels indicate a study in children 2–6 years old.
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Related In: Results  -  Collection

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psp412101-fig-0003: Physiologically based pharmacokinetic (PBPK) modeling performance of oral drugs in adults and children. Predictions are expressed as ratios of predicted over observed of area under the curve (AUC) and peak plasma concentration (Cmax) values: mean AUC (blue triangles) and Cmax (red circles) with SD (bars). The dashed line represents the identity (predicted/observed ratio = 1), and the gray shade represents the 0.5–2.0 ratio window. Some literature sources are presented in the Supplementary Material online. Observed data sources for ceftibuten,S4,S34,S35 cetirizine,S11,S36,S38 levocetirizine,S8,S39,S40 pregabalin,S18,S41 and sotalol.S23,S42 The bottom two labels in the cetirizine young children groups indicate a study in children 2–4 years old and the bottom two labels indicate a study in children 2–6 years old.
Mentions: The predicted AUC and Cmax for five orally administrated drugs compared with those observed clinically are shown in Figure3. The exposure values of these drugs were reasonably predicted for all age groups, and the ratios of predicted over observed AUC or Cmax values mostly fall in the range of 0.67 and 1.5 (50% error). There were slightly larger errors in Cmax for cetirizine in infants 0.5–2 years (ratio of 1.56) and Cmax for sotalol in those younger than 1 month (ratio of 1.51). The predicted concentration‐time profiles of pregabalin overlaid with observed exposure in adults and all pediatric age groups are presented in Figure4a. Clinical observed plasma concentrations evenly distributed along with the model predicted profile and most observations were within the 5th percentile and 95th percentile of the prediction. The predicted concentration‐time profiles overlaid with observed exposure for other drugs can be found in Supplementary Figures S1–S8. The plots indicated that the developed PBPK models can reasonably predict the exposure for these renal eliminated drugs in children down to the age of 1 month (Supplementary Table S5). About 70% of administered meropenem is eliminated unchanged through the kidneys and 30% of meropenem is metabolized by renal dehydropeptidase‐1 (DHP‐1). Two PBPK models were constructed to assess the ontogeny of DHP‐I for 3‐month to 2‐year‐old infants. Model 1 (final model presented in Figure1) assumes DHP‐1 had a similar maturation profile as GFR, whereas model 2 assumes full maturation at birth for this nonrenal elimination pathway. The median prediction trends of clearance values by two models were compared with those observed in infants 3 months to 2 years old (Figure5). Without consideration of the maturation of DHP‐1, model 2 overpredicted meropenem clearance in infants. The mean ratios of predicted over observed clearance of meropenem in infants from 3 months to 1 year and 1 to 2 years were 1.23 and 1.02, respectively, by using the model 1 approach.

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.