Therapeutic drug monitoring of levetiracetam in clinical practice

Background: The clinical utility of levetiracetam therapeutic drug monitoring (TDM) has not been established in clinical trials and clear guidelines for monitoring have yet to be defined. However, monitoring could be associated with an effective and well-tolerated therapy. At our hospital, we have incorporated its determination in routine clinical practice in patients with specific situations (epileptic status, refractory to treatment, no adherence, drug interactions, renal insufficiency, pregnancy, critical patients and adverse effects). The aim of this study was to evaluate the clinical utility of levetiracetam TDM in our routine practice. Methods: Retrospective observational study of 100% patients >16 years who met the previous requirements, between February 2012 and 2013.Variables analyzed: age, weight, height, kidney function, toxic habits, disease and evolution, concomitant medications, pregnancy, levetiracetam dose and trough plasma levels (Ctrough), reason for monitoring and clinical decision. Ctrough were measured by spectrophotometry in ARCHITECT-C8000 using the ARK Levetiracetam Assay (therapeutic range: 12-42 mcg/mL). Standard levetiracetam dose: 500-3000 mg/day. Statistical analysis was carried out on SPSS 19.0.A descriptive analysis of the variables was performed, using Spearman's correlation coefficient to analyze the association between quantitative variables. Results: Thirty-six patients were included (64% female), 56.8 ± 19.8 years, 65 ± 15 kg, levetiracetam dose 2068.9 ± 1072.3 mg/day (31.4 ± 16.8 mg kg-1 d-1), Ctrough = 23.4 ± 16.6 mcg/mL (55.7% of patients were within the established range, 32.7% were below and 11.5% above the therapeutic window). Three patients had impaired renal function (MDRD-4, 5.5, 34.5 and 46.5 mL/min per 1.73 m2) and the remaining 33 showed a MDRD-4, >70 mL/min per 1.73m2. Sixty-seven percent of patients were in anticonvulsivant polytherapy. The reasons for monitoring were: uncontrolled seizures, epileptic status, refractory epilepsy and adverse reactions. After monitoring, 33.8% of patients continued to be treated with the same dose, 26.7% required a reduced dose and 31.1% an increased dose. Levetiracetam was discontinued in 11.1% (3 because of delusional disorder and 1 because of inefficiency). Two patients in epileptic status after hypothermia required higher doses (5000 mg/d) than those recommended for better clinical management, although Ctrough were within range. The Spearman correlation coefficient between Ctrough and dose per day was r = 20.036 (P = 0.814) and r = 20.054 (P = 0.724) with body-weight-adjusted dose. Conclusions: The results of this study show that the TDM of levetiracetam was very useful for improved patient management and for treatment individualization. We also found a major interindividual variability between the dose and the obtained levetiracetam concentrations.