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Keywords:

  • Antiepileptic drugs;
  • Eslicarbazepine acetate;
  • Eslicarbazepine;
  • Pharmacokinetics;
  • Drug interactions

Summary

  1. Top of page
  2. Summary
  3. Biopharmaceutic Properties
  4. Pharmacokinetics in Laboratory Animals
  5. Pharmacokinetics in Humans
  6. Pharmacokinetics in Special Populations
  7. Drug Interactions
  8. Interactions with Other AEDs
  9. Interactions with Other (Non-AED) Medications
  10. Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship
  11. Summary
  12. Disclosure
  13. References

Eslicarbazepine acetate (ESL) is a novel once-daily antiepileptic drug (AED) approved in Europe since 2009 that was found to be efficacious and well tolerated in a phase III clinical program in adult patients with partial onset seizures previously not controlled with treatment with one to three AEDs, including carbamazepine (CBZ). ESL shares with CBZ and oxcarbazepine (OXC) the dibenzazepine nucleus bearing the 5-carboxamide substitute, but is structurally different at the 10,11 position. This molecular variation results in differences in metabolism, preventing the formation of toxic epoxide metabolites such as carbamazepine-10,11-epoxide. Unlike OXC, which is metabolized to both eslicarbazepine and (R)-licarbazepine, ESL is extensively converted to eslicarbazepine. The systemic exposure to eslicarbazepine after ESL oral administration is approximately 94% of the parent dose, with minimal exposure to (R)-licarbazepine and OXC. After ESL oral administration, the effective half-life (t1/2,eff) of eslicarbazepine was 20–24 h, which is approximately two times longer than its terminal half-life (t1/2). At clinically relevant doses (400–1,600 mg/day) ESL has linear pharmacokinetics (PK) with no effects of gender or moderate liver impairment. However, because eslicarbazepine is eliminated primarily (66%) by renal excretion, dose adjustment is recommended for patients with renal impairment. Eslicarbazepine clearance is induced by phenobarbital, phenytoin, and CBZ and it dose-dependently decreases plasma exposure of oral contraceptive and simvastatin.

Eslicarbazepine acetate (ESL) is available in Europe in the form of tablets under the trade name Zebinix® (manufactured by: BIAL – Portela & Co, S. Mamede do Coronado, Portugal) and its suspension form is under clinical development. ESL is not currently available in the United States; it is pending U.S. Food and Drug Administration (FDA) approval under the trade name Stedesa® for the adjunctive treatment of partial-onset seizures in adult patients with epilepsy. ESL pharmacokinetics (PK) has been studied following oral administration to healthy young and elderly adults, adults, and pediatric patients with epilepsy, and patients with renal and hepatic impairment. In addition, ESL is under investigation in patients older than 65 years of age with partial epileptic seizures.

After oral administration, ESL undergoes a rapid presystemic (main hepatic and minor intestinal) metabolic hydrolysis to eslicarbazepine, also known as (S)-licarbazepine (Almeida et al., 2009). Unlike oxcarbazepine (OXC), which is metabolized to its two enantiomeric monohydroxy derivatives (MHDs)—eslicarbazepine (80%) and (R)-licarbazepine (20%) (Flesch et al., 1999; Volosov et al., 1999; Bialer, 2002), ESL is metabolized initially solely to eslicarbazepine and then subsequently undergoes a minor chiral inversion (through oxidation to OXC) to (R)-licarbazepine, resulting in an eslicarbazepine-to-(R)-licarbazepine area under the plasma concentration time curve (AUC) ratio of approximately 95%/4.5% = 19, with approximately 0.5% circulating as OXC (Fig. 1). Exposure to (R)-licarbazepine or OXC after administration of ESL is therefore minimal. As depicted in Fig. 1, OXC does not undergo complete biotransformation to licarbazepine, and 13% of the OXC dose is metabolized via conjugation to glucuronic and sulfuric acids and not by metabolic reduction to licarbazepine (Shutz et al., 1986; Bialer, 2002; Flesch, 2004). Therefore, the exposure of eslicarbazepine measured in terms of AUC is ∼16% greater following oral administration of ESL than after oral intake of an equivalent molar dose of OXC (Hainzl et al., 2001; Bialer et al., 2004; Bialer, 2006; Bialer et al., 2009; Bialer & White, 2010).

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Figure 1.   Metabolic pathways of eslicarbazepine acetate (ESL) and oxcarbazepine (OXC) to eslicarbazepine and (R)-licarbazepine. ESL is metabolized solely to eslicarbazepine that subsequently undergoes a minor chiral inversion (presumed through oxidation to OXC) to (R)-licarbazepine resulting in an eslicarbazepine-to-(R)-licarbazepine AUC ratio of 95%/5% = 19. (%)–% in relation to total ESL metabolites excreted (recovered) in urine (Perucca et al., 2011).

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Biopharmaceutic Properties

  1. Top of page
  2. Summary
  3. Biopharmaceutic Properties
  4. Pharmacokinetics in Laboratory Animals
  5. Pharmacokinetics in Humans
  6. Pharmacokinetics in Special Populations
  7. Drug Interactions
  8. Interactions with Other AEDs
  9. Interactions with Other (Non-AED) Medications
  10. Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship
  11. Summary
  12. Disclosure
  13. References

ESL is slightly soluble (<1 mg/ml) in aqueous buffer solutions at different pH. As a neutral compound, ESL is nonionizable at physiologic conditions (Almeida et al., 2009). The chemical hydrolysis of the ESL ester moiety to produce eslicarbazepine occurs at low and high pH (1.2 and 10, respectively [BIAL-data on file]). In contrast to ESL, eslicarbazepine has a water solubility of 4.2 mg/ml, which is >10-fold higher than the water solubility of ESL, OXC, or carbamazepine (CBZ) (Faigle & Menge, 1990). The n-octanol/water partition coefficient (pH = 7.4 at 25°C) of eslicarbazepine and OXC are 8.8 and 20.4, respectively, confirming OXC higher lipophilicity compared to eslicarbazepine (Flesch et al., 2011). In the past decade, a biopharmaceutic classification system (BCS) has been established to categorize drugs according to their water solubility and ability to pass across membranes (Amidon et al., 1995; Wu & Benet, 2005; Rowland & Tozer, 2010). The BCS allows prediction of in vivo pharmacokinetic performance of drug products from measurements of permeability (assessed by extent of oral absorption) and water solubility. Drugs whose drug content at the highest strength can dissolve in 250 ml of water throughout the physiologic pH range of 1–7.5 are considered as highly soluble drugs. Drugs showing complete oral absorption are said to be highly permeable. Therefore, ESL is a highly permeable-poorly soluble (BCS class II) drug, whereas eslicarbazepine is a highly soluble-highly permeable (BCS class I) drug. Generally, BCS class I drugs tend to be orally absorbed, distributed to tissues (except in the brain), and eliminated from the body, with minimal influence by transporters (Wu & Benet, 2005).

