Pharmacokinetic interactions and dosing rationale for antiepileptic drugs in adults and children: PK interactions in epilepsy pharmacotherapy

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Abstract

<div class="section"> <a class="named-anchor" id="bcp13400-sec-0001">  </a> <h5 class="section-title" id="d642993e245">Aims</h5> <p id="d642993e247">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. </p> </div><div class="section"> <a class="named-anchor" id="bcp13400-sec-0002">  </a> <h5 class="section-title" id="d642993e250">Methods</h5> <p id="d642993e252">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. </p> </div><div class="section"> <a class="named-anchor" id="bcp13400-sec-0003">  </a> <h5 class="section-title" id="d642993e255">Results</h5> <p id="d642993e257">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. </p> </div><div class="section"> <a class="named-anchor" id="bcp13400-sec-0004">  </a> <h5 class="section-title" id="d642993e260">Conclusions</h5> <p id="d642993e262">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. </p> </div>

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Vancomycin continuous infusion in neonates: dosing optimisation and therapeutic drug monitoring.

Xavier Durrmeyer, Valerie Biran, Emmanuel Lopez … (2013)

Because pharmacokinetic data are limited, continuous infusions of vancomycin in neonates are administered using different dosing regimens. The aim of this work was to evaluate the results of vancomycin therapeutic drug monitoring (TDM) under three different dosing regimens and to optimise vancomycin therapy. Vancomycin TDM concentrations were noted and compared prospectively in three hospitals. Population pharmacokinetic analysis was performed to optimise dosing using NONMEM software. Patient-tailored optimised dosing regimens were evaluated in a prospective study. Two hundred and seven serum vancomycin concentrations from 116 neonates were analysed. Only 48 neonates (41%) had serum vancomycin concentrations within the therapeutic range of 15-25 mg/l using a current dosing regimen. Concentrations ranged from 5.1 to 61.5 mg/l. Loading doses were required to decrease the risk of sub-therapeutic levels during early treatment. An optimised dosing regimen, taking into account birth weight, current weight, postnatal age and serum creatinine, was developed based on a one-compartment pharmacokinetic model. A prospective validation study in 58 neonates demonstrated a higher percentage of neonates (70.7%, n=41) reaching the therapeutic range and early dosage adaptation (6-12 h post-dose) using an optimised dosing regimen. A patient-tailored optimised dosing regimen should be used routinely to individualise vancomycin continuous infusion therapy in neonates.

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Epilepsy after the first drug fails: substitution or add-on?

Sonia M. Brodie, Bryan P. Kwan (2000)

When and how a combination of antiepileptic drugs (AEDs) should be used in patients unresponsive to monotherapy is not known. We followed up prospectively 248 patients in whom treatment with the first AED was unsuccessful. When treatment failed due to intolerable adverse events, a second (substituted) drug was prescribed. When failure was due to lack of efficacy, either AED substitution or combination (add-on) was undertaken. Patients were considered to be seizure-free if they had no seizures for at least 1 year. Among patients with inadequate seizure control on the first well tolerated AED, those who received substituted monotherapy (n= 35) and those who received add-on treatment (n= 42) had similar seizure-free rates (substitution vs. add-on: 17% vs. 26%) and incidence of intolerable side effects (substitution vs. add-on: 26% vs. 12%). Based on the drugs' perceived primary mode of action, more patients became seizure-free when the combination involved a sodium channel blocker and a drug with multiple mechanisms of action (36%) compared to other combinations (7 %, P= 0.05). None of the 11 patients who received add-on treatment after a second drug had also failed became seizure-free, compared to 26% in those who received add-on as soon as the first tolerated AED proved to be ineffective (n= 42, P= 0.05). These preliminary observations have generated verifiable hypotheses regarding the early management of epilepsy. A randomized study comparing substitution and combination after the failure of the first AED is underway. Copyright 2000 BEA Trading Ltd.

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Drug interactions with the newer antiepileptic drugs (AEDs)--part 1: pharmacokinetic and pharmacodynamic interactions between AEDs.

P Patsalos (2013)

Since 1989 there has been an exponential introduction of new antiepileptic drugs (AEDs) into clinical practice and these include eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin, retigabine (ezogabine), rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide; 16 in total. Because often the treatment of epilepsy is lifelong, and because patients are commonly prescribed polytherapy with other AEDs, AED interactions are an important consideration in the treatment of epilepsy and indeed can be a major therapeutic challenge. For new AEDs, their propensity to interact is particularly important because inevitably they can only be prescribed, at least in the first instance, as adjunctive polytherapy. The present review details the pharmacokinetic and pharmacodynamic interactions that have been reported to occur with the new AEDs. Interaction study details are described, as necessary, so as to allow the reader to take a view as to the possible clinical significance of particular interactions. The principal pharmacokinetic interaction relates to hepatic enzyme induction or inhibition whilst pharmacodynamic interactions principally entail adverse effect synergism, although examples of anticonvulsant synergism also exist. Overall, the new AEDs are less interacting primarily because many are renally excreted or not hepatically metabolised (e.g. gabapentin, lacosamide, levetiracetam, topiramate, vigabatrin) and most do not (or minimally) induce or inhibit hepatic metabolism. A total of 139 pharmacokinetic interactions between concurrent AEDs have been described. The least pharmacokinetic interactions (n ≤ 5) are associated with gabapentin, lacosamide, tiagabine, vigabatrin and zonisamide, whilst lamotrigine (n = 17), felbamate (n = 15), oxcarbazepine (n = 14) and rufinamide (n = 13) are associated with the most. To date, felbamate, gabapentin, oxcarbazepine, perampanel, pregabalin, retigabine, rufinamide, stiripentol and zonisamide have not been associated with any pharmacodynamic interactions.