What place do carbamazepine-related antiepileptic drugs have in the modern day treatment of epilepsy?

KEYWORDS:

• Carbamazepine
• oxcarbazepine
• eslicarbazepine acetate
• epilepsy

1. Introduction

Carbamazepine (CBZ), oxcarbazepine (OXC), and eslicarbazepine acetate (ESL) are all members of the dibenzazepine carboxamide family. CBZ is the oldest in this class of antiseizure medications (ASMs) and one of the most used drugs to treat epilepsy worldwide. In the 1980 s, an analog – OXC – was introduced to overcome pharmacokinetic and tolerability issues associated with CBZ. The efficacy of OXC was found to be primarily due to the S-enantiomer of its major metabolite, which was further developed into ESL, an acetate derivative of eslicarbazepine [1].

Albeit chemically related, significant differences exist between the three molecules. Here, we provide a summary of the main characteristics of these drugs and discuss their role in the treatment of patients with epilepsy.

2. Chemistry and pharmacology

CBZ is featured by a dibenzazepine nucleus with a 5-carboxyamide substituent. OXC is a structurally related derivative with a ketone substitution at the 10-position and ESL is structurally different at the 10, 11-position on the dibenzazepine ring (Table 1) [2].

Table 1. Summary of characteristics.

	Carbamazepine	Oxcarbazepine	Eslicarbazepine acetate
Oral bioavailability, %	75–85	90	>90
Serum protein binding, %	70–80	<40	<40
Maine route(s) of elimination	Oxidation (CYP3A4; metabolite: epoxide hydrolase)	Oxidation (arylketone reductase); conjugation (>50%); renal excretion (<30%)	Glucuronidation (UGT1A4, 1A9, 2B4, 2B7, 2B17)
Active metabolites	Carbamazepine-10,11- epoxide	Mono-hydroxy derivative (licarbazepine)	-
Half-life, hours	25–65 (single dose); 12–18 (repeated doses)	~2 (parent drug); ~9 (metabolite)	20–24
Effects on CYP/UGT	CYP induction (CYP3A4, 2C9, 1A2) UGT induction	CYP induction (CYP3A4) ^aCYP inhibition (CYP2C19) UGT induction (UGT1A4)	CYP induction (CYP3A4) ^aCYP inhibition (CYP2C19)
Dosing	Bis in die	Bis in die; (extended release: daily)	Daily
Starting dose and titration	400 mg/day; increase 200 mg/day at weekly intervals	600 mg/day; increase 600 mg/day at weekly intervals	400 mg/day; increase 400 mg/day at weekly intervals
Recommended dose	1000–1200 mg/day	1200 mg/day	800–1200 mg/day

^aWeak inhibition.

Abbreviations: CYP = cytochrome P-450, UGT = uridine glucuronyl transferase.

The mechanism of actions of these drugs consists mainly of the inhibition of the voltage-gated sodium channels (VGSC). Compared to CBZ and OXC, ESL has a lower affinity for the resting and a higher affinity for the inactivated states of VGCS, and reduces the VGSC availability by selectively enhancing slow rather than fast inactivation [2]. These properties result into a stabilization of hyper-excitable neuronal membranes, a greater inhibition of rapidly firing ‘epileptic’ neurons over cells with normal activity and, hence, a low propensity to disturb physiological functions [3]. Differences also exist in regard of the effects on calcium channels expressed in the brain: the interaction of CBZ is mediated via L-type, whereas OXC exerts its effect via N- and/or P- and/or R-type calcium currents; unlike CBZ and OXC, ESL are much more selective for the Cav3.2 T-type calcium channels.

CBZ is metabolized in the liver by cytochrome P-450 (CYP) 3A4 into CBZ-10,11-epoxide, which is the active metabolite and also the main responsible for neurological toxicity and untoward adverse events. CBZ is a strong inducer of several CYPs-450 and uridine-glucuronyl transferases and can be involved in many pharmacokinetic drug–drug interactions. Furthermore, with the chronic use, CBZ can also induce its own metabolism [4,5].

