Neonatal clinical pharmacology

Abstract

Effective and safe drug administration in neonates should be based on integrated knowledge on the evolving physiological characteristics of the infant who will receive the drug, and the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. Consequently, clinical pharmacology in neonates is as dynamic and diverse as the neonates we admit to our units while covariates explaining the variability are at least as relevant as median estimates. The unique setting of neonatal clinical pharmacology will be highlighted based on the hazards of simple extrapolation of maturational drug clearance when only based on ‘adult’ metabolism (propofol, paracetamol). Secondly, maturational trends are not at the same pace for all maturational processes. This will be illustrated based on the differences between hepatic and renal maturation (tramadol, morphine, midazolam). Finally, pharmacogenetics should be tailored to neonates, not just mirror adult concepts. Because of this diversity, clinical research in the field of neonatal clinical pharmacology is urgently needed, and facilitated through PK/PD modeling. In addition, irrespective of already available data to guide pharmacotherapy, pharmacovigilance is needed to recognize specific side effects. Consequently, paediatric anesthesiologists should consider to contribute to improved pharmacotherapy through clinical trial design and collaboration, as well as reporting on adverse effects of specific drugs.

Pharmacokinetics in neonatal prescribing: evidence base, paradigms and the future

“…A diet based on infant formula rather than breast milk [14] and antenatal exposure to cigarette smoke [33] can increase the rate of CYP enzyme development. Further, the routes of metabolism seen in adults may not be mirrored in neonates due to the activity or inactivity of particular CYP enzymes [3], summarized in Table 1.…”

“…Genetic polymorphisms are well documented to result in drug metabolism variability in adults, and similar effects are expected in neonates although observations of these are currently limited [3,7]. The maturation of drug metabolism pathways can make it difficult to determine the effects of genetic polymorphisms.…”

“…However, human growth and development is not a linear process and such an approach is known to be problematic [3]. Size alone is not adequate for determining doses across the range of developmental processes that occur throughout childhood as it cannot fully explain clearance, even when considered with other variables such as age and renal function [4].…”

“…Clinically, the development of drug metabolizing enzymes is an important factor in determining drug selection. For example codeine is not commonly used in the first month of life as conversion to morphine via CYP2D6 is low, limiting effectiveness [3] while midazolam is cleared by CYP3A4 at a slower rate causing increased duration of sedation [28].…”

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“…Neonatologists often lack a real knowledge of the basic pharmacodynamic and pharmacokinetic properties of the drugs that they administer. Karel Allegaert from Leuven, Belgium, emphasized the unique features of neonatal pharmacology [13] in his presentation and discussed how pharmacokinetic modelling tools were helping to reverse this lack of knowledge. He mentioned the interplay between drugs used in neonatal medicine and the renal function of preterm infants [14] as well as stressing the importance of performing follow-up studies in order to exclude unanticipated long-term adverse effects [6,15].…”