Aptiom - Scientific Information
|Manufacture:||Sunovion Pharmaceuticals Inc.|
|Ingredients:||eslicarbazepine acetate, croscarmellose sodium, magnesium stearate, povidone|
|Proper name:||Eslicarbazepine acetate|
|Chemical name:||(S)-enantiomer, is (S)-10-Acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-|
|Molecular formula and molecular mass:||C17H16N2O3|
|M.W. = 296.32|
|Physicochemical properties:||Eslicarbazepine acetate is a white to off-white, odorless|
Eslicarbazepine acetate is insoluble in hexane, very
slightly soluble in aqueous solvents and soluble in organic
solvents such as acetone, acetonitrile, and methanol.
Study Demographics and Trial Design
The efficacy of APTIOM (eslicarbazepine acetate) as adjunctive therapy in the treatment of partial-onset seizures was established in three 12-week, randomized, double-blind, placebo-controlled, fixed-dose, multicenter trials in adult patients with epilepsy. The total number of APTIOM-treated patients was 992 (placebo: 418). Patients enrolled had partial-onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant Anti-Epileptic Drugs (AEDs). Overall, 69% of the patients used 2 concomitant AEDs and 28% used 1 concomitant AED. The most commonly used AEDs were carbamazepine (50%), lamotrigine (24%), valproic acid (21%), and levetiracetam (18%). Oxcarbazepine was not allowed as a concomitant AED.
During an 8-week baseline period, patients were required to have an average of ≥4 partial-onset seizures per 28 days with no seizure-free period exceeding 21 days. In these 3 trials, APTIOM patients had a mean duration of epilepsy of 22 years (range 1 to 70 years) and a mean [Standard Deviation (SD)] baseline seizure frequency of 15 (22) per 28 days. Similarly, placebo patients had a mean duration of epilepsy of 22 years (range 1 to 65 years) and a mean (SD) baseline seizure frequency of 15 (18) per 28 days.
Studies 301 and 302 compared doses of APTIOM 400, 800, and 1200 mg once daily with placebo. Study 304 compared doses of APTIOM 800 and 1200 mg once daily with placebo. In all three trials, following an 8-week Baseline Phase to establish baseline seizure frequency prior to randomization, subjects were randomized and titrated to the randomized dose. During the Titration Phase in Study 301, dosing was initiated at 400 mg once daily and increased weekly in 400 mg increments. In Study 302, in the 400 mg and 800 mg groups, dosing was initiated at 400 mg and 800 mg once daily, respectively. For the 1200 mg group, dosing was initiated at 800 mg once daily and increased to 1200 mg once daily after 2 weeks. In Study 304, for the 800 mg group, dosing was initiated at 400 mg for 2 weeks and then increased to 800 mg, and the 1200 mg group was initiated at 800 mg for 2 weeks and then increased to 1200 mg. For all 3 studies, the Titration Phase lasted 2 weeks and was followed by a Maintenance Phase that lasted 12 weeks, during which patients were to remain on a stable dose of APTIOM. Among patients randomized to and who received APTIOM in the three trials, 89% in the 400 mg dose group, 82% in the 800 mg dose group, and 71% in the 1200 mg dose group completed the studies (Placebo: 87%).
A statistically significant decrease in median seizure frequency (from Baseline compared to the Maintenance Phase) versus placebo was observed at the 800 mg dose in Studies 301 and 302 and at the 1200 mg dose in Studies 301, 302 and 304. The proportion of responders (≥50% reduction seizure frequency) was also significantly better than placebo in both 800 and 1200 mg treatment arms in Studies 301 and 302 and in the 1200 mg treatment arm in Study 304. The efficacy of APTIOM was consistent regardless of the type of concomitant AED that was used.
|AEDs + APTIOM
|Median % Reduction||15.0||26.4||36.1||38.7|
|p-value vs. placebo1||-||0.31||0.01||0.01|
|Responder Rate (%)||18.9||24.2||33.0||42.5|
|p-value vs. placebo2||-||0.49||0.05||0.001|
|Median % Reduction||5.6||20.7||32.6||28.2|
|p-value vs. placebo1||-||0.17||0.006||0.05|
|Responder Rate (%)||18.2||20.2||35.6||35.8|
|p-value vs. placebo2||-||0.86||0.01||0.01|
|Median % Reduction||21.8||-||29.7||35.6|
|p-value vs. placebo1||-||-||0.08||0.02|
|Responder Rate (%)||23.1||-||30.5||42.7|
|p-value vs. placebo2||-||-||0.11||<0.0001|
1p-value for LS mean comparisons from ANCOVA model with treatment and baseline standardized seizure frequency
2p-value from pairwise test of applicable group comparisons based on Chi Square test with continuity adjustment
3all randomized subjects with at least one dose of study medication who had at least one post-baseline seizure frequency assessment
In the baseline to treatment (i.e., titration + maintenance) period, statistically significant differences in percent reduction in median seizure frequency were observed with APTIOM 800 mg in Studies 301, 302 and 304 and APTIOM 1200 mg in Studies 301 and 304 compared to placebo. Statistically significant differences in 50% responder rates were also observed during this period with APTIOM 400 mg in Study 301, APTIOM 800 mg in Studies 301 and 302, and APTIOM 1200 mg in Studies 301, 302 and 304 compared to placebo.
