Pharmacokinetics Of Levetiracetam Research Articles

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

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.

What Are the Predictors for Achieving Therapeutic Levetiracetam Serum Concentrations in Adult Neurological Patients?

Emerging studies suggest that levetiracetam pharmacokinetics can be difficult to predict in certain special patient populations, including the elderly, critically ill patients, and pregnant women. To determine clinical characteristics that predict the attainment of target serum concentrations in a heterogeneous group of patients prescribed levetiracetam. A retrospective observational study was conducted in adult neurological patients prescribed levetiracetam for the treatment or prophylaxis of seizures. Serum samples were collected after steady-state was reached, with a trough/steady-state serum concentration between 6 and 20 mg/L considered therapeutic. Logistic regression was used to identify significant predictors associated with the attainment of therapeutic concentrations. One-hundred thirty patients (63 male) were included. The median (interquartile ranges) serum trough/steady-state concentration (Cmin/ss) was 16.2 (9.8-26.1) mg/L. The dose-normalized median (interquartile range) Cmin/ss was 11.5 (7.0-16.5) mg/L. The coefficient of variation of Cmin/ss and dose-normalized Cmin/ss were 69.4% and 64.2%, respectively. A weak correlation was observed between levetiracetam Cmin/ss and patient age (r = 0.21; P = 0.020), creatinine clearance (r = -0.26; P = 0.004), and daily dose (r = 0.42; P < 0.001). Logistic regression analysis identified age and daily levetiracetam dose as significant factors predicting target Cmin/ss attainment. The influence of concomitant antiepileptic therapy was not determined. Age and daily dose were the most significant predictors of levetiracetam target-concentration attainment and should be considered in further investigations to develop a dosing algorithm for optimal levetiracetam therapy.

Pharmacokinetics of Subcutaneous Levetiracetam in Palliative Care Patients.

Background: Seizure control is challenging in the palliative care setting. Subcutaneous (SC) levetiracetam (LEV) is currently an off-label route of administration and effectiveness, tolerability, and pharmacokinetics studies for this route are scarce. Objectives: This prospective study aimed at evaluating effectiveness and tolerability of SC LEV as well as characterizing its pharmacokinetics. Subjects: Patients (n = 7) who attended the palliative care clinic between September 2018 and January 2019 with diagnosis of seizures, ≥18 years, and in need of SC route of administration were included in the study. Measurements: LEV plasma levels were determined using high-performance liquid chromatography and pharmacokinetic analysis were performed using Monolix 2018R2 (France). pH and osmolality of the three SC infusion solutions were also determined. Results: Seven patients took part in the study. Seizures were controlled in six out of seven patients with doses of 1000 and 3000 mg/day. Adverse effects were mild. pH and osmolality of the SC infusion solutions were within the accepted values reported in the literature. Mean plasma LEV concentrations were 14.4 mg/L (1000 mg/day) and 27.7 mg/L (2000 mg/day). The population clearance (2.5 L/h) and the elimination half-life (10.4 hours) were successfully estimated. Conclusions: Based on this data, SC LEV was effective and well tolerated. Pharmacokinetic parameters for the SC route were successfully determined.

Population Pharmacokinetics and Dosing Recommendations of Levetiracetam in Adult and Elderly Patients With Epilepsy

The objective was to develop and externally validate a population pharmacokinetic model of levetiracetam in adult and elderly patients with epilepsy, and to perform dosing simulations to propose individualized dosing regimens more likely to achieve therapeutic concentrations. This prospective study included 367 plasma samples from 107 patients receiving oral levetiracetam. Samples were analyzed by HPLC-UV. Pharmacokinetic data, as well as patient demographic, clinical characteristics, other drug therapy, and the use of innovator or generic products of levetiracetam, were collected. Population modeling was performed with NONMEM and included internal and external validations of the final model. Simulations were used to propose optimized dosing regimens. The pharmacokinetics of levetiracetam was described by a one-compartment model with first-order absorption and linear elimination. Body surface area had a significant effect on the apparent volume of distribution, as did creatinine clearance (CrCL) over the drug clearance (p < 0.01). The final model performed adequately during external validation testing. The final model showed a better predictive performance. Dosing simulations support 1000 mg 12-hourly dosing of levetiracetam for patients with CrCL ~60-75 mL/min with higher dose needed for higher values (1500 mg 12-hourly for CrCL ~93-111 mL/min). Dosing regimens should be personalized to the patient’s CrCL to maximize the likelihood of therapeutic concentrations.