Pharmacokinetics in Laboratory Animals

  1. Top of page
  2. Summary
  3. Biopharmaceutic Properties
  4. Pharmacokinetics in Laboratory Animals
  5. Pharmacokinetics in Humans
  6. Pharmacokinetics in Special Populations
  7. Drug Interactions
  8. Interactions with Other AEDs
  9. Interactions with Other (Non-AED) Medications
  10. Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship
  11. Summary
  12. Disclosure
  13. References

Plasma and urine concentrations of ESL and its metabolites can be monitored by solid phase extraction followed by high-performance liquid chromatography, with ultraviolet or mass spectrometric detection (liquid chromatography with mass spectrometry) (Fontes-Ribeiro et al., 2005; Fortuna et al., 2010; Loureiro et al., 2011b). ESL metabolism varies significantly across species (Fig. 2). In general, following oral administration to animals or humans, only minimal or no measurable concentrations of the parent compound (ESL) have been observed or quantified. In the rat, ESL was metabolized primarily to OXC, with eslicarbazepine and (R)-licarbazepine as minor metabolites. In the mouse, hamster, and rabbit, eslicarbazepine was the major metabolite, and OXC and (R)-licarbazepine were minor metabolites. In the dog, eslicarbazepine was a major metabolite and OXC and (R)-licarbazepine were minor metabolites, but measurable amounts of ESL were observed up to 2 h after dosing. In the cynomolgus monkey, measurable amounts of ESL were found up to 1.5 h after administration, with eslicarbazepine representing up to 96.5% of active moieties; no measurable amounts of OXC and (R)-licarbazepine were found (BIAL-data on file). In humans, ESL was metabolized extensively, mainly to eslicarbazepine; (R)-licarbazepine and OXC were minor metabolites (Almeida et al., 2009). Therefore the mouse, hamster, and rabbit are the most relevant animal species, since their ESL metabolic pathways are the most similar to humans.

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Figure 2.   Disposition and systemic exposure of ESL and its metabolites in mammals after ESL oral administration, indicating that in all species (except rats) including humans eslicarbazepine is the major metabolite and active entity. GLU, glucuronide conjugate.

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In the mouse, following oral administration of eslicarbazepine and (R)-licarbazepine to parallel groups, the brain ratio of the two licarbazepine enantiomers— AUCbrain(eslicarbazepine)/AUCbrain((R)-licarbazepine)—was greater than that in plasma (AUCplasma(eslicarbazepine)/AUCplasma((R)-licarbazepine)) (1.87 vs. 1.10), suggesting that brain distribution of eslicarbazepine in mice is greater than that of (R)-licarbazepine (Alves et al., 2008). In the mouse, eslicarbazepine brain-to-plasma maximum concentration (Cmax) or AUC ratio was found to be two times higher than that for (R)-licarbazepine (Alves et al., 2008). This suggests that there is enantioselectivity in licarbazepine crossing of the mouse blood–brain barrier, with (R)-licarbazepine having considerably more difficulty in brain access.

To assess whether the preceding enantiospecific differences in brain penetration in the mouse are related to susceptibility to the efflux transporters P-glycoprotein (P-gp) or multidrug resistance protein (MRP), mice were pretreated with verapamil or probenecid (Almeida et al., 2009). Verapamil and probenecid failed to affect the eslicarbazepine brain-to-plasma AUC ratio. In contrast, verapamil, but not probenecid, markedly increased the (R)-licarbazepine brain-to-plasma ratio. This indicates that eslicarbazepine is a substrate for neither P-gp nor MRP, whereas (R)-licarbazepine is a substrate for P-gp but not for MRP. It is interesting to underline the fact that the (R)-licarbazepine brain-to-plasma AUC ratio after verapamil treatment was equal to that of eslicarbazepine in vehicle-treated animals. These findings support those described by other authors who showed that the racemic (R,S)-licarbazepine does not appear to cross the blood–brain barrier by a simple passive diffusion, but rather by a P-gp–mediated active transport (Marchi et al., 2005). Because eslicarbazepine and (R)-licarbazepine enantiomers have different pharmacodynamic and pharmacokinetic properties, it would be better to evaluate them individually with use of stereospecific methods for specific scientific purposes.

Pharmacokinetics in Humans

  1. Top of page
  2. Summary
  3. Biopharmaceutic Properties
  4. Pharmacokinetics in Laboratory Animals
  5. Pharmacokinetics in Humans
  6. Pharmacokinetics in Special Populations
  7. Drug Interactions
  8. Interactions with Other AEDs
  9. Interactions with Other (Non-AED) Medications
  10. Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship
  11. Summary
  12. Disclosure
  13. References

Pharmacokinetics after single dose

After oral administration to humans, ESL is rapidly and extensively biotransformed to eslicarbazepine by a hepatic first-pass hydrolytic metabolism, and consequently ESL plasma concentrations usually remain below the limit of quantification (Almeida et al., 2005). The bioavailability of eslicarbazepine following oral administration of ESL is high and has been shown not to be affected by food. More than 90% of ESL oral dose has been shown to be recovered as ESL metabolites in urine (Fig. 1) (Almeida et al., 2005; Maia et al., 2005).

Eslicarbazepine fraction bound (fb) to human plasma proteins was 30% and its fb to human blood cells was 46%; binding was concentration-independent at concentrations up to 100 mg/L. A concentration of 100 μg/ml is twice the maximum eslicarbazepine steady-state plasma concentration (Cmax,ss) obtained following ESL 2,400 mg/day (Vaz-da-Silva et al., 2005). [14C]-Eslicarbazepine binding to plasma proteins was unaffected by warfarin, diazepam, digoxin, phenytoin (PHT), and tolbutamide. Similarly, eslicarbazepine did not affect the plasma protein binding of [14C]-warfarin, [14C]-diazepam, [3H]-digoxin, [14C]-PHT, and [14C]-tolbutamide (Almeida & Soares-da-Silva, 2007).

In pharmacokinetic studies, ESL metabolites in plasma or urine were quantified using achiral and chiral methods. When a chiral method is used, the assay is able to distinguish between eslicarbazepine (the main active enantiomer of ESL) and (R)-licarbazepine (the minor metabolite of ESL) (Falcão et al., 2007; Almeida et al., 2008; Maia et al., 2008). Achiral assay methods cannot distinguish between eslicarbazepine and (R)-licarbazepine. Consequently, the racemic mixture (R,S)-licarbazepine has been monitored and reported as BIA 2-005 (Falcão et al., 2007; Almeida et al., 2008). An approximately dose-proportional increase in (R,S)-licarbazepine Cmax and a greater than dose-proportional increase in its AUC have been found following ESL single oral doses from 20 to 1,200 mg (Almeida et al., 2008). However following multiple dosing of clinically-relevant doses of 400–2,400 mg/day, a dose proportionality was observed in AUC within a dosing interval at steady-state (AUCss) values with small deviation of <10% (Almeida & Soares-da-Silva, 2007).

