Interlaboratory variability in the quantification of new generation antiepileptic drugs based on external quality assessment data

PURPOSE: To assess interlaboratory variability in the determination of serum levels of new antiepileptic drugs (AEDs). METHODS: Lyophilised serum samples containing clinically relevant concentrations of felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), the monohydroxy derivative of oxcarbazepine (OCBZ; MHD), tiagabine (TGB), topiramate (TPM), and vigabatrin (VGB) were distributed monthly among 70 laboratories participating in the international Heathcontrol External Quality Assessment Scheme (EQAS). Assay results returned over a 15-month period were evaluated for precision and accuracy. RESULTS: The most frequently measured compound was LTG (65), followed by MHD (39), GBP (19), TPM (18), VGB (15), FBM (16), and TGB (8). High-performance liquid chromatography was the most commonly used assay technique for all drugs except for TPM, for which two thirds of laboratories used a commercial immunoassay. For all assay methods combined, precision was <11% for MHD, FBM, TPM, and LTG, close to 15% for GBP and VGB, and as high as 54% for TGB (p < 0.001). Mean accuracy values were <10% for all drugs other than TGB, for which measured values were on average 13.9% higher than spiked values, with a high variability around the mean (45%). No differences in precision and accuracy were found between methods, except for TPM, for which gas chromatography showed poorer accuracy compared with immunoassay and gas chromatography-mass spectrometry. CONCLUSIONS: With the notable exception of TGB, interlaboratory variability in the determination of new AEDs was comparable to that reported with older-generation agents. Poor assay performance is related more to individual operators than to the intrinsic characteristics of the method applied. Participation in an EQAS scheme is recommended to ensure adequate control of assay variability in therapeutic drug monitoring.     

Overview of the Safety of Newer Antiepileptic Drugs

Summary: Standard antiepileptic drugs (AEDs) are associated with a wide variety of acute and chronic adverse events and with many interactions with each other and with non-AEDs that complicate patient management. The safety and interaction profiles of the newer AEDs have also been intensively studied. Safety data are available for six of the newer AEDs, lamotrigine (LTG), vigabatrin (VGB), gabapentin (GBP), tiagabine (TGB), felbamate (FBM), and topiramate (TPM). The potential for the most recently developed AEDs for producing rare idiosyncratic reactions cannot be ascertained until additional patient exposures have been reported from careful postmarketing surveillance.     

Interaction between anticonvulsants and human placental carnitine transporter

PURPOSE: To examine the inhibitory effect of anticonvulsants (AEDs) on carnitine transport by the human placental carnitine transporter. METHODS: Uptake of radiolabeled carnitine by human placental brush-border membrane vesicles was measured in the absence and presence of tiagabine (TGB), vigabatrin (VGB), gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), valproic acid (VPA), and phenytoin (PHT). The mechanism of the inhibitory action of TGB was determined. RESULTS: Most of the AEDs inhibited placental carnitine transport. Kinetic analyses showed that TGB had the greatest inhibitory effect [50% inhibitory concentration (IC50, 190 microM)], and the order of inhibitory potency was TGB > PHT > GBP > VPA > VGB, TPM > LTG. Further studies showed that TGB competitively inhibited carnitine uptake by the human placental carnitine transporter, suggesting that it may be a substrate for this carrier. CONCLUSIONS: Although the involvement of carnitine deficiency in fetal anticonvulsant syndrome requires further evaluation, potential interference with placental carnitine transport by several AEDs was demonstrated. Despite the higher inhibitory potency of TGB, given the therapeutic unbound concentrations, the results for VPA and PHT are probably more clinically significant.     

Clinical Significance of Animal Seizure Models and Mechanism of Action Studies of Potential Antiepileptic Drugs

Summary: More than 50 million persons worldwide suffer from epilepsy, many of whom are refractory to treatment with standard antiepileptic drugs (AEDs). Fortunately, new AEDs commercialized since 1990 are improving the clinical outlook for many patients. Our growing understanding of anticonvulsant mechanisms and the relevance of preclinical animal studies to clinical antiepileptic activity have already contributed to the design of several new AEDs and should be increasingly beneficial to further efforts at drug development. Mechanisms have been identified for older AEDs [phenytoin (PHT), carbamazepine (CBZ), valproate (VPA), barbiturates, benzodiazepines (BZDs), ethosuximide (ESM)] and newer AEDs [vigabatrin (VGB), lamotrigine (LTG), gabapentin (GBP) tiagabine (TGB), felbamate (FBM), topiramate (TPM)]. Several novel anticonvulsant mechanisms have recently been discovered. FBM appears to be active at the strychnine-insensitive glycine binding site of the NMDA receptor. TPM is active on the kainate/AMPA subtype of glu-tamate receptor and at a potentially novel site on the GABA_A receptor. For several reasons, availability of a single AED with multiple mechanisms of action may be preferred over availability of multiple AEDs with single mechanisms of action. These reasons include ease of titration, lack of drug-drug interactions, and reduced potential for pharmacodynamic tolerance.     