Therapeutic drug monitoring of levetiracetam in newborns

Neonatal seizures in full-term and preterm infants represent a common neurological syndrome. Levetiracetam (LEV) is one of the new and widely prescribed second- or third-line antiepileptic drug for the treatment of seizures. Routine therapeutic drug monitoring of LEV was not recommended due to its almost ideal pharmacokinetic profile: linear pharmacokinetics, predictable dose-concentration relationship, wide therapeutic index, favourable safety profile, and unlikely clinically significant drug-drug pharmacokinetic interactions. In newborns, drug pharmacokinetics may be under the influence of maturation process. LEV pharmacokinetics in newborns appears to be age (gestational, postnatal) dependent and highly variable within the age ranges. These aspects make therapeutic drug monitoring a useful procedure for therapy optimization in this specific patient population. In population modeling based on therapeutic drug monitoring and nonlinear mixed effects models, covariates were found that should significantly affect the LEV clearance and volume of distribution in newborns — creatinine clearance and total body weight. Using of these regression equations can help to adjust the LEV doses without the patient's measured concentration data. But the significant magnitudes of the interindividual variability remaining in these final regression models justify the need for therapeutic drug monitoring and Bayesian adaptive control for personalization of LEV dosage regimens in neonates.

Levetiracetam optimal dose-finding as first-line treatment for neonatal seizures occurring in the context of hypoxic-ischaemic encephalopathy (LEVNEONAT-1): study protocol of a phase II trial

IntroductionTherapeutic schedules for treating neonatal seizures remain elusive. First-line treatment with phenobarbital is widely supported but without strong scientific evidence. Levetiracetam (LEV) is an emerging and promising antiepileptic drug (AED)....

Therapeutic levetiracetam monitoring during pregnancy: “mind the gap”

Background:Epilepsy is one of the most common chronic neurological conditions and its treatment during pregnancy is challenging. Levetiracetam (LEV) is an antiepileptic medication frequently used during pregnancy. Only a few small studies have been published on LEV monitoring during pregnancy, demonstrating decreased serum LEV levels during the first and second trimester; however, the most significant decrease was observed during the third trimester of pregnancy. In this study we aimed to evaluate LEV pharmacokinetics during different stages of pregnancy.Methods:We followed up and monitored serum levels of pregnant women treated with LEV for epilepsy.Results:Fifty-nine women with 66 pregnancies during the study period were included. The lowest raw LEV serum concentrations were observed during the first trimester. Compared with the pre-pregnancy period, raw serum concentration was lower by 5.76 mg/L [95% confidence interval (CI) (2.78, 8.75), p = 0.039] during the first trimester. Comparing the decrease in the first trimester with either the second or the third, no significant changes were observed (p = 0.945, p = 0.866). Compared with pre-pregnancy measurements, apparent clearance was increased by 71.08 L/day [95%CI (16.34, 125.83), p = 0.011] during the first trimester. About 30% of LEV serum levels during pregnancy were below the laboratory quoted reference range.Conclusions:Raw LEV serum levels tend to decrease during pregnancy, mainly during the first trimester contrary to previous reports. Monitoring of LEV serum levels is essential upon planning pregnancy and thereafter if pre-pregnancy LEV levels are to be maintained. However, more studies are needed to assess the correlation with clinical outcome.

Influence of Sex, Age, and Weight on Levetiracetam Pharmacokinetics.

