A Multicenter Randomized Controlled Trial on the Clinical Impact of Therapeutic Drug Monitoring in Patients with Newly Diagnosed Epilepsy

Abstract

Summary:Purpose: To assess the clinical impact of monitoring serum concentrations of antiepileptic drugs (AEDs) in patients with newly diagnosed epilepsy.Methods: One-hundred eighty patients with partial or idiopathic generalized nonabsence epilepsy, aged 6 to 65 years, requiring initiation of treatment with carbamazepine (CBZ), valproate (VPA), phenytoin (PHT), phenobarbital (PB), or primidone (PRM) were randomly allocated to two groups according to an open, prospective parallel-group design. In one group, dosage was adjusted to achieve serum AED concentration within a target range (10-20 p,g/ml for PHT, 1 5 4 0 pg/ml for PB, 4-11 pg/ml for CBZ, and 40-100 pg/ml for VPA), whereas in the other group, dosage was adjusted on clinical grounds. Patients were followed up for 24 months or until a change in therapeutic strategy was clinically indicated.Results: Baseline characteristics did not differ between the two groups. Most patients with partial epilepsy were treated with CBZ, whereas generalized epilepsies were most commonly managed with PB or VPA. PHT was used only in a small minority of patients. A total of I16 patients completed 2-year follow-up, and there were no differences in exit rate from any cause between the monitored group and the control group. The proportion of assessable patients with mean serum drug levels outside the target range (mostly below range) during the first 6 months of the study was 8% in the monitored group compared with 25% in the control group (p < 0.01). There were no significant differences between the monitored group and the control group with respect to patients achieving 12-month remission (60% vs. 61 %), patients remaining seizure free since initiation of treatment (38% vs. 41%), and time to first seizure or 12-month remission. Frequency of adverse effects was almost identical in the two groups.Conclusions: Only a small minority of patients were treated with PHT, the drug for which serum concentration measurements are most likely to be useful. With the AEDs most commonly used in this study, early implementation of serum AED level monitoring did not improve overall therapeutic outcome, and the majority of patients could be satisfactorily treated by adjusting dose on clinical grounds. Monitoring the serum levels of these drugs in selected patients and in special situations is likely to he more rewarding than routine measurements in a large clinic population.

The Laboratory Should Actively be Involved in the Therapeutic Drug Monitoring (TDM) Process

“…Phenytoin is not the most common AED in clinical management of epilepsy but is frequently ordered due to its nonlinear pharmacokinetics which makes it very difficult to estimate blood concentration. 5 Our results were similar to a previuos study from two university hospitals that reported phenytoin test results with highest subtherapeutic percentage. 8 The distribution of parameters in total AED TDM requests, differs in literature.…”

“…5,6 The utility of TDM has not been clearly established. TDM is costly and pressure continues within the healthcare system of many countries to provide services at the lowest possible cost.…”

Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications

“…Only two randomized, controlled studies of AED TDM have been conducted and neither showed clinical benefits. Both studies did show, however, that physicians often apply information from TDM incorrectly, diminishing the clinical impact of TDM [3,4]. Better education of medical practitioners on TDM is a priority for the future.…”

Therapeutic Drug Monitoring of Antiepileptic Medications

“…First-generation AEMs generally have significant inter-individual variability in their pharmacokinetics (absorption, distribution, metabolism, and excretion) and low therapeutic indices. Two randomized, controlled studies of AEM TDM showed that practitioners often apply information from TDM incorrectly (Fröscher et al, 1981;Januzzi et al, 2000). Consequently, improved education of medical practitioners on TDM is important for the future.…”