To characterize the disposition of licarbazepine enantiomers, (R,S)-licarbazepine was administered intravenously (250 mg infused over 30 min) to 12 healthy adults and the following mean (± standard deviation, SD) PK parameters were calculated for licarbazepine individual enantiomers (Flesch et al., 1999, 2011). For eslicarbazepine: clearance (CL) = 3 ± 0.7 L/h; renal clearance (CLr) = 0.9 ± 0.2 L/h; fraction excreted unchanged in urine (fe) = 16 ± 3.1%; volume of distribution (V) = 46 ± 9 L; and terminal half-life (t1/2) = 10.6 ± 2.6 h. For (R)-licarbazepine: CL = 4.2 ± 0.9 L/h; CLr = 0.9 ± 0.2 L/h; fe = 11 ± 1.9%; V = 55 ± 11 L; and t1/2 = 9.0 ± 1.5 h (Flesch et al., 1999; Bialer, 2002). The above 12 healthy subjects also received OXC (300 mg) orally in a randomized, two-way crossover, single-dose design. Consequently licarbazepine (pooled R- and S-enantiomers) mean absolute bioavailability (F) after OXC oral dosing was found to be 89% (Bialer, 2002).

Pharmacokinetics after multiple dosing

Healthy subjects

Following ESL oral dosing in healthy volunteers, (R,S)-licarbazepine-t1/2 ranged between 9 h (ESL-dose = 20 mg) and 17 h (ESL-dose = 1,200 mg). OXC was found to be a minor metabolite of ESL, representing approximately 1% of plasma exposure (AUC) to (R,S)-licarbazepine (Almeida & Soares-da-Silva, 2007). Following repetitive oral dosing of ESL (400, 800, and 1,200 mg/day) to healthy subjects, (R,S)-licarbazepine Cmax was reached 2.5–3 h after dosing (Almeida & Soares-da-Silva, 2004). Thereafter, (R,S)-licarbazepine t1/2 ranged between 10 h (400 mg/day) and 13 h (1,200 mg/day) (Almeida & Soares-da-Silva, 2004). Following multiple dosing of ESL, (R,S)-licarbazepine Cmax,ss and AUCss increased in an approximately dose-proportional manner. ESL PK in healthy subjects was not affected significantly by age or gender (Almeida et al., 2005; Falcão et al., 2007).

Eslicarbazepine and other ESL metabolites are eliminated mainly in the urine (Almeida & Soares-da-Silva, 2003, 2004; Almeida et al., 2008; Maia et al., 2008). Following ESL multiple dosing (800 mg/day) to healthy subjects, 92% of the ESL dose was excreted in urine as eslicarbazepine, two-thirds (67%) as free (unconjugated) form, and one third (33%) as the glucuronide conjugate (Almeida et al., 2008). Previous reports on OXC metabolism showed that the urinary conjugated licarbazepine metabolites are O-glucuronides, with a eslicarbazepine-GLU/(R)-licarbazepine-GLU ratio of 6.9, almost twice as high as eslicarbazepine plasma enantiomeric ratio (3.8) (Schutz et al., 1986; Flesch, 2004; Flesch et al., 2011). In contrast to humans, in mice liver microsomes, two glucuronides of eslicarbazepine were found; however, only one was hydrolyzed by Escherichia coliβ-glucuronidase (Loureiro et al., 2011a), an enzyme that hydrolyzes O-glucuronides preferentially over N-glucuronides (Zenser et al., 1999). Technical difficulties in producing standards of eslicarbazepine glucuronides precluded the distinction between its possible N- or O-glucuronides; however, the selectivity reported for E. coliβ-glucuronidase coupled with the fact that the OXC active metabolite 10-monohydroxy derivative (licarbazepine) is excreted as O-glucuronide (Schutz et al., 1986; Flesch, 2004), suggest that conjugation of eslicarbazepine may be on the hydroxyl group (O-glucuronide; Fig. 1).

The remaining 8% of the ESL dose was excreted in urine as (R)-licarbazepine, OXC and glucuronide conjugates of ESL, eslicarbazepine, (R)-licarbazepine, and OXC (Fig. 1). In vitro studies in human liver microsomes indicated that the following uridine diphosphate glucuronosyl transferases (UGTs) appear to be involved in eslicarbazepine glucuronidation: UGT1A4, UGT1A9, UGT2B4, UGT2B7, and UGT2B17 (Loureiro et al., 2011a). Eslicarbazepine glucuronidation is another example showing that UGT isozymes exhibit distinct but overlapping (more than cytochrome P450 [CYP]) substrate selectivity (Wen et al., 2007). The UGT with the highest affinity for eslicarbazepine conjugation that may play a major role in its glucuronidation was UGT2B4, with Michaelis-Menten constant (Km) values of 163 and 22 μm in the absence and presence of bovine serum albumin (BSA), respectively (Loureiro et al., 2011a).

Following ESL multiple dosing (400–1,200 mg/day) in healthy volunteers, the mean observed accumulation ratio (Rac) or accumulation index of (R,S)-licarbazepine was 1.4–1.7. Rac was estimated by the quotient AUCss/AUC0–24 for (R,S)-licarbazepine (equation 1) and is consistent with an effective half-life (t1/2,eff) or accumulation half-life of 20–24 h. The t1/2,eff was calculated from equations 1 and 2 (Kwan et al., 1984; Boxenbaum & Battle, 1995; Sahin & Benet, 2008).

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For most drugs there is no single half-life that can adequately predict appropriate dosing interval and drug accumulation following multiple dosing. This is because concentration–time curves of drugs are best described by a multiexponential function that yields more than one half-life to describe the drug plasma profile (Sahin & Benet, 2008). For (R,S)-licarbazepine (and its individual enantiomers), like many other drugs, the half-life that is usually reported is the terminal half-life (t1/2). However, for many drugs, t1/2 may represent only a small fraction of the drug total body clearance. In fact, during the first hours after dosing, the elimination rate appears lower, since drug continues to enter the systemic circulation through absorption. Therefore, t1/2 can be measured reliably only after completion of absorption, and during much of the dosing interval it is not t1/2 that is most relevant. Consequently, t1/2 has a minimal effect on the extent of accumulation (Rac) of (R,S)-licarbazepine obtained following ESL multiple (daily) dosing. Effective half-life in contrast to t1/2 estimates drug accumulation utilizing Rac and therefore is a function of absorption rates and the dosing interval, as opposed to being only a drug-related parameter (Sahin & Benet, 2008). In the case of eslicarbazepine, t1/2,eff is a function of ESL absorption rate as well as eslicarbazepine formation and elimination rates. Consequently, t1/2,eff of eslicarbazepine was two times longer than its t1/2. Steady-state plasma concentrations of eslicarbazepine were reached 4–5 days after repeated ESL dosing, consistent with a t1/2,eff of 20–24 h.