Levetiracetam (LEV) is a second-generation antiepileptic drug extensively used in therapeutics. The aim of this study was to evaluate the influence that sex, age, and weight exert on LEV pharmacokinetics in clinical practice. We conducted a 6-year retrospective observational study. Patients were classified in subgroups according to sex, weight (normal range, overweight, and obese), and age (young adult: 16-30 years old, middle-aged adult: 31-50 years old, advanced adult: 51-64 years old, and elderly adult: ≥65 years old). We compared LEV apparent oral clearance (LEV CL/F) between the subgroups. A total of 238 LEV basal serum concentrations (LEV C0) corresponding to 156 patients were identified. Significant differences were observed in LEV CL/F between males and females when LEV CL/F was expressed as L/h [mean (SD): 4.79 (1.84) L/h in males versus 4.13 (1.64) L/h in females; P < 0.001]. These differences were not significant when LEV CL/F was normalized by weight [mean (SD): 60.64 (24.90) mL/h/kg in males versus 64.10 (28.87) mL/h/kg in females; n.s.]. Weight in females was 17% lower compared with males. A progressive reduction in LEV CL/F was observed with increasing age, in a proportion that was similar to the decline in renal function. The elderly patients presented 30% lower LEV CL/F (mL/h/kg) and 43% lower creatinine clearance (CCr) in comparison with adults. No statistically significant differences were observed in LEV CL/F calculated in L/h between weight subgroups. However, when LEV CL/F was expressed in mL/h/kg, a progressive reduction was observed [normal weight: 72.21 (28.97); overweight: 57.84 (25.38); obese: 49.45 (14.50); P < 0.001]. A significant and positive correlation between CCr and LEV CL/F was observed, confirming the important role of the renal function in LEV CL/F. The CCr increased in each sex group when weight increased; however, LEV CL/F (L/h) remained constant. Sex, age, and weight affect LEV pharmacokinetics, having an impact on the individual dosage regimen needed to achieve the therapeutic objective. Sex is a conditioning factor of LEV CL/F, although its influence is principally due to the weight. LEV CL/F decreases with advancing age, proportionally to the decline in renal function. It is confirmed that LEV dosage per body weight is not required, and prescribing higher doses of LEV in obese patients is not justified. These data suggest that routine LEV therapeutic drug monitoring in the elderly patients, patients with renal dysfunction, and obese patients is indicated.

Population pharmacokinetics of extended-release levetiracetam in epileptic dogs when administered alone, with phenobarbital or zonisamide.

BackgroundExtended‐release levetiracetam (LEV‐XR) has gained acceptance as an antiepileptic drug in dogs. No studies have evaluated its disposition in dogs with epilepsy.Hypothesis/ObjectivesTo evaluate the pharmacokinetics of LEV‐XR in epileptic dogs when administered alone or with phenobarbital or zonisamide.AnimalsEighteen client‐owned dogs on steady‐state maintenance treatment with LEV‐XR (Group L, n = 6), LEV‐XR and phenobarbital (Group LP, n = 6), or LEV‐XR and zonisamide (Group LZ, n = 6).MethodsPharmacokinetic study. Blood samples were collected at 0, 2, 4, 8, and 12 hours after LEV‐XR was administered with food. Plasma LEV concentrations were determined by high‐pressure liquid chromatography. A population pharmacokinetic approach and nonlinear mixed effects modeling were used to analyze the data.ResultsTreatment group accounted for most of the interindividual variation. The LP group had lower C MAX (13.38 μg/mL) compared to the L group (33.01 μg/mL) and LZ group (34.13 μg/mL), lower AUC (134.86 versus 352.95 and 452.76 hours·μg/mL, respectively), and higher CL/F (0.17 versus 0.08 and 0.07 L/kg/hr, respectively). The half‐life that defined the terminal slope of the plasma concentration versus time curve (~5 hours) was similar to values previously reported for healthy dogs.Conclusions and Clinical ImportanceConsiderable variation exists in the pharmacokinetics of LEV‐XR in dogs with epilepsy being treated with a common dose regimen. Concurrent administration of phenobarbital contributed significantly to the variation. Other factors evaluated, including co‐administration of zonisamide, were not shown to contribute to the variability. Drug monitoring may be beneficial to determine the most appropriate dose of LEV‐XR in individual dogs.

