Prediction of Clearance in Neonates and Infants ( 3 Months of Age) for Drugs That Are Glucuronidated: A Comparative Study Between Allometric Scaling and Physiologically Based Pharmacokinetic Modeling (original) (raw)
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The Journal of Clinical Pharmacology, 2016
The objective of this study was to evaluate the predictive performances of allometric models and a physiologically based pharmacokinetic model (PBPK) to predict clearance of glucuronidated drugs in neonates (ࣘ 3 months of age). From the literature, clearance values for 9 drugs (glucuronidated) for neonates and adults were obtained. Three allometric models were used to predict clearances of these glucuronidated drugs. A PBPK model was developed using the physicochemical, biopharmaceutical, and metabolic properties together with known pediatric physiology and enzymatic ontogeny. The model was first developed for adult subjects and then verified using external data and then applied to simulations in neonates. The predictive performances of allometric and PBPK models were evaluated by comparing the predicted values of clearance with the observed clearance values in the neonates. For 9 drugs, there were 13 age groups (preterm and term neonates) for which prediction error in mean clearance values within 0.5-to 1.5-fold was observed in 10 and 11 age groups by 2 allometric models and a PBPK model, respectively. The proposed allometric methods can predict mean clearances of glucuronidated drugs in preterm and term neonates (ࣘ 3 months of age) with reasonable accuracy (within 0.5-to 1.5-fold or 50% error) and are of practical value during neonatal drug development. The predicted mean clearance values of glucuronidated drugs in neonates ࣘ 3 months of age by 2 allometric methods were comparable with the PBPK model.
Pharmacokinetics of drugs: newborn perspective
Pediatric Medicine
Safe and effective drug administration are pivotal goals of neonatal pharmacokinetics. Integrated knowledge of evolving pharmacokinetic principles, physiological characteristics, and maturational differences in term and preterm neonates is essential for effective, safe, and predictable drug response. Instances like 'Grey baby syndrome' chloramphenicol toxicity due to impaired glucuronidation and encephalopathy after hexachlorophene bath (to treat impetigo) due to increased transdermal absorption and impaired clearance have raised questions about our understanding of the complex interplay of factors in neonatal drug pharmacokinetics. This underscores the significance of knowledge and understanding of pharmacokinetic principles and the need for a population-specific approach. One must consider the complex relationship between multiple factors and differences among preterm neonates and young infants in terms of drug disposition before prescribing medications to the neonatal population. Consequently, clinical pharmacokinetics in neonates is as dynamic and diverse as the population. This review describes these dynamic changes leading to variable therapeutic efficacy or inadvertent exposures that can occur through the neonatal period. Therapeutic drug monitoring must be utilized to individualize the dosing of drugs in this vulnerable population whenever feasible. The objective of the review is to elucidate the principles of neonatal pharmacokinetics and the contribution of development, maturation, neonatal physiologic and pathologic states that govern neonatal pharmacokinetics so that drugs can be used efficaciously.
A pharmacokinetic standard for babies and adults
Journal of Pharmaceutical Sciences, 2013
The pharmacokinetic behavior of medicines used in humans follows largely predictable patterns across the human age range from premature babies to elderly adults. Most of the differences associated with age are in fact due to differences in size. Additional considerations are required to describe the processes of maturation of clearance processes and postnatal changes in body composition. Application of standard approaches to reporting pharmacokinetic parameters is essential for comparative human pharmacokinetic studies from babies to adults. A standardized comparison of pharmacokinetic parameters obtained in children and adults is shown for 46 drugs. Appropriate size scaling shows that children (over 2 years old) are similar to adults. Maturation changes are generally completed within the first 2 years of postnatal life; consequently babies may be considered as immature children, whereas children are just small adults.
Size does Matter : drug glucuronidation in Children
2007
The maturation of UGT2B7-mediated drug glucuronidation was studied in preterm and term neonates up to infants of three years of age using a population approach. A pharmacokinetic model was developed for morphine, which was used as a paradigm compound. In this model, the maturation of morphine glucuronidation is described by a bodyweight-based exponential relationship with an exponent of 1.44. The model-derived dosing algorithm was evaluated prospectively in a clinical trial and it was shown that this dosing algorithm may reduce overdosing of neonates and exposure to ineffective doses in older infants. Additionally, it was found that the bodyweight-based exponential relationship that describes the maturation of morphine glucuronidation can be directly applied to the maturation of zidovudine, which is also a UGT2B7 substrate. This expedites the development of paediatric pharmacokinetic models and evidence-based paediatric drug dosing algorithms. Based on a study using physiologically-...
