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).
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.
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).
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.