Therapeutic Drug Monitoring of Levetiracetam in Select Populations.

Levetiracetam (LEV) is a broad spectrum antiepileptic drug (AED) that has a more favorable side effect profile compared to older AEDs. Therapeutic drug monitoring (TDM) of LEV is generally unnecessary given its linear and predictable dose-serum concentration relationship, lack of drug-drug interactions, and broad therapeutic window. However, there is growing evidence showing that alteration of LEV pharmacokinetics (PK) may occur in special populations calling for the need for TDM. The purpose of this review was to summarize current literature surrounding altered LEV PK in special patient populations and determine if there is a need for levetiracetam TDM. A literature search of MEDLINE (1946 - November 2017) database of available evidence pertaining to altered LEV PK in humans was conducted. A total of 51 articles were found. There has not been a positive correlation shown between LEV levels and efficacy or toxicity. Variable LEV levels are reported in the literature with respect to adverse effects, seizures and efficacy occurring below, within and above the supposed reference ranges. Age is a major contributor to altered pharmacokinetics of LEV as shown in elderly patients and pediatric patients. Compared to adults, clearance of LEV has been shown to be decreased by almost half in patients over 65 and increased by 30-40% in pediatric patients. LEV pharmacokinetics varied further when data from its use in neonates was explored. LEV clearance declined in a linear fashion with declining estimates of creatinine clearance but was variable in patients with end-stage renal failure or those requiring renal replacement therapy. In patients who were critically ill, LEV clearance may be augmented and these patients may require higher doses of medications to maintain drug levels. In patients who are pregnant, LEV levels are likely to decline as pregnancy progresses due to changes in glomerular filtration rate and remain variable in the post-partum period. Routine TDM of levetiracetam is not recommended for all populations, however, it may be beneficial to maintain an individual therapeutic range in patients where the PK of LEV may be altered, such as in patients who are critically ill patients, pregnant, pediatrics or elderly.

Pharmacokinetics of rectal levetiracetam as add-on treatment in dogs affected by cluster seizures or status epilepticus

BackgroundLevetiracetam can be used for seizure control alone or in combination with other antiepileptic medications. A previous study achieved the minimum targeted serum drug concentration after rectal administration of levetiracetam in healthy dogs. The purpose of the present study was to determine the pharmacokinetics of rectal LEV in dogs presented for cluster seizures or status epilepticus and potentially in treatment with other anti-epileptic drugs. Furthermore, preliminary information on response to this treatment as add-on to the standard treatment protocol is reported.ResultsEight client-owned dogs were enrolled. Plasma levetiracetam concentrations (measured at 0, 30, 60, 90, 120, 180, 240, 360, 720, and 1440 min after drug administration) reached the minimum target concentration (5 μg/ml) at 30 min in all but one patient. At T1 (30 min) the mean concentration was 28.2 ± 15.5 μg/ml. Plasma concentrations remained above the targeted minimum concentration in all patients until 240 min and in 7/8 until 360 min. Six out of eight patients experienced no seizures in the 24-h period after hospitalization and were classified as “responders”.ConclusionsMinimum plasma levetiracetam concentration can be reached after rectal administration of 40 mg/kg in dogs affected by cluster seizures and status epilepticus and concurrently receiving other antiepileptic drugs. These preliminary results may encourage the evaluation of rectal levetiracetam as an additional treatment option for cluster seizures and status epilepticus in a larger number of dogs.

Population pharmacokinetics of levetiracetam in neonates with seizures.

