Approaches to Dose Finding in Neonates, Illustrating the Variability between Neonatal Drug Development Programs (original) (raw)
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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.
Current pharmacotherapy in the newborn
Research and Reports in Neonatology, 2012
Several drugs are used in newborns in spite of the lack of specific clinical research in this particularly vulnerable population with particular needs. In the newborn, the individual response to a drug in terms of efficacy and safety is highly variable, and predicting drug dosing is complex since rapid physiological changes occurring during the perinatal and early postnatal periods affect the pharmacokinetic profile of many drugs. Neonatal disorders such as renal and hepatic diseases may also have significant implications for drug pharmacokinetics. Therefore, pharmacotherapy in the newborn brings difficulties in accurate drug delivery and carries a high risk of adverse drug reactions. In addition, the neonatal population, especially that treated in neonatal intensive care units, is highly exposed to the risk of medication errors, with potentially serious adverse events. This paper reviews some current issues related to neonatal pharmacotherapy that are of paramount importance for the clinician. In particular, the peculiar pharmacokinetics of drugs during the neonatal period and its clinical implications are discussed. The use of therapeutic drug monitoring to individualize drug dosage and to optimize pharmacotherapy is also described. Finally, the relevant issue of medication errors in neonatology is examined in order to highlight their main causes and key strategies in preventing these type of errors. In the future, pharmacometabolomics and other "omic" sciences could play an important role in designing personalized neonatal health care.
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.
Standard dose development for medications commonly used in the neonatal intensive care unit
The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG, 2014
To establish standardized, rounded doses of medications for neonates in the neonatal intensive care unit (NICU) through a multi-institutional peer-reviewed process. Pediatric faculty and pediatric pharmacy residents from the Ernest Mario School of Pharmacy (Piscataway, NJ) conducted a systematic review of rounded, weight-based medication information for neonatal patients from September 2010 to April 2011. After initial review, an expanded workgroup of expert neonatal pharmacy clinicians from academic institutions throughout the United States were invited to conduct a final review. The workgroup identified 74 medications or indications in the NICU. Recommended standardized doses were established for discrete weight categories at workgroup consensus web meetings conducted from June to December 2011. Workgroup recommendations were cross-referenced with published neonatal pharmacology resources. Consensus was obtained when references provided insufficient information on medication infor...
International Journal of Molecular Sciences
Therapeutic drug monitoring (TDM) should be adopted in all neonatal intensive care units (NICUs), where the most preterm and fragile babies are hospitalized and treated with many drugs, considering that organs and metabolic pathways undergo deep and progressive maturation processes after birth. Different developmental changes are involved in interindividual variability in response to drugs. A crucial point of TDM is the choice of the bioanalytical method and of the sample to use. TDM in neonates is primarily used for antibiotics, antifungals, and antiepileptic drugs in clinical practice. TDM appears to be particularly promising in specific populations: neonates who undergo therapeutic hypothermia or extracorporeal life support, preterm infants, infants who need a tailored dose of anticancer drugs. This review provides an overview of the latest advances in this field, showing options for a personalized therapy in newborns and infants.
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.
Development of Best Evidence Dosing Recommendations for Term and Preterm Neonates (NeoDose Project)
Neonatology
Many drugs are used off-label in neonates which leads to large variation in prescribed drugs and dosages in neonatal intensive care units (NICUs). The NeoDose project aimed to develop best evidence dosing recommendations (DRs) for term and preterm neonates using a three-step approach: 1) drug selection, 2) establishing consensus-based DRs, and 3) establishing best evidence DRs. Methods: The selection of drugs was based on frequency of prescribing, availability of a neonatal DR in the Dutch Pediatric Formulary, and the labeling status. Clinical need, pharmacological diversity, and Working Group Neonatal Pharmacology (WGNP) preferences were also taken into account, using a consensusbased approach. For the second step, we requested local dosing protocols from all ten Dutch NICUs and established consensus-based DRs within the WGNP, consisting of neonatologists, clinical pharmacologists, hospital pharmacists, and researchers. In the third step, the consensus-based DRs were compared with the available literature, using standardized PubMed searches. Results: Fourteen drugs were selected for which the local dosing protocols were collected. These protocols differed mostly in total daily dose, dosing frequency, and/or route of administration. Strikingly, almost none of the dosing protocols of these 14 drugs distinguished between preterm and term neonates. The working group established consensus-based DRs, which after literature review needed modification in 56%, mainly in terms of a dose
Expert Opinion on Drug Metabolism & Toxicology, 2021
Introduction:Pediatric patients, especially neonates and infants, are more susceptible to adverse drug events as compared to adults. In particular, immature small molecule drug metabolism and excretion can result in higher incidences of pediatric toxicity than adults if the pediatric dose is not adjusted.Area covered:We reviewed the top 29 small molecule drugs prescribed in neonatal and pediatric intensive care units and compiled the mechanisms of their metabolism and excretion. The ontogeny of Phase I and II drug metabolizing enzymes and transporters (DMETs), particularly relevant to these drugs, are summarized. The potential effects of DMET ontogeny on the metabolism and excretion of the top pediatric drugs were predicted. The current regulatory requirements and recommendations regarding safe and effective use of drugs in children are discussed. A few representative examples of the use of ontogeny-informed physiologically-based pharmacokinetic (PBPK) models are highlighted.Expert opinion:Empirical prediction of pediatric drug dosing based on body weight or body-surface area from the adult parameters can be inaccurate because DMETs are not mature in children and the age-dependent maturation of these proteins is different. Ontogeny-informed-PBPK modeling provides a better alternative to predict the pharmacokinetics of drugs in children.