There were no significant differences in seizure control as a function of gender, age or race/ethnicity although data on race were limited (19% of patients were non-Caucasian).
The precise mechanism(s) by which eslicarbazepine exerts its anticonvulsant actions are not fully characterized. In vitro electrophysiological studies indicate that eslicarbazepine stabilizes the inactivated state of voltage-gated sodium channels, preventing their return to the activated state resulting in an inhibition of repetitive neuronal firing. The affinity for the inactive state is 60-fold greater than the affinity for the resting state. In addition, eslicarbazepine has been shown to inhibit T-type calcium channels in vitro which may contribute to its anticonvulsant effects.
In vitro assays designed to detect potential secondary targets demonstrated that eslicarbazepine did not interact with any of a wide range of receptors (neurotransmitter related, ion channels, secondary messengers, growth factors/hormones, and brain/gut peptides) at clinically relevant concentrations.
Eslicarbazepine does not modulate γ-aminobutyric acid (GABA) or glycine induced currents in vitro. In vitro and in vivo studies demonstrate that eslicarbazepine does not lead to increases in either excitatory or inhibitory neurotransmitters.
In humans, following oral administration, the pharmacological activity of APTIOM (eslicarbazepine acetate) is primarily exerted through the active metabolite eslicarbazepine.
APTIOM and eslicarbazepine demonstrate anticonvulsant effects in animal seizure models. APTIOM protects against seizures induced by biciculline, picrotoxin, and 4-aminopyridine in mice while having no effect on those induced by N-methyl-DL-aspartate (NMDLA), kainite or strychnine. Both APTIOM and eslicarbazepine protect against electrically induced seizures and the progression of kindling in the maximum electroshock (MES) test in mice.
Biotransformation of APTIOM is very rapid in all animal species. Eslicarbazepine is the major metabolite in all species investigated (including humans) with the exception of the rat where oxcarbazepine is the major metabolite and concentrations of eslicarbazepine are lower. The differing species specific metabolic profiles for APTIOM following oral administration are shown below in Table 2.
|% of Circulating Moieties that Correspond to Parent and Metabolite Following Oral
Administration of SEP-0002093*
ND = not detected
Preclinical Safety Pharmacology
The cardiovascular effects of eslicarbazepine acetate and/or its metabolites were assessed in in vitro and in vivo studies. In vitro, eslicarbazepine acetate and its metabolites inhibited hERG channel repolarization in transfected mammalian cells by less than 20% at the highest concentration (100 μg/mL) evaluated. In isolated canine Purkinje fibers, eslicarbazepine acetate and its metabolites at 10 and 100 μg/mL resulted in concentration related shortening of the action potential duration. The latter finding was interpreted to be related to inhibition of cardiac sodium channels in this assay. Oral administration of eslicarbazepine acetate to anesthetized dogs had no effect on cardiovascular parameters. In conscious dogs, an oral dose of 210 mg/kg produced a transient increase in heart rate as well as reduced QT and QTc intervals. No treatment-related arrhythmias or other changes in the morphology of the ECG were noted. The highest plasma concentrations of eslicarbazepine determined in the in vivo dog studies were lower than clinical Cmax in anesthetized dogs and about 50% higher in conscious dogs.
Animal toxicology studies revealed no behavioral effects of eslicarbazepine acetate which would suggest abuse liability. No observations of withdrawal behaviors were noted in recovery group animals following cessation of dosing with eslicarbazepine acetate. A drug discrimination study conducted in rhesus monkeys indicated that eslicarbazepine acetate doses up to 320 mg/kg resulting in systemic exposures to eslicarbazepine comparable to those at the MRHD did not show benzodiazepine-like subjective effects.
