The therapeutics of novel antiepileptic drugs in paediatric patients in Malta

Abstract

Therapeutic drug monitoring is important for drugs that exhibit inter-individual variability in pharmacokinetics, and where drug-drug interactions, concurrent disease or age alters the kinetics of that drug. This is of particular importance in a chronic neurological condition such as epilepsy. In this study, the value of therapeutic drug monitoring for lamotrigine, a novel anti epileptic drug, was investigated in a group of paediatric patients. Plasma lamotrigine levels in 20 paediatric patients (mean ± S.D., age 8.85 ± 3.47 years and weight, 32.22 ± 20.81 kg) were measured using a novel validated high performance liquid chromatography (HPLC) technique that gave a retention time for lamotrigine and internal standard of 1.258 min and 2.30 min respectively. The method proved to be linear, precise and reproducible over the plasma concentration range of 0.08 - 20 mg/L. Plasma lamotrigine levels at steady state (mean ± S.D.) in epileptic patients were thus measured using this novel analysis. The levels thus estimated were 10.1 ± 4.95 mg/L in lamotrigine monotherapy group. In valproate co-medication group; carbamazepine co-medication group; clonazepam co-medication group; and valproate and clonazepam co-medication group, these were 8.11 ± 5.48, 1.89 ± 1.55, 8.33 ± 0.91 and 8.86 ± .98 mg/L respectively. A statistically significant difference (P < 0.05) was obtained between valproate co-medication group and carbamazepine co-medication group, between valproate co-medication group and clonazepam co-medication group, and between valproate co-medication group and valproate, clonazepam co-medication group. The pharmacokinetic parameters in the four groups (lamotrigine alone, valproate co-medication group, carbamazepine co-medication group, and clonazepam co-medication group) were estimated in this study using non-compartmental pharmacokinetic equations. The only significant difference (P < 0.05) was obtained between the four groups in the case of estimated volume of distribution, predicated minimum plasma concentration, estimated area under the curve and average plasma concentration. The data was also analysed using a modification of a one compartment first order absorption model with an Adapt® population simulation programme. Overall, the results thus obtained from the studies in this research, indicate the important need to streamline pharmacokinetic data for the use of anti epileptic drugs in children. Most physicians use ad hoc reasoning in the design of therapeutics and dosage regimens for these drugs in children. Our studies have shown that there are too many variables that could influence the plasma drug concentrations obtained. There is still a lack of satisfactory models and software packages that will allow accurate predictions of drug levels with these drugs in these populations.