Abstract:Health and Environmental Sciences Institute (HESI) (https://hesiglobal.org). HESI is a publicly supported, tax-exempt organization that provides an international forum to advance the understanding of scientific issues related to human health, toxicology, risk assessment, and the environment through the engagement of scientists from academia, government, industry, nongovernmental organizations, and other strategic partners. This HESI scientific initiative is primarily supported by in-kind contributions from pub… Show more
“…The decision to use allometric scaling for the extrapolation was based on the fact that the main enzymes involved in SPIR and CAN metabolism remain understudied. It was considered that by the age of 2 years (youngest target age for initial clinical studies) the main enzymes involved in the metabolism were already mature, and the main differences adequately correlate with body weight [24][25][26]. During the evaluation of covariates as part of the adult model development, body weight was not statistically significant for the BSV of clearance or volumes of distribution.…”
Section: Discussionmentioning
confidence: 99%
“…The parent metabolite model built for the pediatric population, as described above, was used to simulate SPIR and CAN plasma profiles in pediatric patients of different ages receiving different doses of the oral suspension within the range 0.25-2 mg/kg. Moreover, the following was also considered for the pediatric dose selection: (1) existing guidelines and recommendations for SPIR administration in pediatric subjects with edematous conditions [4,5]; (2) differences in SPIR exposures when administered as an oral suspension with and without food, and differences in exposures when administered as tablets (Aldactone ® ) versus oral suspension (CaroSpir ® ); and (3) in vitro characterization of SPIR metabolism (i.e., main CYP enzymes identified as contributors to SPIR metabolism in in vitro studies, namely cytochrome CYP2C8 and CYP3A4/5, as well as Flavin-containing monooxygenases (FMOs), are already mature by the age of 2 years [24][25][26]).…”
Quantitative pharmacology brings important advantages in the design and conduct of pediatric clinical trials. Herein, we demonstrate the application of a model-based approach to select doses and pharmacokinetic sampling scenarios for the clinical evaluation of a novel oral suspension of spironolactone in pediatric patients with edema. A population pharmacokinetic model was developed and qualified for spironolactone and its metabolite, canrenone, using data from adults and bridged to pediatrics (2 to <17 years old) using allometric scaling. The model was then used via simulation to explore different dosing and sampling scenarios. Doses of 0.5 and 1.5 mg/kg led to target exposures (i.e., similar to 25 and 100 mg of the reference product in adults) in all the reference pediatric ages (i.e., 2, 6, 12 and 17 years). Additionally, two different sampling scenarios were delineated to accommodate patients into sparse sampling schemes informative to characterize drug pharmacokinetics while minimizing phlebotomy and burden to participating children.
“…The decision to use allometric scaling for the extrapolation was based on the fact that the main enzymes involved in SPIR and CAN metabolism remain understudied. It was considered that by the age of 2 years (youngest target age for initial clinical studies) the main enzymes involved in the metabolism were already mature, and the main differences adequately correlate with body weight [24][25][26]. During the evaluation of covariates as part of the adult model development, body weight was not statistically significant for the BSV of clearance or volumes of distribution.…”
Section: Discussionmentioning
confidence: 99%
“…The parent metabolite model built for the pediatric population, as described above, was used to simulate SPIR and CAN plasma profiles in pediatric patients of different ages receiving different doses of the oral suspension within the range 0.25-2 mg/kg. Moreover, the following was also considered for the pediatric dose selection: (1) existing guidelines and recommendations for SPIR administration in pediatric subjects with edematous conditions [4,5]; (2) differences in SPIR exposures when administered as an oral suspension with and without food, and differences in exposures when administered as tablets (Aldactone ® ) versus oral suspension (CaroSpir ® ); and (3) in vitro characterization of SPIR metabolism (i.e., main CYP enzymes identified as contributors to SPIR metabolism in in vitro studies, namely cytochrome CYP2C8 and CYP3A4/5, as well as Flavin-containing monooxygenases (FMOs), are already mature by the age of 2 years [24][25][26]).…”
Quantitative pharmacology brings important advantages in the design and conduct of pediatric clinical trials. Herein, we demonstrate the application of a model-based approach to select doses and pharmacokinetic sampling scenarios for the clinical evaluation of a novel oral suspension of spironolactone in pediatric patients with edema. A population pharmacokinetic model was developed and qualified for spironolactone and its metabolite, canrenone, using data from adults and bridged to pediatrics (2 to <17 years old) using allometric scaling. The model was then used via simulation to explore different dosing and sampling scenarios. Doses of 0.5 and 1.5 mg/kg led to target exposures (i.e., similar to 25 and 100 mg of the reference product in adults) in all the reference pediatric ages (i.e., 2, 6, 12 and 17 years). Additionally, two different sampling scenarios were delineated to accommodate patients into sparse sampling schemes informative to characterize drug pharmacokinetics while minimizing phlebotomy and burden to participating children.
“…The relative expression of 7 human phase II drug-metabolizing enzymes at different ages is shown in Fig. 3 ( 51 – 53 ). Figure 3 Relative expression of human hepatic phase II enzymes at different ages ( 48 – 50 ) …”
Section: Adme Of Pediatric Pbpk Modelmentioning
confidence: 99%
“…c Hepatic intrinsic CYP2D6 clearance of tramadol at different ages. d CYP2D6 fraction metabolized of tramadol at different ages ( 52 , 53 ) …”
Pediatric drug development faces many difficulties. Traditionally, pediatric drug doses are simply calculated linearly based on the body weight, age, and body surface area of adults. Due to the ontogeny of children, this simple linear scaling may lead to drug overdose in pediatric patients. The physiologically based pharmacokinetic (PBPK) model, as a mathematical model, contributes to the research and development of pediatric drugs. An example of a PBPK model guiding drug dose selection in pediatrics has emerged and has been approved by the relevant regulatory agencies. In this review, we discuss the principle of the PBPK model, emphasize the necessity of establishing a pediatric PBPK model, introduce the absorption, distribution, metabolism, and excretion of the pediatric PBPK model, and understand the various applications and related prospects of the pediatric PBPK model.
“…Multiple, excellent reviews have been published that address each of the components we address below though in much greater depth. The reader is referred to several publications for specifics 4,5,12–14 …”
Section: Summary Of Relevant Factors That Influence Drug Disposition In Premature Infantsmentioning
In premature infants, effective and safe drug therapy depends on optimal dose selection and requires a thorough understanding of the underlying disease(s) of these fragile infants as well as the pharmacokinetics and pharmacodynamics of the drugs selected to treat their diseases. Differences in gestational and postnatal age or weight are the major determinants of the observed variability in drug disposition and effect in these infants. This article presents an outline on how to translate the results of a population pharmacokinetic/pharmacodynamic study into rational dosing regimens, and how physiologically based pharmacokinetic modeling, electronic health records, and the abundantly available data of vital functions of premature infants during their stay in the neonatal intensive care unit for evaluation of their pharmacotherapy can be used to tailor the most safe and effective dose in these infants.
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