In a group of healthy subjects administered ESL 800 mg/day for 8 days, the chiral method was used for monitoring plasma and urine levels of eslicarbazepine and its metabolites as free (unconjugated) and glucuronide conjugates (Almeida et al., 2008). The mean steady-state plasma concentrations of eslicarbazepine and its metabolites during a 24-h dosing intervals are presented in Fig. 3. Using AUCss as a measure of systemic exposure, eslicarbazepine corresponded to approximately 91% of the sum (AUC) of all circulating ESL-related entities (parent compound and metabolites). The minor metabolites in plasma (R)-licarbazepine, OXC, and glucuronide conjugates of eslicarbazepine, (R)-licarbazepine and OXC, corresponded to 9% of total plasma exposure or AUC (Almeida et al., 2008). The main metabolic pathway of ESL in comparison to OXC is presented in Fig. 1.

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Figure 3.   Mean plasma concentration-time profiles during a 24 h dosing interval at steady-state of ESL metabolites following the last dose of an 8-day treatment with ESL 800 mg/day in healthy subjects (n = 8). GLU, glucuronide conjugate. The inset magnifies the minor metabolites profiles.

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A comparative parallel PK analysis recently assessed the cerebrospinal fluid and plasma concentrations of ESL and OXC and their metabolites following oral dosing over 9 days (including a 3-day titration period) of either ESL (1,200 mg/day) or OXC (600 mg twice/day) to seven healthy subjects in each group (Kharidia et al., 2010). In the ESL group, the relative plasma exposure to eslicarbazepine, (R)-licarbazepine, and OXC was 93.8%, 5.2%, and 0.9%, respectively, and the cerebrospinal fluid relative exposure was 92.0%, 7.1%, and 1.0%, respectively. In the OXC group the relative plasma exposure to eslicarbazepine, (R)-licarbazepine, and OXC was 78.0%, 18.5%, and 3.5%, and the cerebrospinal fluid relative exposure was 76.4%, 21.4%, and 2.2%, respectively. The study showed that: (1) eslicarbazepine and its minor metabolites had an even distribution between cerebrospinal fluid and plasma; (2) compared to OXC, ESL oral administration resulted in more eslicarbazepine, less (R)-licarbazepine, and less OXC in plasma and cerebrospinal fluid; (3) following ESL oral administration there was a smaller apparent peak-trough fluctuation of eslicarbazepine in cerebrospinal fluid (1.5) than in plasma (2.9), with a long apparent half-life of eslicarbazepine in cerebrospinal fluid (24.8 ± 8.08 μg/ml); (4) with the oral administration of OXC 600 mg twice daily, an early peak of OXC was observed both in plasma and cerebrospinal fluid, and peak-trough fluctuations of (R)-licarbazepine and OXC in both plasma and cerebrospinal fluid were wider (Kharidia et al., 2010).

Patients with epilepsy

Following ESL multiple dosing (1,200 mg/day) in adult patients with partial-onset seizures (n = 18), the mean steady-state eslicarbazepine plasma levels fluctuated between a peak (Cmax,ss) of 23 μg/ml and a trough (Cmin,ss) of 12 μg/ml (Perucca et al., 2011). This is consistent with a t1/2,eff of 20–24 h. When a drug is dosed at a time interval (τ) equal to its effective half-life (τ = t1/2,eff), the peak trough (Cmax,ss/Cmin,ss) fluctuations are 100%, or 2. The degree of accumulation or accumulation index (Rac, equation 1) is 2, namely the multiple dose steady-state plasma levels and plasma exposure (AUCss) is twice higher than those observed following a single dose (Rowland & Tozer, 2010). When ESL is given at 600 mg twice daily, the Cmax,ss/Cmin,ss fluctuations are only 40%, or 1.4. Following multiple dosing once every half of a half-life (τ = 0.5t1/2,eff), the Rac is higher than those obtained following once every half-life and is equal to 3.3 (Rowland & Tozer, 2010). Therefore, eslicarbazepine steady-state plasma levels and plasma exposure (AUCss) are 3.3 higher than those observed following ESL single dosing.

In a phase II placebo-controlled, adjunctive therapy study in adult patients with partial-onset seizures, once-daily ESL was found to be efficacious and well tolerated at 800 and 1,200 mg, but the same dose given twice-daily was not significantly more efficacious than placebo (Elger et al., 2007). Furthermore, a comparison between once-daily and twice-daily regimens showed a statistically significant difference (58.0% vs. 32.6%, p = 0.022) at the 800-mg dose with respect to responder rate (primary end point). With respect to 1,200 mg ESL, the superiority of the once-daily over the twice-daily regimen on responder rate (54.0% vs. 41.3%, p = 0.299) did not attain statistical significance (BIAL-data on file). These results may indicate that ESL antiepileptic activity correlates better with eslicarbazepine Cmax,ss than with its AUCss, since AUCss depends on clearance only and is unaffected by the dosing frequency (τ) and is consequently the same following once-daily and twice-daily dosing of the same daily dose. In fact, it has been demonstrated previously that although eslicarbazepine AUCss is the same following once-daily and twice-daily dosing, its Cmax,ss is 33% higher following ESL 900 mg daily than 450 mg twice daily (Almeida et al., 2006a). Based on phase II results, ESL was dosed once daily in the subsequent phase III studies undertaken and completed in 1,049 patients.

Each of the ESL phase III studies consisted of an 8-week prospective baseline period, followed by a double-blind 2-week titration, and consecutively a double-blind 12-week maintenance period and a 4-week tapering-off period. ESL was studied at doses of 400, 800, or 1,200 mg/day given once daily (Almeida et al., 2009; Elger et al., 2009; Gil-Nagel et al., 2009; Ben-Menachem et al., 2010). Patients were refractory to treatment with one to three concomitant antiepileptic drugs (AEDs). Between 64% and 75% of the patients in each phase III studies were taking two concomitant AEDs, and approximately 60% of the patients were taking CBZ as one of their concomitant AEDs, which was the most common AED. At once-daily doses of 800 and 1,200 mg, ESL was associated with a statistically significant decrease in standardized seizure frequency (p < 0.0001) and a median relative reduction in seizure frequency of 29.4% (p < 0.0001, at 800 mg/day) and 30.6% (p < 0.0001, at 1,200 mg/day) versus 8.5% in placebo. Therefore, statistically significant differences in responder rates were found in each of the studies for the 800 and 1,200 mg/day once-daily treatment arms, whereas no statistically significant differences between the 400 mg and placebo arms were found in any of the phase III studies (Almeida et al., 2009; Elger et al., 2009; Gil-Nagel et al., 2009; Ben-Menachem et al., 2010).

During the course of double-blind period of phase III studies, trough-eslicarbazepine plasma concentrations (Cmin,ss) were determined in 571 adult patients with partial epilepsy treated with ESL once daily 400, 800, or 1,200 mg concomitantly with one to three AEDs, whereas CBZ was the most commonly used AED (∼60% of subjects) (BIAL-data on file). The mean (95% confidence interval [CI]) predose (Cmin,ss) plasma concentrations of eslicarbazepine at the end of the maintenance period were dose dependent after ESL 400 mg (n = 160), 800 mg (n = 222), and 1,200 mg (n = 189), as shown in Figure 4, and correlate well with pharmacodynamic and therapeutic benefits observed in this population of adult patients with epilepsy refractory to treatment with one to three concomitant AEDs (BIAL-data on file).

