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Purpose: Gabapentin and pregabalin are antiepileptic drugs (AEDs) with epilepsy and neuropathic pain indications. The purpose of this study was to investigate pharmacokinetic variability of gabapentin and pregabalin and indications for therapeutic drug monitoring (TDM) in clinical practice with focus on gender aspects., Method: Anonymous data from routine TDM-service at the National Center for Epilepsy regarding serum concentration measurements of gabapentin and pregabalin, 2009-2013, were utilised. All included samples were drug-fasting in the morning at steady-state., Results: In total, 356 patients were included; gabapentin 189 (66% women), average age 53 years and pregabalin 167 (56% women), average age 50 years. For gabapentin, mean serum concentration/dose(C/D)-ratio was similar across genders. Only 13% of the patients had concentrations above the lower limit of the reference range (70-120 μmol/L), which indicates a need for reevaluation of the reference range. For pregabalin, the C/D-ratio in women (0.08±0.06) was 42% higher than in men (0.056±0.05; p<0.05). The pharmacokinetic variability (C/D-ratio) was >100-fold for both gabapentin and pregabalin. An indication of use (epilepsy/pain/other) was stated in only 26% of the cases (n=94). Epilepsy was assumed as indication when other AEDs were also measured (50% of patients). This was similar for both genders and for both AEDs. Indications for TDM were stated in 155 cases (44%) and were similar for gabapentin and pregabalin., Conclusion: Gabapentin and pregabalin are more used in women than in men, and routine use of TDM is most common in patients with epilepsy. Pharmacokinetic variability is extensive, highlighting a need for individualisation of therapy regardless of indication., (Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

To explore possible concentration-effect relationships, gabapentin (GBP) and vigabatrin (VGB) serum concentrations were obtained from patients participating in an add-on dose-titration trial comparing GBP and VGB in partial epilepsy. Patients randomized to GBP started on 1800 mg/d and could have their dosage increased stepwise to 2400 and 3600 mg/d if seizures persisted. Those randomised to VGB started on 1000 mg/d, and the dose could be increased to 2000 and 4000 mg/d. Blood samples were obtained at steady state, at a nonstandardized time, from 27 patients randomized to GBP and from 36 randomized to VGB. Serum samples were analyzed using high-performance liquid chromatography. The treatment effect was expressed as percentage reduction in number of seizures from baseline. In addition, patients were classified as responders (>50% reduction in number of seizures from baseline) or nonresponders. There was no significant correlation between serum concentrations of GBP and seizure reduction at the lowest dosage, 1800 mg/d (r = -0.02, P = 0.94, Spearman-rank), nor between VGB serum levels and seizure reduction at 1000 mg/d of VGB (r = -0.14, P = 0.44). The serum GBP concentrations among responders to GBP 1800 mg/d were 26 +/- 12 micro mol/L (mean +/- SD), which was not different from serum concentrations in nonresponders, 28+/-13 micro mol/L. Nor was there a difference between serum concentrations of responders and nonresponders to VGB 1000 mg/d (32 +/- 23 and 44 +/- 36 micro mol/L, respectively). Hence, with the present study design we were unable to identify specific target ranges of GBP and VGB serum concentrations.

The pharmacokinetic properties of a drug are the primary deter-minant of the extent and duration of drug action, and influence susceptibility to clinically important drug interactions. Most of the older-generation antiepileptic drugs (AEDs) are far from ideal in terms of pharmacokinetics and interaction potential. For example, phenytoin, carbamazepine, and valproic acid exhibit non-linear kinetics; carbamazepine and valproic acid have relatively short half-lives; and most of these drugs cause either enzyme induction (phenytoin, phenobarbital, primidone, carbamazepine) or enzyme inhibition (valproic acid). Compared with older agents, certain new-generation AEDs offer a num-ber of pharmacokinetic advantages, particularly in terms of reduced inter-patient variability in drug clearance and a lower interaction potential. One of the most recently developed of these drugs, levetiracetam, comes especially close to fulfilling the desirable pharmacokinetic characteristics for an AED: (1) it has a high oral bioavailability, which is unaffected by food; (2) it is not significantly bound to plasma proteins; (3) it is eliminated partly in unchanged form by the kidneys and partly by hydrolysis to an inactive metabolite, without involvement of oxidative and conjugative enzymes; (4) it has linear kinetics; and (5) it is not vulnerable to important drug interactions, nor does it cause clinically significant alterations in the kinetics of concomitantly administered drugs. Although its half-life is relatively short (6 to 8 hours), its duration of action is longer than anticipated from its pharmacokinetics in plasma, and a twice-daily dosing regimen is adequate to produce the desired response.

Purpose: Our objective was to compare the efficacy and safety of gabapentin and vigabatrin as first-line add-on treatment in patients with partial epilepsy., Methods: This was a multicenter, double-blind, randomized dose titration study. After baseline assessment and randomization, the dose could be increased if seizures persisted and reduced if side effects occurred. Health-related quality of life was assessed at baseline and at the end of the study. By a protocol amendment post hoc, all randomized patients were offered a standardized perimetry examination at the end of the study. Improvement rate was the proportion of patients with a reduction of seizure frequency of at least 50% during an 8-week period without any adverse events causing withdrawal., Results: One hundred two patients were randomized and analyzed on an intent-to-treat basis. The improvement rate was 48% in the gabapentin group and 56% in the vigabatrin group. The improvement rate, when per protocol criteria were fulfilled, was 57% in the gabapentin group and 59% in the vigabatrin group. The proportion of seizure-free patients was 31% in the gabapentin group and 39% in the vigabatrin group. There was no difference in quality-of-life scores between the groups. Perimetry after termination of the study on 64 patients showed abnormal results in 3 of 32 patients in the vigabatrin group., Conclusion: Approximately one third of the patients in both groups became seizure-free. Although no major differences were seen in terms of the improvement rate between the groups, equivalence between the two drugs was not found.

Gabapentin is a new antiepileptic drug. Its mechanism of action is not clearly understood, but it seems to differ from that of other antiepileptic drugs. The favourable pharmacokinetic properties of gabapentin make it simple to use. Our preliminary clinical observations with gabapentin at the National Center for Epilepsy are presented. 58 adult patients (mean age 28.9 years), mainly with refractory partial seizures, had gabapentin added to their existing medication. The follow-up period was 6.9 months on average. Only one patient experienced a reduction in seizures of more than 50%, while 25 patients experienced a moderate reduction in seizures (10-50%). The clinical effect was most favourable in patients with secondary generalized tonic-clonic seizures. Gabapentin was well tolerated, and no clinically significant interactions were encountered. Recent observations show that the doses of gabapentin used in our study may have been too low.

Standard antiepileptic drugs (AEDs) have a number of pharmacokinetic shortcomings, and AEDs with more favorable profiles would be preferred. The pharmacokinetics and interaction profile of the recently developed AED topiramate (TPM), is reviewed and compared with those of other newer AEDs including lamotrigine (LTG), gabapentin (GBP), vigabatrin (VGB), and oxcarbazepine (OCBZ). Although none of these agents meets all of the criteria of the "ideal" AED from the pharmacokinetic standpoint, a number of these drugs, including TPM, have desirable properties that distinguish them from the older AEDs and should contribute to their clinical utility.