Population pharmacokinetics and dose-response relationship of levetiracetam in adult patients with epilepsy

Rhee, Seunghyun; Shin, Jai Moo; Lee, Seung Hwan; Moon, Jangsup; Kim, Tae Joon; Jung, Ki Young; Park, Kyung‐Il; Jung, Keun Hwa; Yu, Kyung‐Sang; Jang, In Jin; Chu, Kon; Lee, Sang Kun

doi:10.1016/j.eplepsyres.2017.02.011

Cited by 32 publications

(39 citation statements)

References 17 publications

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“…A non-linear least-squares method was applied to estimate the pharmacokinetic parameters of levetiracetam using at least two drug plasma concentrations (one trough and one peak) and applying a one-compartment model with first-order absorption and elimination. This compartment model was herein chosen because it has been reported as the model that more accurately describes the pharmacokinetics of levetiracetam [ 38 , 45 , 46 , 47 ]. The apparent volume of distribution (Vd/F) expressed in L, oral clearance (CL/F) expressed in L/h, elimination constant rate (ke) expressed in h −1 , and elimination half-life expressed in h, were estimated.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic Monitoring of Levetiracetam in Portuguese Refractory Epileptic Patients: Effect of Gender, Weight and Concomitant Therapy

et al. 2020

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Levetiracetam is a second-generation antiepileptic drug, widely used in the treatment of focal and generalized epilepsy due to its pharmacokinetic and safety profiles. Its pharmacokinetic monitoring is ascribed as useful to personalize its dosing regimen. The aim of the present study was to describe, for the first time, the pharmacokinetics of levetiracetam in Portuguese refractory epileptic patients. Therefore, a retrospective study was carried out on 65 Portuguese refractory epileptic patients (pharmacokinetic study: 48; validation study: 17) admitted to the Refractory Epilepsy Centre of the Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal. The pharmacokinetic parameters of levetiracetam were estimated by applying a one-compartment model with first-order absorption and elimination analysis. Male patients showed higher distribution volume (Vd/F) and oral clearance (CL/F) than female patients (median Vd/F: 52.40 L in males and 38.60 L in females, p = 0.011; median CL/F: 4.71 L/h in males and 3.91 L/h in females, p = 0.028). Higher values of Vd/F (p = 0.026) and CL/F (p = 0.003) were also found in overweight patients relative to normal weight and obese patients. Carbamazepine was the co-administered antiepileptic drug that mostly affected the pharmacokinetics of levetiracetam, increasing both Vd/F (61.30 L with carbamazepine and 39.10 L without carbamazepine, p = 0.007) and CL/F (6.71 L/h with carbamazepine and 3.91 L/h without carbamazepine, p < 0.001). The pharmacokinetics of levetiracetam was affected by gender, body mass index, and co-administration of carbamazepine. This study highlights the impact of several factors on the CL/ and Vd/F of levetiracetam when administered to refractory epileptic patients. The importance of its pharmacokinetic monitoring in clinical pharmacy stands out, thereby enabling the optimization of antiepileptic drug therapy.

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Section: Methodsmentioning

confidence: 99%

Pharmacokinetic Monitoring of Levetiracetam in Portuguese Refractory Epileptic Patients: Effect of Gender, Weight and Concomitant Therapy

et al. 2020

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“…There was a wide variability in the relationship between trough LEV concentration and clinical outcomes of the adult patients with epilepsy (Lancelin et al, 2007). Similar to adult patients, there was no correlation between trough LEV concentration and its therapeutic response including seizure control and adverse effects, in the pediatric patients with epilepsy (Rhee et al, 2017). The results were also reported not to be affected by other characteristics such as type of the epilepsy seizure, other AEDs, gender or age of the patients.…”

Section: Discussionmentioning

confidence: 87%

“…Although there was no difference in LEV concentrations at these 5 time points for its effect on seizure frequency, the mean LEV C/D ratio at 1 hour following LEV ingestion in the patients with adverse effects was shown to be significantly higher than the patients without adverse effects. There are clinical studies indicating lack of a relationship between serum LEV concentrations and its effect on seizure frequency or its adverse effects (Lancelin et al, 2007;Rhee et al, 2017). There was a wide variability in the relationship between trough LEV concentration and clinical outcomes of the adult patients with epilepsy (Lancelin et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Despite LEV having favorable pharmacokinetics and tolerability characteristics, there are patients with poor therapeutic response with uncontrolled seizures or adverse effects (Bootsma et al, 2007;Lee et al, 2013;Rhee et al, 2017). According to the consensus proposal of ILAE commission on therapeutic strategies for drug resistant epilepsy, one case with LEV was shown as an example for the 'treatment failed' category (Kwan et al, 2010).…”