This study developed a population pharmacokinetic (PK) model of levetiracetam (LEV) for treating neonatal seizures (NS) and determined the influence of clinically relevant covariates to explain the interindividual variability and residual error. Twenty newborns admitted to the Neonatal Intensive Care Unit at the Hospital Central "Dr. Ignacio Morones Prieto" were included. LEV doses were administered by intermittent infusion. Blood samples were drawn 3 times post-infusion. Levetiracetam was quantified by a chromatographic technique. NONMEM software was used to determine the population PK model of LEV in neonates and the influence of clinical covariates on drug disposition. The LEV PK in neonates is described by a one-compartment open model with first-order elimination. The influence of creatinine clearance (CRCL) and body weight (BW) on clearance (CL[L/h]=0.47*CRCL), as well as the volume of the distribution (Vd[L]=0.65*BW) of LEV, were confirmed, considering interindividual variabilities of 36% and 22%, respectively, and a residual error of 13%. Based on the PK of LEV in neonates and the influence of the final PK model, a priori dosing guidelines are proposed considering CRCL, BW and LEV plasma concentrations between 6 and 20mg/L for NS treatment.

Pharmacokinetic interactions and dosing rationale for antiepileptic drugs in adults and children.

Population pharmacokinetic modelling has been widely used across many therapeutic areas to identify sources of variability, which are incorporated into models as covariate factors. Despite numerous publications on pharmacokinetic drug-drug interactions (DDIs) between antiepileptic drugs (AEDs), such data are not used to support the dose rationale for polytherapy in the treatment of epileptic seizures. Here we assess the impact of DDIs on plasma concentrations and evaluate the need for AED dose adjustment. Models describing the pharmacokinetics of carbamazepine, clobazam, clonazepam, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, valproic acid and zonisamide in adult and paediatric patients were collected from the published literature and implemented in NONMEM v7.2. Taking current clinical practice into account, we explore simulation scenarios to characterize AED exposure in virtual patients receiving mono- and polytherapy. Steady-state, maximum and minimum concentrations were selected as parameters of interest for this analysis. Our simulations show that DDIs can cause major changes in AED concentrations both in adults and children. When more than one AED is used, even larger changes are observed in the concentrations of the primary drug, leading to significant differences in steady-state concentration between mono- and polytherapy for most AEDs. These results suggest that currently recommended dosing algorithms and titration procedures do not ensure attainment of appropriate therapeutic concentrations. The effect of DDIs on AED exposure cannot be overlooked. Clinical guidelines must consider such covariate effects and ensure appropriate dosing recommendations for adult and paediatric patients who require combination therapy.

A Review on Pharmacokinetics of Levetiracetam in Neonates.

Neonatal seizures are the most common clinical manifestation of Central Nervous System (CNS) dysfunction and are associated with various neurological sequelae. There are currently no evidence-based guidelines for the management of neonatal seizures and currently used drugs such as phenobarbital, and phenytoin have limited efficacy and potential toxicities. Newer second line anticonvulsant, levetiracetam, has been used in refractory neonatal seizures despite limited data and off-label use. In this review, we will discuss various pharmacological properties of levetiracetam when used in neonatal population. A PubMed search for MEDLINE was undertaken to look for studies using the terms "Levetiracetam", AND "Neonates" as key words from year 1995 to January 2017. Relevant articles were selected and information was extracted about pharmacokinetics, pharmacodynamics and clinical uses of levetiracetam in neonates. Levetiracetam is an active, water-soluble S-enantiomer of racemic pyrrolidine acetamide which exerts its antiepileptic action by binding to the synaptic vesicle protein within the brain. Metabolism of levetiracetam does not include the CYP P450 system and it is mainly eliminated through kidneys after rapid absorption. Also, no significant interactions with other drugs have been identified. Unlike other commonly used antiepileptic drugs, levetiracetam is not bound to plasma proteins, thereby, reducing the chances of toxicity and severe, life threatening side effects have not been reported. In fact, it has been shown to prevent neuro-degeneration after hypoxia/ischemia in rodent models of epilepsy. Levetiracetam has been emerging as a potential therapeutic option for refractory neonatal convulsions owing to its non-hepatic elimination, linear pharmacokinetics, low protein binding and better safety profile.

