Ion-Channel Antiepileptic Drugs: History
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Subjects: Chemistry, Analytical | Clinical Neurology
Contributor:
Roberto Mandrioli

The term seizures includes a wide array of different disorders with variable etiology, which currently represent one of the most important classes of neurological illnesses. As a consequence, many different antiepileptic drugs (AEDs) are currently available, exploiting different activity mechanisms and providing different levels of performance in terms of selectivity, safety, and efficacy. AEDs are currently among the psychoactive drugs most frequently involved in therapeutic drug monitoring (TDM) practices. Ezogabine (or retigabine), lacosamide, and zonisamide are the TDM of three AEDs belonging to the class of ion channel agents.

  • ezogabine
  • lacosamide
  • neuroprotection
  • retigabine
  • zonisamide
  • therapeutic drug monitoring
  • analytical methods
  • sample pretreatment

1. Introduction

Epilepsy, and more generally seizures, are one of the most widespread and incapacitating neurologic disorders. Recent reports have calculated a 0.63% prevalence of epilepsy over the total world population, corresponding to about 50 million people [1].

The first effective antiepileptic drugs (AEDs) were bromides, introduced in the mid-1850s, and then paraldehyde, in the late 1880s. Since then, many other, vastly more effective and safer drugs have been devised, belonging to many chemical classes, starting from barbiturates in the 1910s, their analogues oxazolidinediones and pyrimidinediones, and hydantoins in the 1930–1960s. Then, benzodiazepines, carboxamides, fatty acids, and their derivatives, fructose derivatives, γ-aminobutyric acid (GABA) derivatives, hydantoins, pyrrolidines, succinimides, sulphonamides, and triazines have been used against seizures [2]. Pharmacological activity mechanisms are equally varied, although for some drugs, and entire chemical classes, the precise mechanism is still uncertain [3]. The two oldest AEDs, bromide and paraldehyde, are thought to non-selectively depress brain activity; if they have any molecular target, it is still unknown. A large group of AEDs interacts directly with ion channels, acting either as sodium channel blockers (such as carbamazepine, oxcarbazepine, lamotrigine, phenytoin) or as calcium channel blockers (such as ethosuximide); ezogabine seems to act as a potassium channel opener. Many AEDs interact with GABAergic transmission; since GABA is known as the main inhibitory neurotransmitter in the brain, its activation or facilitation is intuitively connected with a possible anticonvulsant effect. Thus, GABA transaminase inhibitors (vigabatrin) and glutamic acid decarboxylase (GAD) inducers (gabapentin) are used as antiepileptic agents. On the other hand, glutamate is generally recognized as the main excitatory brain neurotransmitter, and therefore drugs acting on the glutamatergic system (topiramate) are also known as antiepileptic agents [4]. The exact mechanisms of activity of valproic acid, levetiracetam, and stiripentol are still unknown, although of course hypotheses have been proposed [5].

2. Ion Channel Agents

2.1. Ezogabine (Retigabine)

EZG (ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate, Figure 1a), also known as retigabine in the USA, was used as an add-on treatment for drug-resistant partial onset seizures with or without secondary generalization in people aged 18 or older [6]. It was approved in Europe and the USA in 2011, commercialized by GlaxoSmithKline under the name Trobalt. Since 2013, it has been known to produce blue skin discoloration and eye abnormalities [7]. In 2016, the manufacturer stopped its production, probably for commercial reasons (i.e., limited clinical use) [8].
EZG exerts its activity by activating the Kv7 (KCNQ) slowly-inactivating voltage-gated potassium channels [9], which is a mechanism different from that of most other antiepileptic drugs.
In vivo in humans, EZG is mainly N-glucuronidated (Figure 1b,c) by uridine diphosphate-glucuronosyltransferases (UGT) 1A1, 1A3, 1A4, and 1A9 and, to a lesser extent, N-acetylated after decarbamoylation (Figure 1d) [10]. The N-acetyl metabolite has weak biological activity [11].
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Figure 1. Metabolic pathways of ezogabine.