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confidence: 99%

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The effect of serum levetiracetam concentrations on therapeutic response and IL1-beta concentration in patients with epilepsy

et al. 2018

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Objective: Assessment of the relevance between serum drug concentration to its therapeutic response is a valid monitoring strategy for the clinical efficacy of antiepileptic drugs (AEDs). Levetiracetam (LEV) is a broad spectrum AED with a possible anti-inflammatory effect. We aimed to determine the relationship between LEV concentrations and its therapeutic response, and the effect of LEV on IL1-beta concentrations in patients with epilepsy. Methods: Patients on monotherapy (n=7) or polytherapy (n=15) with LEV for their seizures management were included. Blood samples of each patient were collected: just before LEV intake, 1 hour, 2 hours, 4 hours and 8 hours following the last dose. Serum LEV concentrations were measured by liquid chromatography mass spectrometry and IL1-beta concentrations by chemiluminescent immunometric assay. Concentration to dose (C/D) ratio values was used for analyses. LEV concentrations were compared between responders (≤1 seizure/month) and nonresponders (>1 seizure/month) and patients with or without adverse reactions. IL1-beta concentrations before and at 2 hours following LEV ingestion were compared in order to detect the effect of the increase in serum LEV concentration on IL1-beta. Results: Although there was no change in LEV (C/D) ratio or LEV maximum concentration (Cmax)/D ratio of the responders and non-responders, the C/D ratio following 1 hour of LEV intake (2.17±0.59 kg.day/L) and Cmax/D ratio (2.25±0.56 kg.day/L) in the patients with adverse effects was significantly higher than for the patients without adverse effects (1.09±0.12 kg.day/L and 1.49±0.14 kg.day/L respectively). A statistically significant decrease was found in the IL1-beta concentration to LEV (C/D) ratio with the increase in LEV concentration in patients on LEV monotherapy. Conclusion: The possible relationship between LEV Cmax and its therapeutic response or IL1beta concentrations may be an importance indication of LEV antiepileptic efficacy. Consequently, monitoring LEV Cmax values may enhance LEV adherence because patients would be less likely to develop adverse effects.

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“…The minimum therapeutic value targeted in this study (5 μg/mL) is the lower end of a commonly referenced therapeutic range that has been extrapolated from humans for use in veterinary species . Recent studies in humans have suggested a new target peak range of 12‐40 μg/mL and a trough range of 6‐20 μg/mL for optimum seizure control using LEV monotherapy . Though serum concentrations were not above 12 μg/mL for all cats in this study, it did exceed 5 μg/mL.…”

Section: Discussionmentioning

confidence: 64%

Serum levetiracetam concentrations after transdermal levetiracetam administration, 3 times daily, to healthy cats

Smith

Heller

Reif

et al. 2019

Veterinary Internal Medicne

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Background Repeated oral administration of antiepileptic drugs can be challenging for cat owners, resulting in reduced compliance, poor seizure control, and reduced quality of life for cats. Levetiracetam (LEV) has several properties that make it an appealing drug for transdermal application. Objectives The aims were to (1) determine if transdermal LEV, in a lipophilic, liposomic cream vehicle, resulted in serum concentrations above 5 μg/mL; (2) identify clinical adverse effects; and (3) evaluate the concentration of LEV in a lipophilic liposomic cream at set intervals. Animals Six healthy, client‐owned cats weighing ≤5 kg. Methods Prospective clinical trial. Transdermal LEV was applied to the inner pinna at a dosage of 60 mg/kg (400 mg/mL concentration) at home for 6 days. Day 7, cats were hospitalized for blood sample collection for LEV concentration at times 0 (before dose administration), 0.5, 1, 2, 3, and 4 hours after administration. Results Median (range) timed serum concentrations were 16.6 (8.6‐39.6) μg/mL, 16.1 (6.8‐34.4) μg/mL, 15.4 (10.1‐36.7) μg/mL, 17.4 (9.2‐32.7) μg/mL, 15.1 (8.3‐25.9) μg/mL, and 14.8 (11.9‐28.4) μg/mL, respectively. Adverse events were limited to sedation (1/6 cats) and pinna crusting (1/6 cats). The LEV, in the proposed vehicle, retained concentration above 95% at 400 mg/mL up to 5 weeks. Conclusions and Clinical Importance Thrice daily transdermal LEV resulted in median serum concentrations ≥5 μg/mL throughout the sampling period and clinical adverse events were minimal. Transdermal LEV can provide an alternative for cats resistant to administration of other forms of anticonvulsant medication.

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Population pharmacokinetics and dose-response relationship of levetiracetam in adult patients with epilepsy

Cited by 32 publications

References 17 publications

Pharmacokinetic Monitoring of Levetiracetam in Portuguese Refractory Epileptic Patients: Effect of Gender, Weight and Concomitant Therapy

Pharmacokinetic Monitoring of Levetiracetam in Portuguese Refractory Epileptic Patients: Effect of Gender, Weight and Concomitant Therapy

The effect of serum levetiracetam concentrations on therapeutic response and IL1-beta concentration in patients with epilepsy

Serum levetiracetam concentrations after transdermal levetiracetam administration, 3 times daily, to healthy cats

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