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Figure 4.   Mean and 95% CI eslicarbazepine plasma “trough” (pre-dose) concentrations following ESL 400, 800, and 1,200 mg/day administration in phase III clinical trial epileptic subjects concomitantly treated with one to three AEDs.

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In a group of 51 adult patients (ESL 400 mg [n = 7], 800 mg [n = 26], or 1,200 mg [n = 18] once-daily) non-randomly selected as a subgroup from among subjects that entered the long-term open-label extension following the completion of the double-blind placebo-controlled period of the phase III study and had at least 1 year exposure, full pharmacokinetic profiles were obtained (Perucca et al., 2011). These subjects were treated concomitantly with one or two AEDs (except for one patient who received ESL monotherapy), and CBZ was the most frequently used AED (in 67% of the patients). For the 800 mg ESL dose, median Cmax was 15.5 (SD 5.0) μg/ml and median Cmin was 4.2 (SD 3.2) μg/ml. For the 1,200-mg ESL dose, median Cmax was 23.0 (SD 5.3) μg/ml and median Cmin was 8.9 (SD 4.2) μg/ml. Areas under the plasma concentration–time curve over the dosing interval (AUC0–24) were 205 and 336 μg/h/ml in patients receiving ESL doses of 800 and 1,200 mg once daily, respectively. These pharmacokinetic parameters (Cmax and AUC0–24) were dose proportional and appear to represent exposure at therapeutic levels. Eslicarbazepine Cmax,ss was reached 2 h after ESL dosing and declined thereafter in a multiphasic manner, with a mean t1/2 of 13–20 h. The plasma exposure of the minor metabolites (R)-licarbazepine and OXC was dose-proportional, but not linear. (R)-Licarbazepine-Cmax,ss was reached 6–8 h after ESL dosing and declined thereafter in a multiphasic manner, with a mean t1/2 of 25–61 h. OXC-Cmax,ss was reached 3 h after ESL dosing and declined thereafter in a multiphasic manner, with a mean t1/2 of 12–14 h. These findings favor the view that the minor chiral inversion of eslicarbazepine, subsequent to ESL administration, proceeds through oxidation to OXC followed by reduction to (R)-licarbazepine, as indicated in Figure 1.

No time dependency was observed in eslicarbazepine PK for up to 1 year of treatment, suggesting that ESL did not affect its own metabolism or oral clearance (Almeida et al., 2009).

Population pharmacokinetic analysis of ESL in patients with epilepsy gave the following pharmacokinetic parameters for eslicarbazepine: CL/F – 3.82 L/h and V/F – 188 L.

Pharmacokinetics in Special Populations

  1. Top of page
  2. Summary
  3. Biopharmaceutic Properties
  4. Pharmacokinetics in Laboratory Animals
  5. Pharmacokinetics in Humans
  6. Pharmacokinetics in Special Populations
  7. Drug Interactions
  8. Interactions with Other AEDs
  9. Interactions with Other (Non-AED) Medications
  10. Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship
  11. Summary
  12. Disclosure
  13. References

ESL PK was also characterized in an open-label phase IIa study in children and adolescents with epilepsy (aged 2–6 years [n = 11], 7–11 years [n = 8], and 12–17 years [n = 10]) treated with one to three concomitant AEDs (Almeida et al., 2008). The study consisted of three consecutive 4-week periods with administration of ESL 5 mg/kg/day in weeks 1–4, 15 mg/kg/day in weeks 5–8, and 30 mg/kg/day or 1,800 mg/day (whichever was less) in weeks 9–12. Similar to in adults, ESL was rapidly metabolized to eslicarbazepine in children and adolescents. In all age groups, eslicarbazepine Cmax,ss and AUCss were dose proportional. Eslicarbazepine Cmax,ss normalized to ESL dose (mg/kg) was similar between age groups but dose-normalized AUCss depended on age, indicating faster clearance in younger children compared to adolescents. Eslicarbazepine peak concentrations were reached 0.5–3 h after ESL dosing and provided higher clearance values in younger children (92–102 mL/h/kg) compared to adolescents (61–69 mL/h/kg) (Nunes et al., 2007; Almeida et al., 2008).

To assess the effect of renal function on ESL PK, a study was conducted in which a single dose of ESL 800 mg was administered to five groups (n = 8 each): four with different degrees of renal function (normal, mild, moderate, and severe) and a fifth with end-stage renal disease requiring hemodialysis (Maia et al., 2008). Eslicarbazepine Cmax did not differ significantly between the groups. However, eslicarbazepine-AUC0–∞ increased significantly in the mild, moderate, and severe renal impairment groups. A significant relationship was found between creatinine clearance (CLCR) and eslicarbazepine renal clearance (CLr). The PK of the minor ESL metabolites (eslicarbazepine–glucuronide, (R)-licarbazepine, (R)-licarbazepine–glucuronide, OXC, and OXC–glucuronide) were also significantly affected by renal function. Tubular reabsorption is the most likely explanation for an eslicarbazepine CLr (7.3 mL/min) lower than glomerular filtration rate in the group of subjects with normal renal function (CLCR > 80 mL/min) (Maia et al., 2008). The total amount of eslicarbazepine recovered in urine was similar in the groups with normal renal function and mild renal impairment, but was markedly decreased in the moderate and severe renal impairment groups. Major ESL metabolites recovered in urine were eslicarbazepine and eslicarbazepine–glucuronide. However, the fraction of ESL dose excreted in urine (Am/D) as eslicarbazepine decreased by 54% and 77% compared to the control group, and the Am/D of eslicarbazepine–glucuronide increased in the moderate and severe renal impairment groups, indicating that renal excretion of eslicarbazepine is most likely more affected than that of eslicarbazepine–glucuronide by renal impairment (Maia et al., 2008).

Because ESL PK is renal-function dependent, dose adjustment is recommended in subjects with renal impairment. Analysis of existing data supports the recommendation of no dose adjustment in patients with a CLCR > 60 mL/min and half-dose for patients with CLCR = 30–60 mL/min. There are insufficient data to establish a recommendation for dose adjustment in patients with CLCR < 30 mL/min (Maia et al., 2008). Dialysis reduced plasma concentrations of all metabolites, but the decrease only approached the lower limit of quantification after the second dialysis (Maia et al., 2008).

To assess the role of liver function on ESL-to-eslicarbazepine biotransformation as well as on eslicarbazepine metabolism, ESL PK were evaluated following multiple dosing (800 mg/day for 8 days) to patients with moderate liver impairment (n = 8) and to healthy subjects (n = 8) who served as a control group (Almeida et al., 2008). ESL PK were not affected by moderate hepatic impairment, although there were more subjects with measurable ESL plasma concentrations in the hepatic impairment group than in the control group. Still, ESL plasma concentrations remained very low (<0.1% of eslicarbazepine concentrations). No significant differences were found in ESL and eslicarbazepine concentration–time profiles in patients with and without portal-systemic shunting, suggesting that ESL hydrolytic metabolism to eslicarbazepine during first passage was not affected by portal-systemic shunting. In addition, there were no significant differences between liver-impaired patients and controls in the PK of the glucuronide metabolites, and the relative proportion of other minor metabolites remained unchanged, suggesting that moderate liver impairment has no relevant effect on glucuronidation or on the formation of (R)-licarbazepine and OXC (Almeida et al., 2008).