O-30 Levetiracetam therapeutic monitoring during pregnancy: an observational study

Introduction Levetiracetam is a relatively new anti-ep-ileptic drug (AED), indicated as an adjunctive therapy for partial-onset seizures and primary generalised tonic-clon-ic seizures in adults and children. However, information about the influence of altered pharmacokinetics during pregnancy on levetiracetam dose, serum concentration and clinical efficacy is still limited. This study aims to de-scribe the relation between certain parameters of preg-nant women and levetiracetam blood levels in different stages of pregnancy. Methods Pregnant women treated with levetiracetam for epilepsy from neurology clinics in several medical centres were followed in this study. Trough blood sam-ples were obtained (therapeutic range: 10–37 mg/L) at dif-ferent stages of pregnancy, while sampling frequency for each woman was decided by the neurologist. Levetiracetam dose, pregnancy week, and seizure occurrence were recorded, and levetiracetam blood concentrations were quantified using HPLC-based method. These data were analysed in order to reveal the changes in levetiracetam blood concentrations before and during pregnancy, and their potential clinical implications. Results Fifty two pregnant women treated with leveti-racetam for epilepsy participated in this study. In many of these patients, levetiracetam plasma concentrations decreased during pregnancy, and the drug dose was in-creased gradually to maintain the concentrations in the therapeutic range. Despite this, levetiracetam plasma concentrations were below and above the therapeutic range in 41% and 5.5% of the collected samples, respec-tively. Based on the dose-normalised levetiracetam plas-ma concentrations, exposure to a given dose of the drug decreases by approximately 35% during the first trimester, and stays reduced over the 2nd and 3rd trimesters. Overall, many patients were exposed to sub-therapeutic leveti-racetam plasma concentrations during substantial parts of pregnancy. However, no clear correlation between the levetiracetam plasma concentrations and occurrence of seizures was identified. Conclusion Levetiracetam blood concentrations tend to decrease during pregnancy as opposed to pre-preg-nancy state, apparently due to increased drug clearance. As a result, levetiracetam blood concentrations during pregnancy may decline below the therapeutic range, leading to a higher risk of seizures. Therefore, monitoring of levetiracetam blood concentrations during pregnan-cy is needed to maintain therapeutic concentrations via gradual increase in drug doses. More detailed analysis is needed to reveal the pregnancy-related changes in the levetiracetam pharmacokinetics (clearance) and pharma-codynamics.

Experience and pharmacokinetics of Levetiracetam in Korean neonates with neonatal seizures.

PurposeThe aims of this study were to evaluate the safety and pharmacokinetics of levetiracetam (LEV) in neonates with seizures and to establish a population pharmacokinetics (PPK) model by using the software NONMEM.MethodsA retrospective analysis of 18 neonatal patients with seizures, who were treated with LEV, including 151 serum samples, was performed. The mean loading dose was 20 mg/kg, followed by a mean maintenance dose of 29 mg/kg/day.ResultsSeventeen neonates (94%) had seizure cessation within 1 week and 16 (84%) remained seizure-free at 30 days under the LEV therapy. The mean serum concentration of LEV was 8.7 µg/mL. Eight samples (5%) were found above the therapeutic range. No serious adverse effects were detected. In the PPK analysis for Korean neonates, the half-life was 9.6 hours; clearance, 0.357 L/hr; and volume of distribution, 4.947 L, showing differences from those in adults.ConclusionLEV is a safe and effective option for the treatment of neonatal seizures with careful therapeutic drug monitoring.

Population Pharmacokinetic Modeling of Levetiracetam in Pediatric and Adult Patients With Epilepsy by Using Routinely Monitored Data.

