Prediction of the Clearance of Eleven Drugs and Associated Variability in Neonates, Infants and Children

  title={Prediction of the Clearance of Eleven Drugs and Associated Variability in Neonates, Infants and Children},
  author={Trevor N Johnson and Amin Rostami-Hodjegan and Geoffrey T Tucker},
  journal={Clinical Pharmacokinetics},
BackgroundPrediction of the exposure of neonates, infants and children to xenobiotics is likely to be more successful using physiologically based pharmacokinetic models than simplistic allometric scaling, particularly in younger children. However, such models require comprehensive information on the ontogeny of anatomical, physiological and biochemical variables; data that are not available from single sources.The Simcyp® software integrates demographic, genetic, physiological and pathological… 

Development of a Physiologically Based Model for Oseltamivir and Simulation of Pharmacokinetics in Neonates and Infants

Simulations showed agreement with a wide range of observational data, indicating that the processes determining the age-dependent pharmacokinetics of oseltamivir are well described, and exemplifies the utility of PBPK models in predicting pharmacokinetic in the very young.

Preterm Physiologically Based Pharmacokinetic Model. Part II: Applications of the Model to Predict Drug Pharmacokinetics in the Preterm Population

A developed preterm model for the prediction of PK behaviour in preterm patients is not intended to replace clinical studies, but can potentially help with deciding on first-time dosing in this population and study design in the absence of clinical data.

Prediction of drug clearance in children

This analysis established a single equation using the adult clearance value as well as individual age and weight to predict drug clearance in children older than 6 months, which improved the clearance prediction in the 6 months–2 years age group.


The outcome suggests that the current ontogeny profiles result in under-prediction of CL values compared to clinical studies in infants and children and there is a need for better ontogenY models.

Developmental pharmacokinetics in pediatric populations.

  • Hong LuS. Rosenbaum
  • Medicine, Biology
    The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG
  • 2014
The age-related changes in drug absorption, distribution, metabolism, and elimination in infants and children are reviewed, and the age- related dosing regimens for this population are discussed.

Pharmacokinetic predictions in children by using the physiologically based pharmacokinetic modelling

Physiologically based pharmacokinetics is one way to integrate the physiological changes occurring in the childhood and to anticipate their impact on the pharmacokinetic processes: absorption, distribution, metabolism and excretion/elimination.

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

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.

Renal Clearance in Newborns and Infants: Predictive Performance of Population‐Based Modeling for Drug Development

The results suggest that PMA‐based sigmoidal maximum effect (Emax) model, in combination with bodyweight‐based scaling and kidney function assessment, can be used in population PK (PopPK) modeling for drugs that are primarily eliminated via renal pathway to inform initial dose selection for newborns and infants with normal renal function in clinical trials.

Semi-Mechanistic Model for Predicting the Dosing Rate in Children and Neonates for Drugs Mainly Eliminated by Cytochrome Metabolism

This model allows the calculation of the maintenance dose of drugs eliminated mainly by cytochromes and could be used in children aged less than 2 years and in older children, the model reduces to a simple approach based on body surface area or preferably on fat-free mass at power 0.75.

Prediction of metabolic drug clearance in humans: In vitro–in vivo extrapolation vs allometric scaling

IVIVE is more reliable than AS in predicting human clearance values for drugs mainly metabolized by CYP450 enzymes, suggesting that the place of AS methods in pre-clinical drug development warrants further scrutiny.



Prediction of Cytochrome P450-Mediated Hepatic Drug Clearance in Neonates, Infants and Children

The aim of this commentary is to test and critically examine the proposed methods to estimate hepatic clearance (CL) as a function of age (0–20 years), with CYP3A-mediated metabolism as the case in point.

Prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (PBPK) modelling: theophylline and midazolam as model drugs.

  • S. Björkman
  • Medicine
    British journal of clinical pharmacology
  • 2005
A general physiologically based pharmacokinetic (PBPK) model for drug disposition in infants and children, covering the age range from birth to adulthood, and to evaluate it with theophylline and midazolam as model drugs yielded results that generally tallied with literature data.

Physiologically Based Pharmacokinetic (PBPK) Modeling of Caffeine and Theophylline in Neonates and Adults: Implications for Assessing Children's Risks from Environmental Agents

The current analysis utilizes data for caffeine and theophylline, closely related xanthines that are both cytochrome P-450 (CYP) 1A2 substrates, in developing PBPK models for neonates and adults, and a stepwise approach for modeling environmental toxicants in children is proposed.

Pharmacokinetics and Administration Regimens of Vancomycin in Neonates, Infants and Children

The monitoring of serum vancomycin concentrations may be useful in selected neonatal and paediatric patient populations, especially where large interpatient variability occurs and administration guidelines are not clearly established.

Prediction of drug clearance in children from adults: a comparison of several allometric methods.

  • I. Mahmood
  • Medicine
    British journal of clinical pharmacology
  • 2006
No single method is suitable for all drugs or for all age groups and a combination of approaches is suggested which may help in improving the prediction of clearance in children from adult data.

Physiological Modeling of Age-Specific Changes in the Pharmacokinetics of Organic Chemicals in Children

The PBPK model framework developed in this study should be useful for predicting the adult-children differences in internal dose of chemicals for risk assessment applications.

Prediction of in vivo drug clearance from in vitro data. II: Potential inter-ethnic differences

Only partial success in predicting ethnic differences in clearance indicates the need for larger and more reliable databases on relevant variables and in silico predictions might be used with more confidence to decrease theneed for repeating pharmacokinetic studies in different ethnic groups.

Effect of maturation on drug disposition in pediatric patients.

Maturational changes in the physiologic processes that govern drug disposition in pediatric patients are described, and evaluation of data from pediatric drug studies is discussed. Gastrointestinal

Phenotyping of drug metabolism in infants and children: potentials and problems.

  • A. Rane
  • Biology, Medicine
  • 1999
There is almost no information about the maturation of polymorphic traits during ontogenesis, which has therapeutic implications in pediatrics, first, because several drug substrates of the polymorphic enzymes also are used in infants and children, and second, because for many such drugs, the treatment results may not be monitored by objective param-eters.

Vancomycin Pharmacokinetics and Bayesian Estimation in Pediatric Patients

NonMEM population modeling revealed that a weight-adjusted two-compartments model provided a better fit than a comparable one-compartment model and Bayesian estimation with either a single midinterval or trough sample has the potential to provide accurate and precise predictions of vancomycin concentrations.