Educational paper: Do we need neonatal clinical pharmacologists?

Abstract

Effective and safe drug administration in young infants should be based on integrated knowledge concerning the evolving physiological characteristics of the infant who will receive the drug and the pharmacokinetic and pharmacodynamic characteristics of a given drug. Consequently, clinical pharmacology in neonates is as dynamic and diverse as the neonates we are entitled to take care of. Even more than median estimates, covariates of variability within the population are of clinical relevance. We aim to illustrate the complexity and the need for neonatal clinical pharmacology based on the gap between current and likely best clinical practice for two commonly administered compounds (aminoglycosides for infection and ibuprofen for patent ductus arteriosus) and one new compound (bevacizumab, to treat threshold retinopathy of prematurity). Progression has been made to render pharmacokinetic studies child size, e.g., low volume samples, optimal study design, and population pharmacokinetics. Challenges to further improve clinical pharmacology in neonates include, when appropriate, the validation of off-patent drug dosing regimens and of infant-tailored formulations. Knowledge integration, i.e., the use of available data to improve current drug use and to predict pharmacokinetics/pharmacodynamics for similar compounds is needed. Development of clinical research networks is helpful to achieve these goals.

Antimicrobial dosing in neonates

“…Infants are not just small children or even more small adults. Term and especially preterm neonates are a unique population; one could say that a neonate is a rapidly evolving biological system [14,15]. Growth, maturation, and specific pathophysiological characteristics (e.g.…”

“…body composition, protein binding capacity, renal function and structure) influence PK behavior of antibiotics (absorption, distribution, metabolism, elimination) and result in significant interindividual variability in drug exposure. Moreover, disease characteristics (sepsis, hemodynamic changes, renal impairment, perinatal asphyxia, intrauterine growth restriction), comedications, other treatment modalities like extracorporeal membrane oxygenation, therapeutic hypothermia, and other covariates including pharmacogenetics have a great impact on PK and pharmacodynamic (PD) behaviors of many drugs in neonates, further aggravating the variability within the specific population [14,15]. Such scientific concerns along with regulatory and ethical issues make clinical trials in neonates difficult to perform and study design challenging.…”

Neonates and medicines: a roadmap to further improve neonatal pharmaceutical care

“…PK (e.g., absorption, distribution, and elimination, through either metabolism or primary renal elimination) hereby estimates the relationship between a drug concentration at a specific site (e.g., plasma or cerebrospinal fluid) and time (Bwhat the body does to the drug^). PD describes the concentration effect relationship (Bwhat the drug does to the body^) [1]. Requiring specific consideration is that these maturational changes in physiology are most prominent in early infancy and are highly variable between preterm and term neonates.…”

“…The study group hereby evaluated the impact of a structured intervention (protocol standardization, education) on the number of errors and documented significant improvements in both calculation errors (1.35 to 0 %) and accuracy (54.7 and 38.3 % to 38.3 and 14.6 % in NICU and HP, respectively) [6]. This intervention paper follows on a previous paper which described a pre-intervention phase [5] and illustrates the potential impact of preventive strategies on the extent of drug errors.Development of a roadmap to improve neonatal pharmaceutical care should aim to improve the knowledge on clinical pharmacology, clinical pharmacy, and approaches to improve the knowledge and use of neonatal pharmacovigilance initiatives [1]. Another keystone component of such a roadmap should focus on neonatal drug development, i.e., drug development driven by neonatal pathophysiology (Fig.…”

“…Development of a roadmap to improve neonatal pharmaceutical care should aim to improve the knowledge on clinical pharmacology, clinical pharmacy, and approaches to improve the knowledge and use of neonatal pharmacovigilance initiatives [1]. Another keystone component of such a roadmap should focus on neonatal drug development, i.e., drug development driven by neonatal pathophysiology (Fig.…”