Drug Interactions

  1. Top of page
  2. Summary
  3. Biopharmaceutic Properties
  4. Pharmacokinetics in Laboratory Animals
  5. Pharmacokinetics in Humans
  6. Pharmacokinetics in Special Populations
  7. Drug Interactions
  8. Interactions with Other AEDs
  9. Interactions with Other (Non-AED) Medications
  10. Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship
  11. Summary
  12. Disclosure
  13. References

Human liver microsomes

In human liver microsomes, eslicarbazepine appeared to have minimal or no inhibitory effect on the activity of CYP isoforms—CYP1A2, CYP2A6, CYP2B6, CYP2D6 and CYP2E1, CYP3A4, and CYP4A9/11—as well as on the enzymes UGT1A1 and UGT1A6 and the epoxide hydrolase (EH) (Bialer et al., 2007). A moderate inhibitory effect was found on the CYP2C9-mediated tolbutamide 4-hydroxylation, and the concentration giving one-half the maximum inhibitory effect (IC50) values for eslicarbazepine on CYP2C19 activity (utilizing tolbutamide as a CYP2C19 probe) were 232 μg/ml. Studies with eslicarbazepine in fresh human hepatocytes showed no induction of CYP1A2, CYP3A4, and phase II hepatic enzymes involved in glucuronidation and sulfation (Bialer et al., 2007). This is similar to the reported CYP2C19 inhibition at therapeutic concentrations by CBZ and OXC active entity MHD (licarbazepine) in human liver microsomes (Lakehal et al., 2002).

ESL metabolism was not inhibited by incubating 14C-ESL with the AEDs acetazolamide, clobazam, clonazepam, gabapentin (GBP), lamotrigine (LTG), phenobarbital (PB), PHT, primidone, and valproic acid (VPA) (Almeida & Soares-da-Silva, 2007).

Population pharmacokinetics studies

A pooled population PK analysis of ESL phase III clinical studies in which ESL was given concomitantly with other AEDs to patients with epilepsy who received mainly CBZ (n = 526), LTG (n = 203), or VPA (n = 209) led to the following conclusions. The estimated oral clearance of concomitantly administered AEDs (CBZ, clobazam [CLB], GBP, LTG, levetiracetam [LEV], PB, PHT, topiramate [TPM], and VPA]) were in agreement with clearance values reported in the literature. All other AEDs were given to fewer patients (n = 31–118 patents) and their estimated oral clearance should be evaluated with caution (BIAL-data on file). Secondly, ESL slightly increased the oral clearance of CBZ (∼14%), LTG (∼12%), and TPM (∼15%). These changes in oral clearance do not appear to be clinically relevant and should not require dose adjustment at any of the above AEDs. ESL did not affect the oral clearance of CLB, GBP, LEV, PB, PHT, and VPA.

Interactions with Other AEDs

  1. Top of page
  2. Summary
  3. Biopharmaceutic Properties
  4. Pharmacokinetics in Laboratory Animals
  5. Pharmacokinetics in Humans
  6. Pharmacokinetics in Special Populations
  7. Drug Interactions
  8. Interactions with Other AEDs
  9. Interactions with Other (Non-AED) Medications
  10. Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship
  11. Summary
  12. Disclosure
  13. References

Phenytoin, phenobarbital, and carbamazepine

An average increase of 30–35% in PHT AUC and Cmax values was observed following a short-term (27 days) coadministration of ESL (1,200 mg/day) and PHT (300 mg/day) to 16 healthy subjects. The geometric mean ratios (GMR) and 90% CI of PHT Cmax and AUC (with and without ESL) were 131% (117–146%) and 135% (121–151%), respectively (BIAL-data on file). This PK interaction may be related to CYP2C19 inhibition by eslicarbazepine. However, no relevant effect of ESL on PHT clearance was seen in the analysis of patients with partial-onset epilepsy (BIAL-data on file). Based on individual response, the dose of PHT may need to be decreased if used concomitantly with ESL.

Eslicarbazepine oral clearance (CL/F) increased in patients with epilepsy treated with the inducing AEDs, CBZ, PB, and PHT. In two parallel studies in 16 (PHT) or 20 (CBZ) healthy subjects, concomitant administration of ESL (800 mg/day) and CBZ (Tegretol CR tablets 400 mg twice daily) or ESL (1,200 mg/day) and PHT (300 mg/day) resulted in an average decrease of 21–33% in the plasma exposure (AUC and Cmax, respectively) of eslicarbazepine. The GMRs (90% CI) of eslicarbazepine Cmax and AUC (with and without CBZ) were 78% (73–85%) and 68% (63–73%), respectively. The GMRs (90% CI) of eslicarbazepine Cmax and AUC (with and without PHT) were 69% (65–73%) and 67% (65–70%), respectively (BIAL-data on file). These interactions are most likely due to enzyme induction of the UGTs mediating eslicarbazepine glucuronidation. No change in plasma exposure of CBZ or its metabolite CBZ-epoxide was noted. Results from the subgroup of patients with epilepsy concomitantly treated with ESL and CBZ showed an increased risk for some adverse events, compared to subjects using ESL combined with other (non-CBZ) AEDs. Common adverse events with increased prevalence in ESL–CBZ combination included diplopia (11.4% in patients on ESL + CBZ compared to 2.4% in patients on ESL+ other AEDs, without concomitant CBZ) and abnormal coordination (30% with concomitant CBZ, compared to 2.7% with other AEDs but not CBZ).

Lamotrigine

LTG and eslicarbazepine are metabolized primarily through glucuronidation. A study in two parallel groups of 16 healthy subjects with ESL (1,200 mg/day) and LTG (150 mg/day) coadministered for 19 days after 8 days of ESL treatment gave the following Cmax and AUC GMR (90% CI) for eslicarbazepine—95% (87–102%) and 96 (91–102%)—and for LTG—88% (82–94%) and 86% (81–92%)—respectively. Therefore, there was no significant PK interaction between ESL and LTG in healthy subjects and no dose adjustments appear to be required in either LTG or ESL when they are coadministered (Almeida et al., 2010).