Levetiracetam, a second-generation antiepileptic drug, is frequently used for managing partial-onset seizures. About 70% of the administered dose is excreted in urine unchanged, and dosage adjustment is recommended based on the individual's renal function. In this study, a population pharmacokinetic model of levetiracetam was developed using routinely monitored serum concentration data for individualized levetiracetam therapy. Patients whose serum concentrations of levetiracetam at steady-state were routinely monitored at Kyoto University Hospital from April 2012 to March 2013 were enrolled. The influence of patient characteristics on levetiracetam pharmacokinetics was evaluated using the nonlinear mixed-effects modeling (NONMEM) program. A total of 583 steady-state concentrations from 225 patients were used for the analysis. The median patient age and estimated glomerular filtration rate (eGFR) were 38 (range: 1-89) years and 98 (15-189) mL·min·1.73 m, respectively. Serum concentration-time data of levetiracetam were well described by a 1-compartment model with first-order absorption. Oral clearance was allometrically related to the individual body weight and eGFR. An increase in the dose significantly increased oral clearance. No improvement in model fit was observed by including the covariate of any concomitant antiepileptic drugs. The population mean clearance for an adult weighing 70 kg and with a normal renal function was 4.8 and 5.9 L/h for 500 mg bis in die (bid) and 1500 mg bid, respectively. Oral clearance allometrically related with body weight and eGFR can well predict the routine therapeutic drug monitoring data from pediatric to aged patients with varying renal function. Dosage adjustments based on renal function are effective in controlling the trough and peak concentrations in similar ranges.

36th International Symposium on Intensive Care and Emergency Medicine : Brussels, Belgium. 15-18 March 2016.

36th International Symposium on Intensive Care and Emergency Medicine : Brussels, Belgium. 15-18 March 2016.

Cardiovascular toxicity with levetiracetam overdose

Objective: To describe the cardiovascular toxicity and pharmacokinetics of levetiracetam in overdose. Case Report: A 43-year-old female presented 8 h post ingestion of 60–80 g of levetiracetam with mild central nervous system depression, bradycardia, hypotension and oliguria. Her cardiovascular toxicity transiently responded to atropine and intravenous fluids. A bedside echocardiogram demonstrated normal left and right ventricular contractility. Despite her cardiovascular toxicity and oliguria, she had normal serial venous lactates and renal function; and made a complete recovery over 48 h. Her levetiracetam concentration was 463 mcg/ml 8 h post ingestion (therapeutic range 10–40 mcg/ml) and her concentration–time data best fitted a one-compartment model with first-order input and an elimination half-life of 10.4 h. Discussion: Levetiracetam in large ingestions appears to cause bradycardia and hypotension that is potentially responsive to atropine and intravenous fluids. Based on a normal echocardiogram, the mechanism for this effect may be levetiracetam acting at muscarinic receptors at high concentration. The pharmacokinetics of levetiracetam in overdose appeared to be similar to therapeutic levetiracetam dosing.

THE ROLE OF THE THERAPEUTIC DRUG MONITORING WHEN USING ANTIEPILEPTIC DRUGS

Objective. To define therapeutic drug monitoring (TDM) role when using drugs of valproic acid and a levetira с etam as options of medication with a nonlinear and linear pharmakokinetics. Materials and methods. Analysed are the results of the therapeutic drug monitoring (TDM) among 80 patients who were using valproic acid during the monotherapy and levetiracetam during monotherapy or the combination of any other antiepileptic drugs (AEDs). We determine plasma concentration C min (before use next dose AED). Results. А mong the group consisting of 57 patients and taking valproic acid with the individual daily dosages in the range of 7.5 mg/kg to 30.7 mg/kg, C min of valproic acid equaled to the range of 44 to 111 mcg/ml (therapeutic range is 50-100 mcg/ml). The research determined the presence of significant individual pharmacokinetic features of valproic acid that play a role in achieving clinical effects and appearance of undesired results. 23 patients were taking the daily dosage of levetiracetam starting from 500 to 3000 mg twice or thrice which equal from 7.5 mg/kg/day to 36.9 mg/kg/day individually. TDM confirmed the linear pharmacokinetics of levetiracetam, furthermore determining that the method of determining the daily dosage by the body mass being more effective among the adults. 30 mg/kg can be considered the average effective daily dose of levetiracetam. Conclusion. TDM proved to be a reasonable AEDs treatment not only for patients with the nonlinear pharmacokinetics but also for those with the linear pharmacokinetics.