Clinical Pharmacokinetics of Antiepileptic Drugs in Paediatric Patients

Abstract

This article reviews 119 papers published since 1964 on the pharmacokinetics of phenobarbital, primidone, valproic acid, ethosuximide and mesuximide (methsuximide) in paediatric patients. Particular attention has been paid to the role of age in determining the variability of pharmacokinetic parameters, but the effect of other factors, such as different formulations and routes of administration, concomitant treatments, gender and pathological conditions other than epilepsy, have also been considered. Mean phenobarbital terminal half-life (t1/2z) is very long in neonates (45 to 409 hours) and decreases with age. Therefore, a low dose per kilogram (dose/kg) is recommended during the neonatal period. The dose requirement decreases with increasing age, especially in children also taking valproic acid, which inhibits phenobarbital metabolism. Primidone is metabolised to phenobarbital and phenylethylmalonilamide; the metabolic conversion rate is increased by enzyme-inducing drugs and inversely correlated with age, being virtually absent in neonates. Valproic acid is extensively bound to plasma proteins, but there is a high interindividual and intraindividual diurnal variability in the binding, which depends on the concentration of binding proteins (i.e. albumin) and binding modulators (e.g. free fatty acids) but not on age (at least in those patients aged between 3 months and 65 years). The clearance (CL/F) of valproic acid positively correlates with the unbound concentrations and is strongly age-dependent, being low in neonates and high at the end of the first postnatal month, and progressively decreasing from 2 months to 14 years. The combination of these factors leads to a very poor correlation between plasma concentrations and dose/kg (C/D) and between plasma concentrations of total valproic acid and efficacy. Children also taking enzyme-inducing antiepileptic drugs require a larger valproic acid dose/kg, whereas the coadministration of aspirin (acetylsalicylic acid) may decrease the clearance of unbound drug (CLu/F), and thus require a decrease in the daily dose of valproic acid. Ethosuximide is well absorbed, minimally protein bound and slowly eliminated. Lower C/D ratios are reported in children younger than 10 years old than in older children and in individuals also taking enzyme-inducing drugs (i.e. primidone). According to the only available paper on mesuximide in paediatric patients, the C/D ratio is less sensitive to both age and associated therapy.

Molecular and Therapeutic Potential and Toxicity of Valproic Acid

“…Aspirin, caffeine, and other salicylates can inhibit the clearance of valproic acid and increasing its serum-free concentration up to 4 times [109], this may help to reduce the daily dose of VPA but also increase its cytotoxicity when administered with aspirin [110]. Imipenem, Meropenem, Doripenem, Ertapenem, and Panipenem antibiotics decrease the serum concentrations of valproic acid likely by increasing the metabolism of VPA to VPA glucuronide as well as the renal clearance of VPA glucuronide and by inhibiting the intestinal absorption of VPA [111, 112].…”

Association between Prenatal Tobacco Exposure and Outcome of Neonates Born to Opioid-Maintained Mothers

“…Doses are based on body weight and NAS intensity according to the recommended standards [25] . The recommended protocols for the weaning of neonates from phenobarbital and morphine are based on their pharmacokinetic properties [27,28] .…”

On the Slow Diffusion of Point-of-Care Systems in Therapeutic Drug Monitoring

“…Advancement in PK–PD modeling allow for prediction of the average response profile to a given dosage and evaluation of a therapeutic margin; for identification of susceptibility factors that alter the therapeutic/toxic response, and for quantification of variability response, that can account also for random population variability (Lledó-García et al, 2009; Muller and Milton, 2012; Momper and Wagner, 2013). Establishment of proper PK–PD characterization during drug development generates detailed knowledge of PK–PD parameters that constitute solid reference for translation of dosage adjustment (or for subsequent clinical trials) in the targeted patient’s population and, more importantly, in subpopulations overly under-represented in drug development (Walson, 1998), like pregnancy (Ke et al, 2014), infants (Koren, 1997; Momper and Wagner, 2013), and elderlies (Battino et al, 1995; Perucca, 2005, 2006; Steinman et al, 2011; Etwel et al, 2014). …”