OXC and ESL are prodrugs of the same active compound licarbazepine (LIC), with differences in the stereoselectivity of the formed LIC. Much of OXC is converted to a racemic mixture of S-LIC (the S-enantiomer) and R-LIC (the R-enantiomer) in a 4:1 ratio. OXC is almost completely metabolized through the reduction and conjugation of its keto form to the active monohydroxy derivative (MHD). The formation of MHD occurs through a non-inducible ketoreductase and MHD undergoes glucuronidation through an only weakly inducible UDP-glucuronyltransferase. OXC metabolism, hence, is not induced or inhibited via the CYP system. OXC at high doses can inhibit CYP2C19 and, thus, increase the plasma levels of drugs as phenobarbital and phenytoin. OXC and MHD can induce CYP3A4/5, which are responsible for the metabolism of ASMs as CBZ, oral contraceptives, dihydropyridine calcium channel blockers [4,5].

ESL is rapidly hydrolyzed to S-LIC, which remains the primary circulating metabolite (95%) along with smaller amounts of R-LIC (4.5%) and OXC (0.5%); the net effect is that the exposure of eslicarbazepine is around 15% greater following oral intake of ESL than an equivalent molar dose of OXC [6]. This rapid conversion also allows the administration of ESL once daily, compared to twice daily dosing for CBZ and OXC. ESL can inhibit CYP2C19 and induce CYP3A4; it lacks significant auto-inducing properties [4,5]. The pharmacokinetics of ESL are not affected by enzyme-inducing ASMs or valproic acid and does not affect the metabolism of lamotrigine, in contrast to OXC and CBZ. Interestingly, the potential of ESL for both induction and inhibition of CYP-enzymes is different from the one of OXC due to the stereoselectivity of LIC-enantiomers in the interactions with biological molecules [5].

3. Clinical profile

The results of different studies clearly confirmed the clinical efficacy of CBZ, OXC, and ESL both as mono- and adjunctive therapy in the treatment of children, adolescents, and adults with focal-onset epilepsy. Although efficacy might not be a differentiating factor, differences exist with respect to tolerability and safety issues [7,8].

The most common side effects observed with these ASMs are similar, and include nausea, vomiting, dizziness, somnolence, diplopia, vertigo, and ataxia. Nonetheless, the comparative analyses of double-blind controlled trials demonstrated lower rates of treatment withdrawal due to adverse events with OXC than with CBZ and with ESL than with OXC [9].

Hyponatremia is a common concern reported with all the three drugs and more often with OXC. The risk to develop hyponatremia is greater with elderly, lower baseline sodium levels, increased fluid intake, concomitant intake of sodium‐wasting medications like diuretics, desmopressin, antidepressants, nonsteroidal anti-inflammatory drugs (e.g. indomethacin). Hyponatremia usually develops gradually and is typically subacute to chronic. Most cases are asymptomatic and symptoms rarely occur until levels drop below 120 mEq/L [10]. In terms of metabolism and hormonal balance, e.g. sex hormone levels, ESL and OXC can exhibit a safer profile and offer advantages compared with CBZ and other ASMs with strong enzyme-inducing effects.

CBZ can be associated with serious idiosyncratic adverse effects, including dermatological reactions as toxic epidermal necrolysis and Stevens-Johnson syndrome (SJS). The risk is reduced with OXC and mostly with ESL. In patients known to be positive for HLA-B*15:02 or HLA-A*31:01, medications other than CBZ should be preferred and, as cross-reactivity may occur, CBZ-related compounds also avoided. Strong associations between HLA-genotypes and OXC-induced SJS and maculopapular rash were found. The official summaries of product characteristics contraindicates OXC and ESL in patients with hypersensitivity reactions to CBZ [3]. The safety of ESL in subjects with HLA-B*15:02 or HLA-A*31:01 haplotypes and a history of CBZ- or OXC-induced hypersensitivity reactions remain, however, to be fully addressed [3]. Aplastic anemia and agranulocytosis have been also associated with the use of CBZ, whereas OXC and ESL do not have these black-box warning [2].

