Influence of Comedication on Levetiracetam Pharmacokinetics

Aldaz, Azucena; Alzueta, Natalia; Viteri, C.

doi:10.1097/ftd.0000000000000470

Cited by 17 publications

(13 citation statements)

References 22 publications

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“…Despite the aforementioned tolerability of levetiracetam and ease of dosing, monitoring its serum or plasma concentrations has been reported as useful in patients with altered physiological states, including pediatric and elderly patients [ 28 ], pregnant epileptic women [ 29 , 30 , 31 , 32 ], and critically ill patients [ 33 , 34 , 35 , 36 , 37 ]. Very recently, the co-administration of levetiracetam and enzyme-inducing antiepileptic drugs (EIAEDs) significantly changed the pharmacokinetics of levetiracetam [ 38 , 39 ]. Therefore, distinct pharmacokinetic behaviors are expected to require dosing adjustments.…”

Section: Introductionmentioning

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: Introductionmentioning

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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“…Various LEV reference ranges have been reported including 3 to 34 mg/L, 12 to 46 mg/L or 20 to 40 mg/L and could be attributed to different patient populations being studied Patsalos et al, 2008, Stepanova andBeran, 2014). LEV TDM is particularly helpful for the dose adjustments of elderly patients or patients with renal failure related with the increase in the elimination half-life values of LEV (Aldaz et al, 2018). Although LEV is generally not considered to be involved in clinically significant pharmacokinetic drug-drug interactions, consequent to the fact that it is not metabolized via CYP450 enzymes and is not plasma protein bound, there are some reports indicating a moderate effect of enzyme-inducing AEDs on serum LEV concentrations (Aldaz et al, 2018;May et al, 2003;.…”

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confidence: 99%

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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“…Whether the clinical value is significant, however, has yet to be confirmed by further prospective research. [3] R NS PHT-CBZ-PB NS ND ND ND ND Aldaz [36] R strong CBZ-OXC-PB 44% higher ND ND ND ND P = prospective; R = retrospective; EIDs = enzyme inducing drugs (not defined); LEV = levetiracetam; LEV CL = levetiracetam clearance; ND = not determined; NS = no significant effect; NCR = no clinical relevance; VPA = valproic acid; PB = phenobarbital; PHT = phenytoin; CBZ = carbamazepine; OXC = oxcarbazepine; PRM = primidone; ETS = ethosuximide; *compared to the VPA-treated group; **pooled analysis (4 phase III double-blind trials); ***in the non-elderly group.…”

Section: Discussionmentioning

confidence: 99%

Review on the relevance of therapeutic drug monitoring of levetiracetam

Sourbron

Chan

Heijden

et al. 2018

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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.

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Influence of Comedication on Levetiracetam Pharmacokinetics

Abstract: Comedication with EIAEDs increased LEV CL/F by more than 40%, whereas carbamazepine had the greatest inducing potency with LEV CL/F being 81% higher than that of the monotherapy group. These data suggest that monitoring LEV serum concentration during polytherapy with EIAEDs is indicated.

Cited by 17 publications

References 22 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

Review on the relevance of therapeutic drug monitoring of levetiracetam

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