2.1.1. Therapeutic Drug Monitoring

Just a few analytical methods are available for the TDM of EZG; most of them are based on liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) [12][13][14][15]. One of these methods [12] was applied to evaluate gender differences in EZG pharmacokinetics. Analytical separation was achieved on a C18 column kept at 40 °C with a mobile phase consisting of an aqueous ammonium acetate/methanol/acetonitrile mixture. Sample pretreatment was carried out by liquid–liquid extraction (LLE) of 500 µL of plasma using 5 mL of a diethyl ether/dichloromethane (70/30, v/v) mixture, followed by centrifugation, separation, drying of the organic phase and reconstitution with 100 µL of mobile phase. Detection was performed by MS/MS with triple quadrupole (QqQ) detection. Linearity was achieved in the 10–2000 ng/mL range, with precision RSD values between 1.9% and 9.3%. Extraction yields were in the 88–91% range and accuracy values in the 102–111% range. Stability assays provided recovery values always higher than 80% under all short- and log-term conditions tested. Matrix effect was almost negligible (mean = 3.8%), as was carryover (0.3–0.7% of the limit of quantitation (LOQ) peak area). Instead of a deuterated EZG analogue, oxcarbazepine (Figure 2a) was used as the internal standard (IS), which is obviously a sub-optimal choice. In fact, oxcarbazepine does not bear any close structural resemblance to EZG. Moreover, it is a very popular antiepileptic drug, and this makes its simultaneous administration with EZG quite probable. In these cases, the IS would be totally useless.

Another method included both EZG and its active N-acetyl metabolite and used automated on-line solid-phase extraction in the form of column-switching [13]. In this case, a C8 column specifically suited for basic compounds (LiChrospher RP-Select B) was used, coupled with an acetonitrile/pH 6 ammonium acetate (55/45, v/v) mobile phase. MS/MS detection was carried out by atmospheric pressure chemical ionization (APCI)—QqQ. Sample preparation consisted of a sample dilution step with 800 µL of 13% (v/v) aqueous acetonitrile added to 200 µL of plasma, followed by injection of 500 µL of the mixture into a column-switching system using a preparative C2 column. Interfering matrix components (salts, proteins) were flushed out with 10% (v/v) aqueous acetonitrile, then the analytes were eluted with the mobile phase and switched to the analytical column. In this case, the EZG analogue ethyl N-[2-amino-4-[(2,4,6-trimethylphenyl)methylamino]phenyl]carbamate (Figure 2b) was used as the IS; again, the choice is suboptimal for an LC-MS/MS method, but the structural similarity is quite high.

The third method [14] deals with the determination of the N-acetyl metabolite by LC-APCI-MS/MS(QqQ) after pretreatment of 200 µL of plasma by micro-solid phase extraction (µSPE) in 96-well plates with a hydrophilic-lipophilic balance (HLB) sorbent; washing was carried out with two different ammonium acetate/acetonitrile/isopropyl alcohol mixtures, followed by elution with 1.2 mL of acetonitrile/isopropyl alcohol (40/60, v/v). To avoid the possible back-conversion of N-acetyl-EZG glucuronide to the parent N-acetyl-EZG, all materials and reagents for the dilution and µSPE procedures were refrigerated in ice; moreover, the glucuronide was eliminated from the sample by the washing step of the SPE procedure. However, the method only includes N-acetyl-EZG and has only been applied to dog plasma; hence, its usefulness for TDM is almost negligible. The IS was a 13C6-analogue of the analyte, which is a satisfactory choice.

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Figure 2. Chemical structures of the internal standards (ISs) used in references (a) [12], (b) [13], and (c) [14].

2.1.2. Ezogabine Interactions

Although the acetyl EZG metabolite has the capacity of inhibiting the P-glycoprotein (P-gp) transporter, a clinical study has found just a small increase in the digoxin plasma area under the concentration-time curve, which should not have any clinical significance [16]. EZG did not have any clinically relevant impact on exposure of hormones in a combined oral contraceptive agent containing norethindrone and ethinyl oestradiol, and the hormones did not alter EZG pharmacokinetic parameters [17]. In healthy humans, EZG did not significantly alter the pharmacokinetics of phenobarbital [18] and phenobarbitone [19].

In humans, ethanol increases exposure to EZG, but this interaction is probably not clinically significant [20].

