Lamotrigine and therapeutic drug monitoring: retrospective survey following the introduction of a routine service

Abstract

Aims To review (retrospectively) the relationships between lamotrigine (LTG) dosage and plasma concentrations based on data generated in a routine therapeutic drug monitoring laboratory from a heterogeneous sample of patients with epilepsy. To distinguish patients taking concomitant anti-epileptic therapy which induced or inhibited drug metabolising enzymes, or a combination of both, together with LTG. To survey medical staff who use a routine LTG assay service with a view to establishing the utility of higher plasma LTG concentrations than those used in early clinical trials. Methods All patient assays for LTG received over a 12 month period (339 requests from 149 patients) were reviewed and relationships between dosage and concentration calculated and grouped according to concomitant antiepileptic drug therapy. The doctors requesting the tests were surveyed by questionnaire (n=40 of 67 responded). They were asked for details about the patient's seizure control, rationale used for LTG dosage adjustment and their acceptance of the proposed 'therapeutic range' adopted by the laboratory of 3-14 mg l −1 .Results Linear relationships were demonstrated between LTG dosage and concentration for the 3 treatment groups (LTG plus valproic acid (VPA), LTG plus enzyme inducing antiepileptic drugs, and LTG plus VPA and inducers), however, there were significant differences between groups ( P<0.001) with a 4.4 fold difference in dosage5concentration ratios between the LTG plus VPA group and the LTG plus inducers group. The questionnaire showed that the therapeutic range was well accepted by 88% of responders, none of whom considered this higher range to be wrong. Conclusions Metabolic inhibition by VPA was shown to have a marked effect on LTG kinetics, suggesting either a significant LTG dosage reduction is required if plasma LTG concentrations are elevated, or alternatively, higher plasma LTG concentrations could be attained from lower dosages. The higher therapeutic range adopted by the laboratory (3-14 mg l −1 ) was widely accepted and increasingly applied in clinical practice in the management of patients with epilepsy.

Population pharmacokinetics of lamotrigine in Chinese children with epilepsy

“…Despite LTG's wide clinical use, standard npg dosage regimens continue to be used even though they may often be suboptimal because of the high variability found in CL values in the target population [7,10,[13][14][15][16][17][18] . This observation, together with previous studies that have established definable relationships between LTG blood concentrations and therapeutic and toxic effects [19][20][21] , justify TDM as an indicator of drug exposure for the individualization of LTG doses [4][5] . In this sense, the availability of a population kinetic model able to predict LTG concentrations for different situations is essential for the correct selection of the dosage schedules based on a Bayesian approach.…”

“…Although therapeutic drug monitoring (TDM) of LTG was not initially recommended, LTG use has increased due to high interindividual variability and the effects of certain antiepileptic drugs often associated with LTG, such as inhibitors (eg, valproic acid) or inducers (eg, carbamazepine, phenobarbital, phenytoin and primidone) [4,5] .…”

Comparison of Dissolution Profiles and Serum Concentrations of Two Lamotrigine Tablet Formulations

“…However, the majority of lamotrigine plasma concentrations (six of seven) in patients receiving formulation B were in the range of 3 to 14 mg/mL, which has previously been suggested as the therapeutic range. [26,27] No dose-dependent adverse effects appeared in the patients, and all patients were seizure free. No statistically significant differences were found between dose-normalized concentrations of these two formulations (figure 3b).…”

Therapeutic Drug Monitoring of Antiepileptic Medications

“…The clearance of lamotrigine is higher in children (Bartoli et al, 1997;Perucca, 2006) and much higher (~300%) in pregnancy (Perucca, 2006). A reference range of 3-14 mg/L has been advocated for refractory epilepsy therapy (Morris et al, 1998). The risk of toxicity increases significantly when serum/plasma concentrations exceed 15 mg/L (Besag et al, 1998;Morris et al, 1998).…”

“…A reference range of 3-14 mg/L has been advocated for refractory epilepsy therapy (Morris et al, 1998). The risk of toxicity increases significantly when serum/plasma concentrations exceed 15 mg/L (Besag et al, 1998;Morris et al, 1998). TDM of lamotrigine is useful for several main reasons.…”