Pharmacokinetics of drugs: newborn perspective (original) (raw)
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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.
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.
Pharmaceutics, 2020
Drug dosing in neonates should be based on integrated knowledge concerning the disease to be treated, the physiological characteristics of the neonate, and the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. It is critically important that all sources of information be leveraged to optimize dose selection for neonates. Sources may include data from adult studies, pediatric studies, non-clinical (juvenile) animal models, in vitro studies, and in silico models. Depending on the drug development program, each of these modalities could be used to varying degrees and with varying levels of confidence to guide dosing. This paper aims to illustrate the variability between neonatal drug development programs for neonatal diseases that are similar to those seen in other populations (meropenem), neonatal diseases related but not similar to pediatric or adult populations (clopidogrel, thyroid hormone), and diseases unique to neonates (caffeine, surfactant). Extrapolation of eff...
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.
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.
Determinants of Drug Metabolism in Early Neonatal Life
Current Clinical Pharmacology, 2007
Clinical pharmacology intends to predict drug-specific effects and side effects based on pharmacokinetics (i.e. absorption, distribution, metabolism and elimination) and pharmacodynamics (i.e. dose/effect relationship). Developmental pharmacology focuses on the maturational aspects of these phenomena during perinatal life and later stages of infancy. In general, phenotypic variation in drug metabolism is based on constitutional, environmental and genetic factors but in early neonatal life, it mainly reflects ontogeny. Although the major site of drug metabolism is the liver, the gastrointestinal tract, blood cells and other organs like kidneys or lungs might also be involved in drug metabolism. Important alterations in hepatic drug metabolism occur in early neonatal life. These alterations are of relevance when agedependent aspects of pharmacokinetics,-dynamics or toxicology are considered. Age dependent maturation of various phase I and II processes will be illustrated based on recently reported observations on the in vivo disposition of various analgesics (paracetamol, tramadol) in human neonates and young infants. However, age only in part explains the interindividual variability observed. Therefore, concerted efforts should be developed to simultaneously assess the impact of age, environmental factors, comorbidity and polymorphisms in this specific population. The implementation of multivariable models like non-linear mixed effects (NONMEM) models hereby provide us with the tools to disentangle the impact of various co-variables in this specific population.