Treating disorders of the neonatal central nervous system: pharmacokinetic and pharmacodynamic considerations with a focus on antiepileptics

Abstract

A major consideration in the treatment of neonatal disorders is that the selected drug, dose and dosage frequency is safe, effective and appropriate for the intended patient population. Thus, a thorough knowledge of the pharmacokinetics and pharmacodynamics of the chosen drug within the patient population is essential. In paediatric and neonatal populations two additional challenges can often complicate drug treatment -the inherently greater physiological variability, and a lack of robust clinical evidence of therapeutic range. There has traditionally been an overreliance in paediatric medicine on extrapolating doses from adult values by adjusting for bodyweight or body surface area, but many other sources of variability exist which complicate the choice of dose in neonates. The lack of reliable drug dosage data in neonates has been highlighted by regulatory authorities, as only~50% of the most commonly used paediatric medicines have been examined in a paediatric population. Moreover, there is a paucity of information on the pharmacokinetic parameters which affect drug concentrations in different body tissues, and pharmacodynamic responses to drugs in the neonate. Thus, in the present review, we draw attention to the main pharmacokinetic factors that influence the unbound brain concentration of neuroactive drugs. Moreover, the pharmacodynamic differences between neonates and adults that affect the activity of centrally-acting therapeutic agents are briefly examined, with a particular emphasis on antiepileptic drugs. Neonatal drug treatmentsSafe, effective dosing regimens have not been elucidated for the majority of neonatal drug treatments, with up to 90% of critically ill infants receiving unlicensed (drugs which do not hold a marketing authorization) or off-label (therapeutic agents that are being used outside of the terms of their licence) drugs [1,2]. It is difficult for clinicians to choose a safe, effective dose for unlicensed therapeutic agents and off-label drugs as the doses of these drugs are often decided based on previous experience rather than clinical trial data [3,4]. The choice of dose is further complicated by the greater degree of pharmacokinetic and pharmacodynamic variability in neonates [5]. The central nervous system (CNS) undergoes significant changes as the neonate matures, culminating in major variability in neuroactive drug disposition and action [6]. However, robust clinical data on the pharmacokinetics and pharmacodynamics of centrally acting drugs in both term and preterm neonates is often sparse, which is a challenge when treating disorders of the neonatal CNS [7]. The key aims of the current review are to highlight the main British Journal of Clinical Pharmacology

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