Utility of the Lethargic (lh/lh) Mouse Model of Absence Seizures in Predicting the Effects of Lamotrigine,Vigabatrin, Tiagabine,Gabapentin, and Topiramate Against Human Absence Seizures

Summary: Purpose: Traditional methods of preclinical screening have predicted the effects of a putative antiepi-leptic drug (AED) against human absence seizures by testing its efficacy against clonic seizures in the high-dose pen-tylenetetrazole (PTZ) model. This high-dose PTZ model correctly predicted the efficacy of ethosuximide (ESM), benzodiazepines, and valproate (VPA) and the lack of efficacy of phenytoin (PHT) and carbamazepine (CBZ). However, the high-dose PTZ model erred in predictions for (a) phenobarbital (PB) (PTZ: efficacy; human: noneffi-cacy); (b) lamotrigine (LTG) (PTZ nonefficacy; human: efficacy); (c) vigabatrin (VGB) (PTZ: nonefficacy; human: proabsence effect); and (d) tiagabine (TGB) (PTZ efficacy; human: possibleproabsence). It also appears to have erred in predictions for gabapentin (GBP) (PTZ efficacy) and topiramate (TPM) (PTZ: efficacy). Because the lh/lh genetic model of absence seizures correctly predicted effects of ESM, clonazepam, VPA, PHT, CBZ, and PB against human absence seizures, we performed this study to test the predictive utility of the lWZh model for LTG, VGB, TGB, GBP, and TPM. Methods: Bipolar recording electrodes were implanted bilaterally into frontal neocortex of 8–week-old male lWZh mice. With the exception of VGB, vehicle or drugs were administered intraperitoneally (i.p.) on alternating days, and an EEG was used to record effects on seizure frequency. With VGB, vehicle was administered i.p. on day 1, and gradually increasing doses of VGB were administered on successive days. Drug and vehicle effects were compared in corresponding lfi-min epochs of the 150–min period after administration. Results: LTG (4.8–144 μmol/kg) significantly (p < 0.04) reduced seizure frequency (by 6.5%) compared with vehicle. In contrast, VGB (0.35–11 mmol/kg) and TGB (0.27–27 μmol/kg) significantly increased seizure frequency (300– 700%) and seizure duration (1,700–1,800%; p ≤ 0.001). GBP (18μmol/kg to 1.8 mmol/kg) and TPM (8.9–29.5 pmol/kg) had no significant effect on seizure frequency. Conclusions: In contrast to the high-dose PTZ model, the lh/lh model correctly predicted the antiabsence effect of LTG, the possible proabsence effects of VGB and TGB, and the lack of effect of GBP and TPM. The lWlh model appears to be superior to the high-dose PTZ model in predicting efficacy of putative AEDs against human absence seizures.     

An In Vitro Study of New Antiepileptic Drugs and Astrocytes

Summary:  Purpose: The aim of our research was to study some biochemical modifications elicited in primary rat astrocyte cultures by treatment with gabapentin (GBP), carbamazepine (CBZ), lamotrigine (LTG), topiramate (TPM), oxcarbazepine (OXC), tiagabine (TGB), and levetiracetam (LEV), commonly used in the treatment of epilepsy. We investigated the biologic effects of these anticonvulsants (AEDs) at concentrations of 1, 10, 50, and 100 μg/ml.
Methods: The study was performed by examining cell viability (MTT assay), cell toxicity [lactate dehydrogenase (LDH) release in the medium], glutamine synthetase (GS) activity, reactive oxygen species (ROS) production, lipoperoxidation level (malondialdehyde; MDA), and DNA fragmentation (COMET assay). The level of the expression of 70-kDa heat-shock protein (HSP70) and inducible nitric oxide synthase (iNOS) as oxidative stress–modulated genes also was determined.
Results: Our experiments indicate that CBZ, TPM, and OXC induce stress on astrocytes at all concentrations. GBP, LTG, TGB, and LEV, at low concentrations, do not significantly change the metabolic activities examined and do not demonstrate toxic actions on astrocytes. They do so at higher concentrations.
Conclusions: Most AEDs have effects on glial cells and, when used at an appropriate cell-specific concentrations, may be well tolerated by cortical astrocytes. However, at higher concentrations, GBP, LTG, TGB, and LEV seem to be better tolerated than are CBZ, TPM, and OXC. These findings may reveal novel ways of producing large numbers of new AEDs capable of reducing the extent of inflammation, neuronal damage, and death under pathological conditions such as epilepsy and/or traumatic brain injury.     