In a study in male mice that evaluated the potential effects of abrupt termination of dosing, oral administration of eslicarbazepine acetate at dose levels of 250, 400, or 600 mg/kg/day for 21 days did not produce signs indicative of physical dependence at 250 or 400 mg/kg/day. The maximum systemic AUC-based exposure to eslicarbazepine at these doses was less than that at the maximum recommended human dose (MRHD). In the 600 mg/kg/day group, twitches/tremors and wet dog shakes were seen infrequently during the withdrawal period. Maximum exposure to eslicarbazepine at this dose was 30% higher than the MRHD.
The metabolism of eslicarbazepine acetate to the active moiety, eslicarbazepine, and the primary metabolites oxcarbazepine, and (R)-licarbazepine following administration in animals varies among the species tested and in comparison to the profile seen in humans. In all nonclinical species tested, the relative exposure to oxcarbazepine (when compared to eslicarbazepine) following administration of eslicarbazepine acetate was higher than in humans, but remained a minor metabolite in rabbits and dogs. However, oxcarbazepine is the major metabolite in rats, while eslicarbazepine is the major metabolite in humans, mice, dogs, and rabbits [see Table 2, DETAILED PHARMACOLOGY, Animal Pharmacology, Pharmacokinetics]. Therefore the data from rat studies is considered of limited relevance to human safety assessment. Consequently carcinogenicity testing was confined to the mouse and a full set of developmental toxicology studies conducted in mice.
Single-dose Toxicity Studies
In acute toxicity studies conducted in fasted mice and rats, clinical signs indicative of neurological toxicity were hypoactivity (subdued behavior), unsteady gait/incoordination, piloerection, cold extremities, and partial closure of the eyes at oral doses in excess of 300 mg/kg in both species. Studies performed are listed in Table 3 below.
|Mouse/CD-1||PO||150, 300, 500||300||150 and 300 mg/kg: No noteworthy|
500 mg/kg: Abnormal gait, subdued
behavior, partial eye closure and
piloerection. 1F died. All clinical
observations resolved and there were no
other treatment related findings from Day
|Rat/S-D||PO||150, 300, 500||500||150 and 300 mg/kg: No noteworthy|
500 mg/kg: Abnormal gait, subdued
behavior, piloerection, and cold
extremities. These findings resolved.
Lower weight gain in M. No other
treatment related findings from Day 2
PO: oral; M: male; F: female; h: hour; S-D: Sprague-Dawley
Repeat-dose Toxicity Studies
The majority of the nonclinical toxicity studies were conducted with eslicarbazepine acetate. However, as noted above, oxcarbazepine is the major metabolite in rats (in vivo), and in an effort to more fully characterize the potential toxicity of eslicarbazepine in rodents, 1-month and 3-month toxicity studies were also conducted in Wistar rats with eslicarbazepine as the test article. These data have been provided in Table 4. However, systemic exposure to eslicarbazepine at all eslicarbazepine dose levels was still below that at the MRHD and less than the exposure to oxcarbazepine.
Details of the results of repeat-dose toxicity studies in mice, rats, and dogs are provided in Table 4 below. Overall, dose limiting clinical observations were similar in all species with hypoactivity (subdued behaviour), unsteady gait/incoordination, piloerection, tremors, and prostration seen along with decreased food consumption and reduced body weight gain. Neurological effects also included convulsions that were observed in mice and rats in safety pharmacology studies, in female mice at all dose levels in the carcinogenicity study, and in the juvenile dog study described below. The liver was the primary target organ in mice, rats, and dogs with increases in liver weights seen in all species and hepatocellular hypertrophy (rodents) or hepatocyte rarefaction (dogs) along with increases in serum total protein (rats), cholesterol (rats and dogs), and triglycerides (dogs), and an increase in plasma protein due to higher albumin and/or globulin levels (rats). In addition, haematology findings of decreased red blood cells (RBC) and/or haemoglobin (Hb) occurred in rats and prolonged activated partial thromboplastin time (APTT) was seen consistently in dogs. Clinical pathology was not conducted in mice. All findings generally occurred at systemic eslicarbazepine exposures close to or below that at the MRHD.
|Noteworthy Findings (Dose levels affected)|
|1 and 3|
|150 to 650||Behavioural Effects (≥300 mg/kg): Subdued behaviour,|
piloerection, unsteady gait, irregular breathing, in-
oordination, hunched posture, prostration, weight loss and
Liver (≥150 mg/kg): Increased liver weight and
Kidney (≥300 mg/kg): Increased kidney weight in females.
Spleen (≥150 mg/kg): Increased spleen weight and/or
Body weight (≥150 mg/kg): Weight gain in F.