Pharmacokinetics in the newborn
Advanced Drug Delivery Reviews, 2003
In addition to differences in the pharmacodynamic response in the infant, the dose and the pharmacokinetic processes acting upon that dose principally determine the efficacy and / or safety of a therapeutic or inadvertent exposure. At a given dose, significant differences in therapeutic efficacy and toxicant susceptibility exist between the newborn and adult. Immature pharmacokinetic processes in the newborn predominantly explain such differences. With infant development, the physiological and biochemical processes that govern absorption, distribution, metabolism, and excretion undergo significant growth and maturational changes. Therefore, any assessment of the safety associated with an exposure must consider the impact of these maturational changes on drug pharmacokinetics and response in the developing infant. This paper reviews the current data concerning the growth and maturation of the physiological and biochemical factors governing absorption, distribution, metabolism, and excretion. The review also provides some insight into how these developmental changes alter the efficiency of pharmacokinetics in the infant. Such information may help clarify why dynamic changes in therapeutic efficacy and toxicant susceptibility occur through infancy.
Clinical Pharmacology & Therapeutics, 2018
The objective of this study was to evaluate the predictive performance of population models to predict renal clearance in newborns and infants. Pharmacokinetic (PK) data from eight drugs in 788 newborns and infants were used to evaluate the predictive performance of the population models based on postmenstrual age (PMA), postnatal age, gestational age, and body weight. For the PMA model, the average fold error for clearance (CL) predicted /CL observed was within a twofold range for each drug in all subgroups. For drugs with > 90% renal elimination, the prediction bias ranged from 0.7−1.3. For drugs with 60-80% renal elimination, the prediction bias ranged 0.6-2.0. Our results suggest that PMA-based sigmoidal maximum effect (E max) 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.
Overview of Clinical Pharmacokinetics in Pediatrics: Possible Implications in Therapy
Biomedical & Pharmacology Journal, 2014
Rapid age-related changes in anatomic and physiologic parameters which may profoundly affect pharmacokinetic variables are characteristics of the first post-natal year and continue thereafter in childhood but to a lesser extent. Allometric methods mostly employed in dosage computation in pediatric age group which regrettably consider children as small adults; should be discarded in favour of the physiologically based pharmacokinetic approach considered far more ideal. Delayed gastric emptying resulting from prolongation in time required to achieve maximal plasma concentration (Tmax) occurs commonly in neonates and infants. Developmental changes that occur in body composition and protein binding are very crucial determinants of drug distribution in the pediatric age group. The pharmacokinetics, clinical efficacy and safety profile of administered drugs in children can be profoundly influenced by the developmental expression profile for the enzymes that support phases 1 and 2 metabolism. The lower rate of drug clearance due to impaired renal blood flow in preterm newborns as compared to normal ones necessitates the need for less frequent dosing interval and lower doses for drugs administered during the neonatal period. In conclusion, the outcome of this review emphasizes the need for understanding changes in developmental pharmacology amongst clinicians, particularly age-related variations in pharmacokinetic processes with obvious implications in enhancing clinical response and minimizing adverse effects.
Clinical Pharmacokinetics, 2019
Background Preterm neonates are usually not part of a traditional drug development programme, however they are frequently administered medicines. Developing modelling and simulation tools, such as physiologically based pharmacokinetic (PBPK) models that incorporate developmental physiology and maturation of drug metabolism, can be used to predict drug exposure in this group of patients, and may help to optimize drug dose adjustment. Objective The aim of this study was to assess and verify the predictability of a preterm PBPK model using compounds that undergo diverse renal and/or hepatic clearance based on the knowledge of their disposition in adults. Methods A PBPK model was developed in the Simcyp Simulator V17 to predict the pharmacokinetics (PK) of drugs in preterm neonates. Drug parameters for alfentanil, midazolam, caffeine, ibuprofen, gentamicin and vancomycin were collated from the literature. Predicted PK parameters and profiles were compared against the observed data. Results The preterm PBPK model predicted the PK changes of the six compounds using ontogeny functions for cytochrome P450 (CYP) 1A2, CYP2C9 and CYP3A4 after oral and intravenous administrations. For gentamicin and vancomycin, the maturation of renal function was able to predict the exposure of these two compounds after intravenous administration. All PK parameter predictions were within a twofold error criteria. Conclusion While the developed preterm model for the prediction of PK behaviour in preterm patients is not intended to replace clinical studies, it can potentially help with deciding on first-time dosing in this population and study design in the absence of clinical data.