Carboxamides derivatives as CBZ and OXC are some of the ASMs considered to have a favorable psychiatric effect profile. ESL has been also shown to improve anger levels, mood, and quality of life and produce no significant effects on neurocognitive and behavioral functioning in patients with epilepsy aged 6 to 16 years; a history of psychiatric disorders could be a limiting factor to improve anger.

4. Expert opinion

CBZ, OXC, and ESL are approved for mono- and adjunctive therapy of focal seizures in children and adults; CBZ is also authorized for generalized tonic-clonic seizures. As concerns prescription in women of childbearing potential, the EURAP registry showed a risk for major malformations of 4.5% and 7.2% in children exposed to CBZ at doses less than and above 700 mg/day, respectively. The prevalence of major malformations in children exposed to OXC resulted approximately 3% and consistent with what we observe in children with no known exposure to teratogens. ESL has no teratogenic effects in the rat or rabbit but induced skeletal abnormalities in the mouse; increases in minor skeletal and visceral anomalies were observed at maternal toxic doses in embryo-toxicity studies. To date, there is no enough evidence to draw conclusions about the safety of ESL in pregnant women, and it is unknown whether it is excreted in human milk [3].

Switching between medications may be prompted by poor tolerability and occurrence of side effects including metabolic disorders, hypercholesterolemia, osteoporosis or sexual dysfunction, incomplete seizure control, drug–drug interactions, preference for a simpler dosing schedule.

OXC has been successful in seizure control when other ASMs including CBZ have proved ineffective. In addition, ESL does not only suppress seizure activity, but also inhibits the generation of a hyperexcitable network, and can overcome cellular mechanisms of resistance to sodium-channel blockers [11]. Interestingly, up to half of the patients in controlled clinical trials were receiving CBZ at the time of randomization: they still benefited from the addition of ESL although reported an increased incidence of adverse events. ESL has been also shown to be efficacious in patients who have previously tried and withdrawn the older carboxamides, regardless of the reasons for discontinuation [12].

One major issue is how to best combine di-benzazepine carboxamides for patients requiring polytherapy. Rational polypharmacy is aimed to maximize efficacy and minimize side effects and favorable combinations generally consist of ASMs with different mechanisms of action. Most of the available evidence comes from preclinical studies. In experimental models, coadministration of CBZ and valproic acid (VPA) showed additive antiseizure activity and infra-additive toxicity. Concomitant use of CBZ and phenobarbital (PB) resulted into additivity both in efficacy and toxicity. The coadministration of CBZ or OXC with lamotrigine (LTG) was accompanied by anticonvulsant antagonism and neurotoxic additivity. When OXC was combined with phenytoin (PHT), anticonvulsant infra-additivity was evident at the ratio of 1:1 and additivity at other dose ratios; neurotoxicity additivity occurred at all dose ratios. Gabapentin (GBP) combined with CBZ produced supra-additive efficacy and additive neurotoxicity in the chimney test. Supra-additivity or additivity in seizure control was found in combinations between classical and newer ASMs, including CBZ+topiramate (TPM), CBZ+zonisamide, CBZ+levetiracetam (LEV), CBZ+pregabalin (PGB). Anticonvulsant synergy and additive toxicity occurred combining OXC+TPM. Coadministration of OXC with GBP resulted in supra-additive efficacy and no signs of adverse effects. OXC with tiagabine determined additive efficacy and infra-additive toxicity. Additivity in either efficacy or toxicity was shown when OXC was combined with PGB. OXC+LEV resulted in additive or supra-additive efficacy with no accompanying neurotoxicity. There is only a little evidence about combinations of more than two ASMs: CBZ, PB, and TPM at the fixed-dose ratio of 1:1:1 proved supra-additive effect against seizures [13].