Death (≥500 mg/kg): 4F, 2M
|2 weeks; 1,|
3, and 6
|20 to 500||Behavioural Effects (≥75 mg/kg): Subdued behaviour,|
piloerection, unsteady gait, partially-closed eyes, salivation,
prostration, hunched posture and cold body surface.
Liver (≥50 mg/kg): Increased liver weight and centrilobular
hypertrophy. Effects were reversible.
Kidney (≥20 mg/kg): Increased kidney weight with hyaline
drop formation (males), coloured urine,
increased urine volume, nephropathy.
Adrenal (≥75 mg/kg): Increased adrenal weight.
Thyroid (≥20 mg/kg): Follicular epithelial hypertrophy.
Effects were reversible.
Reproductive (≥20 mg/kg): Ovaries: prominent interstitial
gland and atrophy, increased uterus weights (6-month
Plasma Chemistry (≥20 mg/kg): Increased cholesterol total
protein and globulin and decreased AST. Mildly increased
ALP and ALT at ≥75 mg/kg. Effects were reversible
(except cholesterol in M at 250 mg/kg).
Haematology (≥20 mg/kg): Mildly decreased RBC and Hb,
increased reticulocytes. Effects on RBC and Hb were
Death (500 mg/kg): 4F
Systemic Exposure (<500 mg/kg): Eslicarbazepine
AUC0-24h < that at MRHD.
|1 and 3|
|25 to 2000||Behavioural Effects (≥100 mg/kg): Hypoactivity,|
piloerection, unsteady gait, partially closed eyes, and
Liver (≥75 mg/kg): Increased liver weights with
centrilobular hypertrophy. At >500 mg/kg, increased
incidence of enlarged and darkened livers.
Thyroid (≥100 mg/kg): Epithelial hypertrophy.
Kidney (≥100 mg/kg): Increased kidney weights with
increased hyaline droplet formation.
Ovaries (≥500 mg/kg): Prominent interstitial gland and
increased corpora lutea.
Plasma Chemistry (≥100 mg/kg): Increased total protein,
cholesterol and bilirubin levels.
Death (≥1000 mg/kg): 7M, 11F
Systemic Exposure (≤1000 mg/kg): Eslicarbazepine
AUC0-24h < that at MRHD
|1 and 2|
weeks; 1, 3,
6, and 12
|20 to 210||Behavioural Effects (≥80 mg/kg ): Emesis, unsteady gait,|
subdued behaviour, tremors, muscular rigidity,
incoordination, impaired mobility, drowsiness, lethargy and
Liver (≥40 mg/kg): Increased liver weights with hepatocyte
Gall Bladder (≥40 mg/kg): Increased epithelial vacuolation
and macrophage infiltration.
Salivary Gland (≥160 mg/kg): Decreased serous secretion
in the 3 month study only.
Serum Chemistry (≥40 mg/kg): Increased cholesterol, LDH
Haematology (≥40 mg/kg): Increased APTT
Death (≥160 mg/kg): 1M, 1F (12 month study)
Systemic Exposure (≤210 mg/kg): Eslicarbazepine
AUC0-24h < that at MRHD
S-D: Sprague-Dawley; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase;
APTT: activated partial thromboplastin time; RBC: red blood cells; Hb: haemoglobin; LDH: lactate dehydrogenase
In in vitro genotoxicity studies, eslicarbazepine acetate and the major human metabolite, eslicarbazepine, were not mutagenic in bacterial assays (Ames test) conducted in the absence and presence of rat and human liver metabolic activation systems. Eslicarbazepine acetate was weakly mutagenic in the mouse lymphoma L5178Y cell mutation test without and with metabolic activation. Eslicarbazepine acetate was clastogenic in the Chinese hamster ovary (CHO) cell cytogenetic test, but neither eslicarbazepine acetate nor eslicarbazepine was clastogenic in the chromosomal aberration assay in human peripheral blood lymphocytes. In vivo, eslicarbazepine acetate was not clastogenic in the mouse bone marrow micronucleus test and did not induce DNA repair (as measured by unscheduled DNA synthesis) in the mouse liver.
In a two-year carcinogenicity study in mice, eslicarbazepine acetate was administered orally at doses of 100, 250, and 600 mg/kg/day. These doses were 0.4, 1.0, and 2.3 times the maximum recommended human dose (MRHD) on a mg/m2 basis. An increase in the incidence of hepatocellular adenomas and carcinomas was seen at doses ≥250 mg/kg/day in males and at 600 mg/kg/day in females.