Topiramate

A multiple-dose study was conducted in two parallel groups (groups A and B) of 16 healthy subjects with ESL and topiramate (TPM) (Nunes et al., 2010). In groups A and B the effect of TPM on ESL PK and that of ESL on TPM PK were assessed, respectively. In group A, ESL and TPM were given at the following dosing regimens. ESL once-daily doses were 600 mg on days 1 and 2 and 1200 mg on days 3–27. TPM doses were once-daily 100 mg on days 9 and 10, 100 mg twice-daily on days 11 and 12, and twice-daily 200 mg twice-daily on days 13 to 27. In Group B, TPM and ESL were given at the following once-daily dosing regimens: TPM 100 mg on days 1 and 2 and TPM 200 mg on days 5–27; ESL 600 mg on days 9–10 and 1200 mg QD on days 11–27. In group A, ESL Cmax and AUCss GMR (90% CI) were 86.8% (81.1–92.9%) and 92.7% (89.2–96.3%). In Group B TPM Cmax and AUCss GMR (90% CI) were 81.5% (77.5–85.9%) and 81.1% (79.7–84.0%). Concomitant administration of ESL (1,200 mg/day) and TPM (200 mg/day) showed no significant change in eslicarbazepine plasma exposure but an 18% decreases in TPM plasma exposure possibly due to enzyme induction (Nunes et al., 2010).

Other AEDs

CLB, GBP, LEV, TPM, and VPA did not affect eslicarbazepine plasma exposure (BIAL-data on file). Overall, the magnitude of concomitant ESL effects on CL/F of all concomitant AEDs assessed (except PHT) does not appear to be clinically relevant and should not require a dose adjustment of any of the above AEDs.

Interactions with Other (Non-AED) Medications

  1. Top of page
  2. Summary
  3. Biopharmaceutic Properties
  4. Pharmacokinetics in Laboratory Animals
  5. Pharmacokinetics in Humans
  6. Pharmacokinetics in Special Populations
  7. Drug Interactions
  8. Interactions with Other AEDs
  9. Interactions with Other (Non-AED) Medications
  10. Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship
  11. Summary
  12. Disclosure
  13. References

Oral contraceptives

In a two-way crossover, randomized, open-label study 20 healthy female subjects received Microgynon® (ethinylestradiol/levonorgestrel) manufactured by Schering Lusitana, Lda (Mem Martins, Portugal) tablets a combined oral contraceptive (OC) of ethinylestradiol (30 μg) and levonorgestrel (150 μg) on two occasions: (1) alone and; (2) after pretreatment with ESL (800 mg/day for 15 days. The GMR (90% CI) of levonorgestrel Cmax and AUC (with and without ESL) were: 104% (95–114%) and 89% (82–97%), respectively. The GMR (90% CI) of ethinylestradiol Cmax and AUC (with and without ESL) were 91% (85–97%) and 69% (64–75%), respectively (BIAL-data on file). Therefore, ESL (800 mg QD) did not affect levonorgestrel plasma exposure but did reduce estradiol AUC by 30%.

Administration of Microgynon® (ethinylestradiol/levonorgestrel) tablets with ESL (1,200 mg/day) showed an average decrease of 42% and 37% in levonorgestrel and ethinylestradiol (AUC) (BIAL-data on file), indicating that ESL enzymatic induction of the metabolism of the OC progestin and estrogen components appears to be dose dependent at the clinically relevant doses of 800–1,200 mg/day. Therefore, the concurrent use of ESL and OC may render OC to be less effective. This ESL-OC PK interaction is similar to the previously reported interaction between OC and OXC showing that OXC (1,200 mg QD) decreased ethinylestradiol (50 μg) and levonorgestrel (250 μg) AUC by 48% and 37%, respectively (Fattore et al., 1999). Therefore, to avoid inadvertent pregnancy, women of childbearing potential should use other adequate methods of contraception during treatment with ESL, and up to the end of the current menstruation cycle after the treatment has been discontinued.

Warfarin

Coadministration of ESL (1,200 mg/day for 8 days) with warfarin showed a mild (23%) but statistically significant decrease in (S)-warfarin plasma exposure, with no significant effect on the (R)-warfarin PK or on coagulation (international normalized ratio, INR) (Almeida et al., 2006b; Vaz-da-Silva et al., 2010). The GMRs (90% CI) of (S)-warfarin (warfarin more potent enantiomer) Cmax and AUC (with and without ESL) were 81% (76–86%) and 77% (72–82%), respectively, without any clinically relevant or significant changes in the INR and (R)-warfarin plasma exposure (Vaz-da-Silva et al., 2010). However, due to the high intersubject variability in warfarin PK and pharmacodynamics, special attention should be directed to INR monitoring during the first weeks of initiation (titration) or at the end of concomitant warfarin ESL treatment.

Simvastatin

A two-way crossover, randomized, open-label study in 24 healthy subjects showed a 41–61% decrease in plasma exposure (Cmax and AUC) of simvastatin and its active metabolite β-hydroxyacid simvastatin when a single dose of simvastatin (80 mg) was administered after 14 days of repetitive ESL dosing (800 mg/day). The GMRs (90% CI) of simvastatin Cmax and AUC (with and without ESL) were 39% (30–51%) and 46% (38–55%), respectively (BIAL-data on file). Simvastatin is an inactive lactone prodrug that undergoes hepatic hydrolysis to its active entity (metabolite) β-hydroxy acid simvastatin that can be reconverted back to the lactone and undergoes CYP3A4-mediated oxidative metabolism (Mauro, 1993). The GMR (90% CI) of β-hydroxy acid simvastatin Cmax and AUC (with and without ESL) were 59% (51–69%) and 51% (44–55%), respectively (BIAL-data on file). Because simvastatin and its active entity are CYP3A4 substrates, this PK interaction is most likely due to CYP3A4 induction by eslicarbazepine. Consequently an increase in simvastatin dose may be required when used concomitantly with ESL.

Metformin

In a two-way crossover, randomized, open-label study 20 healthy subjects received metformin (single dose of 850 mg) on two occasions: (1) alone and (2) after ESL pre-treatment (1,200 mg/day) for 6 days. The GMR (90% CI) of metformin Cmax and AUC (with and without ESL) were 88% (77–100%) and 95% (82–106%), respectively. ESL (1,200 mg/day for 6 days) had no clinically relevant effect on metformin PK and plasma exposure in healthy subjects (Rocha et al., 2009).

Digoxin

A two-way crossover, randomized, study in 12 healthy subjects did not reveal any interaction of ESL (1,200 mg/day for 8 days) with digoxin (on days 1–2, 0.5 mg/day and on days 3–8, 0.25 mg/day) with no effect on digoxin AUC [GMR (90% CI):96% (90–103%)], and a slight decrease of in digoxin – Cmax [GMR – (90% CI) 85% (68–107%)] in digoxin Cmax GMR (90% CI) that appears to have no clinical relevance (Vaz-da-Silva et al., 2009).

Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship

  1. Top of page
  2. Summary
  3. Biopharmaceutic Properties
  4. Pharmacokinetics in Laboratory Animals
  5. Pharmacokinetics in Humans
  6. Pharmacokinetics in Special Populations
  7. Drug Interactions
  8. Interactions with Other AEDs
  9. Interactions with Other (Non-AED) Medications
  10. Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship
  11. Summary
  12. Disclosure
  13. References

PK/PD analysis in the pooled population of ESL phase III studies in patients with epilepsy was performed using nonlinear mixed-effect modeling (NONMEM) (Falcão et al., 2012). Efficacy variables derived from the seizure frequency standardized for 4 weeks were best fitted by a combination of a baseline, a placebo effect, and an effect of ESL described by an Emax PD model. The antiepileptic effect of ESL, as assessed by seizure frequency, increased with the increase of ESL dose. The concomitant administration of other AEDs did not affect the eslicarbazepine exposure–response relationship, although CBZ and PB did decrease eslicarbazepine plasma exposure (AUC). Overall, the results of this population PK analysis demonstrated a continuous relationship, with moderate inter-subject variability, between antiepileptic efficacy and eslicarbazepine concentrations or plasma exposure, that were not affected by concomitant AEDs.

