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Related Concept Videos

Drug Dosing: Infants and Children01:29

Drug Dosing: Infants and Children

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Pediatric patient dosages diverge from adults due to disparities in body surface area, total body water, and extracellular fluid per kilogram of body weight. The dosing regimen considers the variations in pharmacokinetics and pharmacology across distinct age groups, encompassing preterm newborns, infants, young children, older children, and adolescents. Calculation of pediatric patient doses is predicated on determining body surface area, which exhibits a superior correlation with the child's...
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In pediatric medicine, understanding the renal function and drug elimination nuances is crucial for administering safe and effective treatments. Newborns, in particular, display markedly slower renal functions than adults, profoundly affecting how drugs are cleared from their bodies. This slower drug clearance requires clinicians to extend the dosing intervals for many medications to prevent drug accumulation and toxicity while ensuring therapeutic efficacy.One key area where these adjustments...
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Drug distribution in the pediatric population exhibits unique challenges and considerations due to the physiological differences between children, particularly neonates and infants, and adults. A crucial aspect of pediatric pharmacology is understanding how these differences impact the pharmacokinetics of various drugs, necessitating age-specific dosing strategies to ensure efficacy and safety.Neonates and infants have a higher total body water content, ~75%–90% of their body weight,...
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In pediatric care, understanding the nuances of hepatic drug metabolism is crucial, as it significantly differs from that of adults. This divergence is primarily due to the developmental stage of drug-metabolizing enzymes, which affects how medications are processed in the body. In neonates, for instance, the activity of Phase I enzymes—critical for the initial breakdown of drugs—is markedly reduced, functioning at just 20–40% of the levels seen in adults. This reduction poses...
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In patients with renal disease, dosage adjustments are necessary to maintain therapeutic plasma drug concentrations and prevent toxicity or subtherapeutic exposure. Renal impairment alters drug pharmacokinetics, especially in conditions like uremia, where changes such as prolonged elimination half-life and altered apparent volume of distribution can significantly affect drug disposition. These changes require careful modification of the dosing regimen to achieve the desired clinical...
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Understanding the physiological differences in the pediatric population is crucial for effective pharmacotherapy. Neonates, infants, and children exhibit significant variations in gastric pH, gastric emptying time, intestinal transit time, and biliary function. These variations profoundly affect oral drug absorption, necessitating a nuanced approach to pediatric dosing.Neonates present with a unique physiological profile, having a gastric pH greater than 4 and faster and more irregular gastric...
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Model-Informed Pediatric Dose Selection for Dapagliflozin by Incorporating Developmental Changes.

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  • 1Modelling and Simulation, Early Oncology, Oncology R&D, AstraZeneca, Cambridge, UK.

CPT: Pharmacometrics & Systems Pharmacology
|January 13, 2021
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Summary

This study developed a physiologically based pharmacokinetic (PBPK) model for dapagliflozin, predicting drug exposure in pediatric patients. The model accurately simulated dapagliflozin pharmacokinetics across various populations and scenarios.

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Area of Science:

  • Pharmacokinetics and Drug Metabolism
  • Quantitative Systems Pharmacology
  • Pediatric Drug Development

Background:

  • Dapagliflozin is a selective SGLT2 inhibitor primarily metabolized by UGT enzymes.
  • Predicting dapagliflozin exposure in pediatric populations is challenging due to UGT1A9 ontogeny and limited clinical data.
  • Physiologically based pharmacokinetic (PBPK) modeling offers a quantitative approach to address these challenges.

Purpose of the Study:

  • To develop and verify a mechanistic PBPK model for oral dapagliflozin.
  • To predict dapagliflozin exposure in pediatric subjects (1 month to 18 years).
  • To guide pediatric dosing regimens based on exposure-response relationships.

Main Methods:

  • Developed a dapagliflozin PBPK model using in vitro metabolism and clinical PK data.
  • Verified the model against observed data in healthy adults, special populations, and drug-drug interaction scenarios (UGT1A9 modulators).
  • Applied twofold acceptance criteria for model-predicted versus observed PK parameters (AUC, Cmax).

Main Results:

  • The PBPK model successfully captured dapagliflozin exposure within twofold of observed data in adults, adolescents, and special populations.
  • Model predictions aligned well with monotherapy data in adults and adolescents.
  • The model provided reliable predictions for pediatric exposures matching adult exposure levels.

Conclusions:

  • A verified PBPK model for dapagliflozin enables accurate exposure prediction in pediatric populations.
  • The model, combined with UGT ontogeny understanding, aids in determining pediatric dosing regimens.
  • This approach supports the development of dapagliflozin in pediatric studies by simulating exposures similar to adult therapeutic doses.