Review on the relevance of therapeutic drug monitoring of levetiracetam

Abstract

Therapeutic Drug Monitoring (TDM) of anti-epileptic drugs (AEDs) is not routinely performed, although this can guide the dosage regimen to achieve greater efficacy and safety. Levetiracetam (LEV) has been introduced as an AED with an almost perfect pharmacokinetic (PK) profile. Nonetheless, recent research challenges this statement and therefore we aimed to explore factors that modify LEV PK. Age and enzyme-inducing drugs (EIDs) appear to be major factors influencing the PK profile of LEV. Therefore, 30-50% lower dosages should be used in the elderly (> 65 years of age) and the dosing regimen should be guided by monitoring SDC (TDM). In contrast, higher LEV dosages are necessary in children aged between 2 months and 12 years (compared to adults) due to a 30-70% increase of LEV clearance (CL). Higher dosages are also required if a patient receives EIDs, again due to a higher CL of LEV (range 24-60%). This could also be true for pregnant women. LEV TDM is currently not common in the clinical setting due to the wide therapeutic range and the low prevalence of side-effects. However, LEV dose should on the one hand be increased in certain physiological situations (pregnancy, neonates) and patients on EIDs (especially carbamazepine). On the other hand, dose reductions are necessary when the LEV CL is impaired (elderly). Nevertheless, current data to support regular LEV TDM are lacking. Prospective research is needed to explore the importance of LEV TDM in elected patient groups; i.e. neonates, elderly, patients on EIDs and pregnant women.

Levetiracetam Therapeutic Drug Monitoring in a Large Cohort of Korean Epileptic Patients

“…Compared to first-generation AEDs, LEV TDM is limited in study, with a lack of large-scale clinical studies [ 19 ]. Previous studies of LEV TDM were based on European populations, with only three studies in Asian populations and no studies in a Korean population [ 16 , 23 , 24 ].…”

“…On the contrary, the half-life was longer and clearance rates were lower in elderly patients, compared to those in young adults and children [ 5 , 18 ]. In patients with renal impairment, LEV clearance was decreased in all ages [ 5 , 16 , 18 , 19 ].…”

“…Due to the pharmacokinetic characteristics of LEV, including a wide reference range and low side-effect rate, therapeutic drug monitoring (TDM) of second-generation AEDs is not performed routinely in clinical settings [ 19 ]. However, considering the inter-patient variability of (both older and newer) AEDs [ 20 ], TDM could serve as an individualized therapy especially in patients on AED poly-therapy, geriatric patients, and those with underlying renal diseases.…”

An elderly case of consciousness disturbance due to levetiracetam and low doses of carbamazepine

“…As LEV is primarily excreted via the kidneys, LEV clearance is limited in elderly people because of the decline in renal function, which is consistent with the in-crease in maximum concentration of LEV [5]. A drug monitoring method for LEV has not yet been established [6]. The Guideline of the American College of Physicians recommends to start LEV at 250 mg/day if the patient's eGFR is lower than 30 mL/min [7].…”

Approach to Optimize Pharmacological Treatment in Children

“…The fundamental point of these instruments is the application of drug monitoring strategies that would contribute on ensuring the safety of the patients and on improving treatment schemes to guarantee the use of drugs in safe and effective manner. 5 However, there are some important situations that must be taken into account in order to carry out therapeutic drug monitoring (TDM): When drugs with narrow therapeutic range are administered; due to lack of desired pharmacological response; for the presence of toxicity manifestations using therapeutic doses; to adjust doses to conditions that alter pharmacokinetics 6 ; to adjust doses in specific physiological conditions for example hepatic or renal dysfunction 7 ; when drugs are administered with a close dose–response relationship; and drugs that follow a nonlinear kinetics. This is important because the most effective therapeutic range of many drugs, far from unnecessarily high concentrations with potential risk of producing toxicity in those taking them, is still unknown.…”