Pharmacokinetic Profile of Topiramate in Comparison with Other New Antiepileptic Drugs

Summary: Antiepileptic drugs (AEDs) in broad use today have a number of pharmacokinetic liabilities, including a propensity for clinically meaningful drug interactions. Therefore, new AEDs with improved pharmacokinetic characteristics would be welcomed. The pharmacokinetic proftles of six newer AEDs—topiramate (TPM), gaba-pentin (GBP), vigabatrin (VGB), lamotrigine (LTG), ox-carbazepine (OCBZ), and felbamate—were reviewed. Some of these AEDs offer an improvement in one or more pharmacokinetic parameters compared with traditional AEDs, with TPM, GBP, VGB, and OCBZ demonstrating the most advantageous overall pharmacokinetic profiles.     

An Overview of the Efficacy and Tolerability of New Antiepileptic Drugs

Summary: To evaluate the efficacy and tolerability of recently developed antiepileptic drugs (AEDs), a systematic review of placebo-controlled, randomized controlled trials (RCTs) of the AEDs as add-on therapy in refractory partial epilepsy was conducted. Two or more RCTs meeting our inclusion criteria were found for gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), and zonisamide (ZNS). The outcome selected for estimation of efficacy was the proportion of patients experiencing a ≥50% reduction in seizure frequency from baseline. Tolerability was estimated on the basis of rates of patient withdrawal from study for any reason. Efficacy and tolerability odds ratios (ORs) and 95% confidence intervals (95% CIs) for each measure were generated for each trial included in the analysis, and overall efficacy and tolerability ORs were calculated for each AED across all trials and drug dosages evaluated. Because 95% CIs for both efficacy and tolerability overlapped for the six drugs, conclusive evidence of between-drug differences in effectiveness or safety were not obtained from the analysis. However, the data suggest that the drug with the highest OR for efficacy (TPM) may be approximately twice as effective as the AED with the lowest OR for efficacy (GBP), and that the treatment that appears to most frequently cause withdrawal (ZNS) may be about four times more likely to do so that the AED with the lowest withdrawal rate (LTG). RCTs comparing newer AEDs with the older standard drugs and with each other are needed to further evaluate their relative utility.     

The use of lamotrigine, vigabatrin and gabapentin as add-on therapy in intractable epilepsy of childhood.

PURPOSE: Lamotrigine (LTG), vigabatrin (VGB) and gabapentin (GBP) are three anti-epileptic drugs (AEDs) used in the treatment of children with epilepsy for which long-term retention rates are not currently well known. This study examines the efficacy, long-term survival and adverse event profile of these three agents used as add-on therapy in children with refractory epilepsy over a 10-year period. METHODS: Three separate audits were conducted between February 1996 and September 2000. All children studied had epilepsy refractory to other AEDs. Efficacy was confirmed if a patient became seizure free or achieved >50% reduction in seizure frequency for 6 months or more after starting therapy. Adverse events and patient survival for each drug were recorded at the end of the study period. RESULTS: Between September 1990 and February 1996, 132 children received LTG, 80 VGB and 39 GBP. At the 10-year follow-up audit, 33% of the children on LTG had a sustained beneficial effect on their seizure frequency in contrast to 19% for VGB and 15% for GBP. No significant difference in efficacy was found in children with partial seizures. Children with epileptic encephalopathy (EE) including myoclonic-astatic epilepsy and Lennox-Gastaut Syndrome (LGS) achieved a more favorable response to LTG. The main reasons for drug withdrawal were lack of efficacy for VGB, apparent worsening of seizures for GBP and the development of a rash for LTG. CONCLUSIONS: Lamotrigine is a useful add-on therapy in treating children with epilepsy. It has a low adverse event profile and a sustained beneficial effect in children with intractable epilepsy.