2.1.3. Neuroprotection

Chemotherapy-induced peripheral neuropathy is a major dose-limiting side effect of many commonly used chemotherapeutic agents, including cisplatin. One mechanism underlying this neuronal damage is via drug-induced membrane depolarization. Accordingly, one potential approach for preventing chemotherapy-induced neuropathy is the maintenance of normal membrane potential during exposure to the neurotoxic drug. In a study, it was found that cisplatin caused membrane depolarization and peripheral axon loss in mice sensory nerves, and both actions were partially prevented by EZG pretreatment [21]. In the rat model, EZG reduced the stimulation of glutamate release and prevented the neuronal damage caused by 4-aminopyridine; however, it did not block its epileptic activity with equal effectiveness [22].

2.2. Lacosamide

LCS ((2R)-2-acetamido-N-benzyl-3-methoxypropanamide, Figure 3a) is used under the tradename Vimpat for the adjunctive treatment of partial-onset seizures and for neuropathic pain. The therapeutic activity of LCS has been attributed to the inactivation of sodium channels, and in particular to selective, fast binding to the slow inactivated state of Na+ channels [23], although slow binding to the fast inactivated state has been alternatively proposed recently [24]. It has also been proposed that LCS targets GABAA receptors as well [25]. LCS is a chiral compound, but it was traditionally only available as a racemate.
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Figure 3. Metabolic pathways of lacosamide.

2.2.1. Therapeutic Drug Monitoring

Single-Drug Methods

A clear relationship has been found between daily dose and plasma concentration of LCS; however, there does not appear to be any clear relationship between concentration and efficacy, and for this reason some authors think that the TDM of LCS is scarcely useful [26]. Nonetheless, the usefulness of TDM has recently been proposed in patients taking enzyme-inducer antiepileptics, in patients with decreased renal function or on dialysis, and older adults, due to the high probability of altered pharmacokinetics in these populations [27]. A paper has reported the use of LC-MS/MS to compare the serum and cerebrospinal fluid levels of LCS. A good correlation was found, thus confirming that serum is a significant and suitable matrix for the TDM of LCS [28]. The AGNP proposes a TDM recommendation level of 3, “useful”, for LCS, with therapeutic plasma levels in the 1–10 µg/mL and toxic levels above 20 µg/mL [29].
A few HPLC-UV methods for LCS analysis in human plasma have been published. One method uses a C18 column and a mobile phase consisting of pH 2 phosphate buffer and methanol; detection is carried out at 225 nm [30]. Sample pretreatment is performed by a simple LLE from 500 µL of plasma with 4 mL of a diethyl ether/dichloromethane (70/30, v/v) mixture. The organic phase was evaporated to dryness at 40 °C under a nitrogen stream, then reconstituted with 200 μL of water/methanol (20:80, v/v). Linearity was achieved in the 0.2–20 µg/mL range and extraction yields ranged from 94% to 95%. Precision RSD was 4.0–7.8% and accuracy ranged from 92.4% to 111.7%. A few short-term stability assays were also carried out, with 94–96% accuracy. The IS was ranolazine (Figure 4a), an anti-angina agent with little structural resemblance to LCS.
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Figure 4. Chemical structures of the internal standards (ISs) used in references (a) [30] and (b) [31].

2.2.2. Lacosamide Interactions

The potential of LCS for interactions, both with other AEDs and with different classes of drugs, seems to be relatively low [32].

In a retrospective study on 157 drug-resistant patients treated with LCS, levetiracetam resulted to be the compound most frequently associated with LCS in the responder subgroup. This allows us to hypothesize that LCS and levetiracetam can interact synergistically at the pharmacodynamic level [25]. Phase I clinical studies have found no significant interactions of LCS with omeprazole [33] or digoxin [34].

2.2.3. Neuroprotection

In rats, LCS has been observed to reduce oxidative stress, inflammation, and apoptosis caused by lipopolysaccharide in rat brain [35]; it also decreases the production of reactive oxygen species by increasing antioxidant enzyme expression, inhibiting lipid peroxidation and attenuating glial cell activation in experimental spinal cord injury [36].

