Pharmacokinetic Variability of Four Newer Antiepileptic Drugs, Lamotrigine, Levetiracetam, Oxcarbazepine, and Topiramate

Landmark, Cecilie Johannessen; Baftiu, Arton; Tysse, Irene; Valsø, Beate; Larsson, Pål G.; Rytter, Elisif; Johannessen, Svein I.

doi:10.1097/ftd.0b013e31825ee389

Cited by 80 publications

(28 citation statements)

References 31 publications

(26 reference statements)

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“…In line with other authors, 12 we classified AED comedication as strong enzyme inducers, including CBZ, PB, and PHT, and not strong enzyme inducers/inhibitors, such as oxcarbazepine (OXC), topiramate, rufinamide, gabapentin, lamotrigine (LTG), levetiracetam (LEV), zonisamide, clobazam (CLB), and enzyme inhibitor (VPA).…”

Section: Subjectssupporting

confidence: 61%

Lacosamide Therapeutic Monitoring in Patients With Epilepsy

Contin

Riva²,

Albani³

et al. 2013

Therapeutic Drug Monitoring

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Our findings confirm, in a real-patient clinical setting, preliminary evidence from randomized, clinical trials showing that carbamazepine, phenobarbital, or phenytoin significantly reduces the overall systemic exposure to LCM. From a practical point of view, patients on concomitant AED strong inducers may require a 30% higher dose of LCM compared with patients not receiving strongly inducing AED cotherapy, to achieve the same plasma drug concentration.

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Section: Subjectssupporting

confidence: 61%

Lacosamide Therapeutic Monitoring in Patients With Epilepsy

Contin

Riva²,

Albani³

et al. 2013

Therapeutic Drug Monitoring

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“…This is particularly important in infants and children, in whom systemic clearance is often higher than adults after normalization for differences in body weight. This general pattern has been shown for various AEDs . At the other extreme of age, in the elderly, systemic clearance is generally reduced compared with younger adults because of less efficient metabolism, reduced renal function, or both .…”

Section: Discussionmentioning

confidence: 62%

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

Dijkman

Rauwé

Danhof

et al. 2017

Brit J Clinical Pharma

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AIMSPopulation 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. METHODSModels 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. RESULTSOur 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. CONCLUSIONSThe 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. British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• First-line and alternative first line antiepileptic drugs (AEDs) are often used in combination with second-line line drugs (i.e. add-on).• Many AED combinations lead to pharmacokinetic drug-drug interactions (DDIs), which may result in large variation in drug exposure.• The implications of such DDIs have not been considered in existing clinical guidelines. WHAT THIS STUDY ADDS• We evaluate how demographic and clinical factors, including comedications (polytherapy), affect systemic exposure to AEDs in the target patient population. In addition, we demonstrate that AED dosing regimens can be optimized to ensure drug concentrations are maintained within a reference therapeutic range.• DDIs can lead to significant changes in systemic exposure and potentially alter the efficacy and safety profile of AEDs in adult and paediatric patients.• These results form the basis for a comprehensive review of clinical guidelines for the use of first and second line AEDs, including novel algorithms for dose adjustment.

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“…Nonetheless, infant SDCs during prolonged breastfeeding remained very low (i.e. < 15% of the maternal SDC) [27,30]. This finding indicates an efficient elimination in newborn infants [22].…”

Section: Pregnancy and Lactationmentioning

confidence: 80%

“…Thus, on a mg/kg basis, children (between 2 months and 12 years of age) should receive 30% higher LEV dosages than adults in order to achieve comparable SDC [16,20,24,27,30].…”

Section: Agementioning

confidence: 99%

Review on the relevance of therapeutic drug monitoring of levetiracetam

Sourbron

Chan

Heijden

et al. 2018

Seizure

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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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Pharmacokinetic Variability of Four Newer Antiepileptic Drugs, Lamotrigine, Levetiracetam, Oxcarbazepine, and Topiramate

Cited by 80 publications

References 31 publications

Lacosamide Therapeutic Monitoring in Patients With Epilepsy

Lacosamide Therapeutic Monitoring in Patients With Epilepsy

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

Review on the relevance of therapeutic drug monitoring of levetiracetam

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