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

Maria D. Donovan, Geraldine B. Boylan, Deirdre M. Murray, John F. Cryan, Brendan T. Griffin

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 especially 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 this review we draw attention to the main pharmacokinetic factors that influence the unbound brain concentration of neuro-active drugs. Moreover, the pharmacodynamic differences between neonates and adults that affect activity of centrally-acting therapeutic agents are briefly examined, with a particular emphasis on anti-epileptic drugs. This article is protected by copyright. All rights reserved.