title: Pharmacokinetics, drug interactions and exposure-response relationship of eslicarbazepine acetate in adult patients with partial-onset seizures: population pharmacokinetic and pharmacokinetic/pharmacodynamic analyses.
abstract: BACKGROUND
  Eslicarbazepine acetate (Zebenix®) is a voltage-gated sodium channel blocker approved in 2009 by the European Medicines Agency as adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization.
  
  
  OBJECTIVE
  The objectives of the current population pharmacokinetic (PK) and PK/pharmacodynamic analyses were to characterize the population PK of eslicarbazepine (the main active metabolite of eslicarbazepine acetate), to evaluate the influence of patient factors and concomitant antiepileptic drugs (AEDs) on the PK variability of eslicarbazepine, to assess the effect of eslicarbazepine acetate on the PK of concomitant AEDs and to investigate the relationship between eslicarbazepine systemic exposure and eslicarbazepine acetate antiepileptic activity in patients with partial-onset seizures uncontrolled with one to three AEDs.
  
  
  METHODS
  Sparse plasma concentrations of eslicarbazepine and concomitant AEDs, along with efficacy data, were obtained from 641 patients enrolled in eslicarbazepine acetate phase III studies. Data were analysed using nonlinear mixed-effect modelling methods. Most analyses used a model using log-transformed data from trough concentration (minimum steady-state plasma concentration during a dosage interval [C(min,ss)]). The model estimated the apparent total body clearance from plasma (CL/F), which is sufficient to predict average plasma concentrations at steady state (C(av,ss)). After the final model was validated, individual concentrations at steady state were predicted, and exposure parameters (area under the plasma concentration-time curve over 24 hours, C(min,ss) and C(av,ss)) for a one-compartmental model with first-order elimination were calculated.
  
  
  RESULTS
  Eslicarbazepine CL/F was affected by bodyweight, dose of carbamazepine (D(CAR)) and co-administration of barbiturates or phenytoin (AED(PB)), as predicted by the equation CL/F = (2.36 + 0.00149 • D(CAR) + 1.41 • AED(PB)) • (weight/70)0.75, which means that CL/F is 2.36 L/h for a subject with a bodyweight of 70 kg and without concomitant carbamazepine and barbiturates/phenytoin. Concomitant use of lamotrigine, valproic acid, topiramate, gabapentin, clobazam and levetiracetam showed no effect on the exposure to eslicarbazepine. Inter-individual variability of eslicarbazepine CL/F was 44% and the residual error (intra-subject variability) was proportional to the log of concentrations, with a coefficient of variation of 6%. Age, ethnicity, sex and creatinine clearance did not affect eslicarbazepine CL/F. Eslicarbazepine acetate did not affect the CL/F of clobazam, gabapentin, phenytoin, phenobarbital, levetiracetam and valproic acid. Eslicarbazepine acetate slightly increased the CL/F of carbamazepine (up to 14%), lamotrigine (up to 12%) and topiramate (up to 16%). The antiepileptic effect of eslicarbazepine acetate, as assessed by a decrease in seizure frequency, increased with the increase of eslicarbazepine acetate dose and eslicarbazepine concentrations. The concomitant administration of other AEDs did not affect the eslicarbazepine acetate exposure-response relationship.
  
  
  CONCLUSIONS
  The magnitude of the effect of eslicarbazepine acetate on the CL/F of the concomitant AEDs assessed appears to be not clinically relevant and does not justify the need for dose adjustment in most patients. A continuous dose-response relationship was observed between eslicarbazepine concentrations and seizure frequency reduction, which was not affected by concomitant AEDs.
authors.affiliation: Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
authors.forename: Amilcar
authors.initials: A
authors.lastname: Falcão
authors.forename: Eliane
authors.initials: E
authors.lastname: Fuseau
authors.forename: Teresa
authors.initials: T
authors.lastname: Nunes
authors.forename: Luis
authors.initials: L
authors.lastname: Almeida
authors.forename: Patricio
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000627:therapeutic use; D017326:Clinical Trials, Phase III as Topic / Q000379:methods; D003984:Dibenzazepines / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D012640:Seizures / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D000927:Anticonvulsants; D003984:Dibenzazepines; C416835:eslicarbazepine acetate