Summary

  1. Top of page
  2. Summary
  3. Biopharmaceutic Properties
  4. Pharmacokinetics in Laboratory Animals
  5. Pharmacokinetics in Humans
  6. Pharmacokinetics in Special Populations
  7. Drug Interactions
  8. Interactions with Other AEDs
  9. Interactions with Other (Non-AED) Medications
  10. Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship
  11. Summary
  12. Disclosure
  13. References

ESL is metabolized solely to eslicarbazepine that subsequently undergoes a minor chiral inversion (through oxidation to OXC) to (R)-licarbazepine resulting in an eslicarbazepine-to-(R)-licarbazepine AUC ratio of approximately 95%/4.5% = 19, with approximately 0.5% circulating as OXC. Therefore, the exposure to OXC or (R)-licarbazepine following oral administration of ESL is minimal. The bioavailability of eslicarbazepine following oral administration of ESL is high and has been shown to not be affected by food. ESL PK in healthy subjects was not significantly affected by food, age, or gender. More than 90% of ESL oral dose has been shown to be excreted in urine as eslicarbazepine, two thirds as free (unconjugated) form and one third as the glucuronide conjugate.

Population PK was analyzed in a subgroup of patients treated concomitantly with one or two AEDs in phase III studies, and eslicarbazepine plasma exposure was roughly dose-proportional. For the 800-mg ESL dose, median Cmin and median Cmax were 4.2 and 15.5 μg/ml, respectively. For the 1,200-mg ESL dose, median Cmin and median Cmax were 8.9 and 23.0 μg/ml, respectively. Eslicarbazepine Cmax,ss was reached 2 h after ESL dosing and declined thereafter in a multiphasic manner, with a mean t1/2 of 13–20 h.

In children with partial-onset seizures, dose-normalized AUCss depended on age indicating faster clearance in younger children compared to adolescents.

Differently from other available AEDs that are dosed more than once daily, in phase II and phase III studies ESL was found to be efficacious and well tolerated as once-daily add-on treatment to one to three AEDs, in adult patients with partial-onset seizures.

The reasons for this distinction in comparison to other AEDs may be found in the optimized PK profile of ESL, which allows for a once-daily dosage: (1) steady-state plasma concentrations of eslicarbazepine are reached 4–5 days after repeated ESL dosing which is consistent with a t1/2,eff of 20–24 h; (2) there is a smaller apparent peak-trough fluctuation of eslicarbazepine in cerebrospinal fluid (1.5) than in plasma (2.9), with a long apparent half-life of eslicarbazepine in cerebrospinal fluid (24.8 ± 8.1 h); (3) there is minimal exposure to (R)-licarbazepine or OXC after ESL oral administration and no OXC peak was observed either in plasma or cerebrospinal fluid, which may explain why once-daily dosage was well tolerated.

Because ESL PK is dependent on renal function, dose adjustment is recommended in subjects with renal impairment (half-dose for patients with creatinine clearance of 30–60 ml/min). ESL PK was not affected by moderate hepatic impairment in humans. In addition, moderate liver impairment has no relevant effect on eslicarbazepine glucuronidation.

The estimated oral clearance of concomitantly administered AEDs (CBZ, CLB, GBP, LTG, LEV, PB, PHT, TPM, and VPA) plus ESL were in agreement with clearance values reported in the literature. ESL slightly increased the oral clearance of CBZ (∼14%), LTG (∼12%), and TPM (∼15%), but these changes do not appear to be clinically relevant and should not require dose adjustment of any of the above AEDs. An average increase of 30–35% in PHT AUC and Cmax values was observed following a short-term (27 days) coadministration of ESL (1,200 mg/day) and PHT (300 mg/day). Based on individual response, the dose of PHT may need to be decreased if used concomitantly with ESL.

Eslicarbazepine oral clearance increased in patients with epilepsy treated with the inducing AEDs, such as CBZ, PB, and PHT. These interactions are most likely due to enzyme induction of the UGTs mediating eslicarbazepine glucuronidation. No dose adjustments appear to be required in either LTG or ESL when they are coadministered. Concomitant administration of ESL (1,200 mg/day) and TPM (200 mg/day) showed no significant change in eslicarbazepine plasma exposure but an 18% decrease in TPM plasma exposure possibly due to enzyme induction.

ESL dose-dependently decreased the exposure to levonorgestrel and ethinylestradiol after administration of Microgynon (ethinylestradiol/levonorgestrel) tablets, indicating that the concurrent use of ESL and OCs may render OCs less effective. Therefore, to avoid inadvertent pregnancy, women of childbearing potential should use adequate contraception during treatment with ESL, and up to the end of the current menstruation cycle after the treatment has been discontinued. Coadministration of ESL with warfarin showed a mild decrease in (S)-warfarin plasma exposure, with no significant effect on the (R)-warfarin PK or on coagulation (INR); special attention should be directed on INR monitoring during titration or at the end of concomitant warfarin ESL treatment. An increase in simvastatin dose may be required when used concomitantly with ESL, as the latter decreased exposure of simvastatin and its active metabolite β-hydroxyacid simvastatin. ESL had no clinically relevant effect on metformin and digoxin plasma exposure in healthy subjects.

Disclosure

  1. Top of page
  2. Summary
  3. Biopharmaceutic Properties
  4. Pharmacokinetics in Laboratory Animals
  5. Pharmacokinetics in Humans
  6. Pharmacokinetics in Special Populations
  7. Drug Interactions
  8. Interactions with Other AEDs
  9. Interactions with Other (Non-AED) Medications
  10. Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship
  11. Summary
  12. Disclosure
  13. References

Dr. Meir Bialer is a consultant to BIAL. In addition he has received in the last 3 years speakers or consultancy fees from BioAvenir, CTS Chemicals, Desitin, Janssen-Cilag, Lundbeck, Rekah, Sepracor, Tombotech, UCB Pharma, and Upsher Smith. Dr. Meir Bialer has been involved in the design and development of new antiepileptic and CNS drugs as well as new formulations of existing drugs. None of the other authors has any conflict of interest to disclose.

We, the authors, confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Biopharmaceutic Properties
  4. Pharmacokinetics in Laboratory Animals
  5. Pharmacokinetics in Humans
  6. Pharmacokinetics in Special Populations
  7. Drug Interactions
  8. Interactions with Other AEDs
  9. Interactions with Other (Non-AED) Medications
  10. Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship
  11. Summary
  12. Disclosure
  13. References
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