2.3. Zonisamide

Zonisamide (1,2-benzoxazol-3-ylmethanesulfonamide, ZNS, Figure 5a) is an anticonvulsant agent used primarily for adjunctive treatment of partial seizures. However, it can also be used for a variety of other indications either on- or off-label, including partial and generalized seizures and absence [37], bipolar depression as a mood stabilizer [38], Parkinson’s disease [39], tardive dyskinesia during antipsychotic therapy [40], and migraine [41]. The mechanism of ZNS antiepileptic activity is still debated, but it is currently reputed to be the blockade of sodium and T-type calcium channels [42]. Moreover, the modulation of GABAergic and glutamatergic neurotransmission could have a role in seizure inhibition [43]. ZNS is mainly metabolized to 2-sulphamoylacetylphenol (cleavage of the benzisoxazole ring, Figure 5b) by CYP3A4, with minor contributions from CYP3A7 and CYP3A5 [44].
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Figure 5. Metabolic pathways of zonisamide.

2.3.1. Therapeutic Drug Monitoring

Single-Drug Methods

Recently, an HPLC-UV method has been used to verify the reliability of a routine TDM kit based on latex particle-enhanced turbidimetric immunoassay (LTIA) for ZNS [45]. The HPLC method used a C18 column and a mobile phase consisting of water, isopropyl alcohol, acetonitrile, and acetic acid. Column temperature was set at 40 °C and detection wavelength at 238 nm. Plasma sample (100 µL) pretreatment was based on a simple PPP with 200 µL of methanol, followed by centrifugation and supernatant injection. The IS was ZNS N,N-dimethylformimidamide (Figure 6a), which is reasonably similar to the analyte; however, the introduction of a relatively big functional group could impair the IS performance and make the method less than ideally reliable. The method was validated for ZNS quantification in the 1–75 µg/mL range, with accuracy in the 93.7–103.7% range and precision RSD values up to 10.3%. The corresponding validation parameters for the LTIA method were: linearity 5–50 µg/mL; accuracy 84.2–106.7; precision RSD ≤ 5.2%. The paper reports strong correlation between the results of the two methods, thus ruling out possible interferences from ZNS metabolites with the LTIA method. However, since the HPLC-UV method did not separate nor analyse any metabolites, and was not validated for selectivity toward them, similar interferences from metabolites in both methods could theoretically not be ruled out.

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Figure 6. Chemical structures of the internal standards (ISs) used in references (a) [46], (b) [47], (c) [48], and (d) [49].

Multi-Drug Methods

Several analytical methods with possible TDM application include ZNS together with other AEDs. Among them, and especially in recent years, methods using microsampling techniques are becoming commonplace. These techniques can provide several advantages over traditional venepuncture sampling, including reduced invasiveness, increased analyte stability, and minimal storage and shipping requirements [50][51][52][53]. For example, LC-MS/MS was used to analyze 14 drugs using volumetric absorptive microsampling (VAMS) [54], a technique based on a plastic device with a porous polymeric tip that is able to absorb fixed biological matrix volumes [55][56][57]. Another microsampling technique exploiting dried sample spot devices (DSSD) was used for plasma sampling. In this case, the DSSD is a simple filter paper sheet where the desired plasma volume is deposited (and absorbed) as a series of spots, which are then dried and properly extracted [58]. Analysis is then carried out by LC-MS/MS. Another miniaturized matrix, dried plasma spots (DPS), was used to analyze six AEDs, including ZNS, by HPLC-UV [59].

2.3.2. Zonisamide Interactions

Carbamazepine, phenytoin, and phenobarbital all increase ZNS clearance by 24–29%, an interaction that may necessitate a dosage increase [60]. Otherwise, ZNS is essentially devoid of clinically significant interactions with other AEDs (such as valproate [61] and lamotrigine [62]), oral contraceptives, and most other classes of therapeutic agents [63]. Conversely, ZNS does not appear to significantly alter the pharmacokinetics of phenytoin [64] and carbamazepine [65], nor those of oral contraceptives [66].

2.3.3. Neuroprotection

In experimental preclinical mouse models of Parkinson’s disease, ZNS reduces neuroinflammation through the downregulation of microglial voltage-gated sodium channels and the decrease of pro-inflammatory cytokine levels [67]. It also reduces nigrostriatal dopaminergic neurodegeneration in a mouse genetic model of Parkinson’s disease [68], possibly by increasing GSH levels by enhancing the astroglial cystine transport system and/or astroglial proliferation [69].

This entry is adapted from the peer-reviewed paper 10.3390/analytica2040016

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