From the clinical perspective, uncontrolled studies and post hoc analyses suggest that combinations of sodium channel blockers are associated with an increased incidence of dose-dependent adverse effects. Indeed, synergistic neurotoxicity has been reported combining CBZ with LTG, OXC, or ESL, and lacosamide with Na+ channel blocking ASMs. LTG has been also shown to be more effective when given in monotherapy than in combination with CBZ in patients with refractory epilepsy. In the analysis of more than 2,300 seizure-free patients, CBZ+VPA, CBZ+LEV, CBZ+TPM, CBZ+PB, CBZ+GBP resulted among the commonest successful duo-therapies and CBZ/LTG/LEV and CBZ/PB/PHT among the commonest successful triple therapy regimens [13].

Compounds with a low level of enzyme induction are more suitable for combination with other ASMs and drugs for the treatment of concomitant diseases. Extended release formulations and drugs with long half-life may reduce peak-trough fluctuations and, hence, improve tolerability and favor the achievement of target doses. Once-daily administration increases treatment adherence and may be preferred in patients who are poorly compliant with two- or three-daily dosing regimen, frequently forget to take their medication, perform work on rotating shifts, and in patients who are poly-medicated. Remarkably, the extended-release formulation of OXC, which provides consistent plasma levels over 24-h, and offers the advantage to be administered once daily, resembles more closely the pharmacological profile of ESL and its advantages.

Measuring serum concentrations of old and new generation ASMs can have a role in optimizing pharmacotherapy. Indications for therapeutic drug monitoring (TDM) include non-response at therapeutic doses, uncertain drug compliance, suboptimal tolerability, or clinical toxicity, pharmacokinetic interactions. Patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with associated diseases or intellectual disabilities [14]. The non-linear pharmacokinetics due to auto-induction, the non-predictable relationship between dose and concentration, the narrow therapeutic index, and the presence of numerous clinically significant drug interactions make TDM particularly useful during CBZ therapy; both CBZ and CBZ-epoxide concentrations should be monitored. Due to wide inter-individual differences in OXC dose to 10-hydroxycarbazepine plasma concentration relationship, TDM is a valuable adjunct in individualizing treatment and MHD monitoring could help in the management of patients on high-dose OXC therapy. Although ESL is subject to very few pharmacokinetic interactions, inter-patients variability in concentration/dose ratios is extensive: TDM may be of aid for individualization of treatment and further studies are needed to clearly demonstrate its usefulness [14].

In patients unsatisfactorily treated with CBZ, overnight switch to OXC at a dose ratio of 1:1.5 resulted feasible and showed similar efficacy and tolerability of progressive switch, even in patients on combination therapy. An observational multicenter study revealed that physicians generally preferred the immediate switch, and antiepileptic polytherapy could represent one factor inducing to opt for the progressive procedure. Notably, immediate switch was associated with higher levels of satisfaction both in clinicians and patients in comparison to the progressive transition.

The switch from OXC to ESL can be performed as a 1:1 dose equivalent and take place overnight; no changes to co-medication are required [3]. Conversely, transitioning from CBZ to ESL is less straightforward and requires considerations on a patient-by-patient basis: a dose ratio of 1:1.3 should be considered and immediate switch over is not recommended. It has been suggested to perform the conversion gradually over 1 to 3 weeks and concomitant medications metabolized by cytochrome enzymes may require dose adjustment. ESL dose may also need to be adjusted once the induction of CYP450 enzyme system by CBZ has resolved [15].

In summary, CBZ, OXC, and ESL represent distinguishable ASMs. Differentiating features make them ASMs in their own right, may render one preparation more advantageous over another in selected patients and allow flexibility in individualizing care.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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Funding

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