Reproduction and Development Toxicology
In a fertility study in mice, eslicarbazepine acetate was administered orally at doses of 150, 350, and 650 mg/kg/day. These doses were 0.6, 1.4, and 2.5 times the MRHD on a mg/m2 basis. Maternal and paternal toxicity was observed at 350 and 650 mg/kg/day, respectively. A dose-related decrease in the number of implantations and number of live embryos was observed at all dose levels and in the absence of accurate counts of corpora lutea could have been the result of embryotoxicity or impairment of female or male fertility. In a study in rats at doses of 65, 125, and 250 mg/kg/day (0.5, 1.0, and 2.1 times the MRHD on a mg/m2 basis), lengthening of estrus cycles and decreased fertility, mating performance, and pregnancy parameters (number of corpora lutea, implantations, and number of live fetuses) were seen at 250 mg/kg/day, a maternally toxic dose. Systemic exposure (AUC) to eslicarbazepine would have been less than that at the MRHD in mice at 150 and 350 mg/kg/day and in rats at all dose levels.
When eslicarbazepine acetate was administered orally at 150, 350, and 650 mg/kg/day to pregnant mice during organogenesis, maternal toxicity occurred at 350 and 650 mg/kg/day. Embryo-fetal toxicity (lower fetal weight) and increased incidences of skeletal abnormalities, including malformations, were evident at 650 mg/kg/day and potentially treatment-related increased incidences of fetal malformations were also observed at 150 and 350 mg/kg/day. Fetal growth retardation occurred at 350 and 650 mg/kg/day. Plasma eslicarbazepine exposure (Cmax and AUC) at 150 mg/kg/day was less than that at the MRHD.
Oral administration of eslicarbazepine acetate at 40, 160, and 320 mg/kg/day to pregnant rabbits during organogenesis resulted in maternal toxicity and fetal growth retardation and increased incidences of minor skeletal abnormalities and variations at ≥160 mg/kg/day. These may reflect developmental delays. The no-effect dose (40 mg/kg/day) is less than the MRHD on a mg/m2 basis and systemic exposure to eslicarbazepine, based on AUC0-24h values, was below that at the MRHD at all eslicarbazepine acetate dose levels. Cmax after 160 and 320 mg/kg/day was slightly above and about triple, respectively, the Cmax at the MRHD.
Oral administration of eslicarbazepine acetate to pregnant rats at 65, 125, and 250 mg/kg/day during organogenesis resulted in maternal toxicity at ≥ 125 mg/kg/day and embryo-lethality at all doses, increased incidences of skeletal variations at ≥ 125 mg/kg/day and fetal growth retardation at 250 mg/kg/day. The lowest dose tested (65 mg/kg/day) is less than the MRHD on a mg/m2 basis and AUC-based systemic exposure to eslicarbazepine would have been less than that at the MRHD at all dose levels.
When female mice were dosed orally with eslicarbazepine acetate (150, 350, and 650 mg/kg/day) during the period of organogenesis and throughout the lactation period, body weight gain to weaning was lower and developmental delays were observed in offspring at the maternally toxic intermediate and high doses (approximately 1.4 and 2.5 times, respectively, the MRHD on a mg/m2 basis). Systemic exposure (AUC0-24h) to eslicarbazepine in pregnant mice at eslicarbazepine acetate dose levels up to 650 mg/kg/day was less than that at the MRHD.
When female rats were dosed orally with eslicarbazepine acetate (65, 125, and 250 mg/kg/day) during the period of organogenesis and throughout the lactation period, all doses were associated with maternal toxicity. At the high dose, a lower live birth index and lower offspring survival were seen. In addition, lower body weight gains and developmental delays were seen in intermediate and high dose offspring (approximately 1.0 and 2.1 times, respectively, the MRHD on a mg/m2 basis). Systemic exposure to eslicarbazepine at all eslicarbazepine acetate dose levels would be predicted to be less than that at the MRHD.
There are no adequate and well-controlled clinical studies of eslicarbazepine acetate in pregnant women. Eslicarbazepine acetate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In a juvenile dog study in which eslicarbazepine acetate (40, 80, and 160 mg/kg/day) was orally administered for 10 months starting on postnatal day 21, bone marrow hypocellularity and lymphoid tissue depletion observed in dead and moribund-sacrificed animals at all dose levels were considered potential evidence of immunotoxicity. Convulsions seen at the high dose were considered treatment-related, while a relationship to treatment for convulsions observed in a low dose animal late in the study was considered equivocal, since they occurred more than a day after the last dose (vs. 0.5-3.5 hours post dose at 160 mg/kg/day) and convulsions were not seen at the mid dose. Adverse effects on bone growth (decreased bone mineral content and density) were seen in females at all doses at the end of the dosing period, but not at the end of a 2-month recovery period. None of these findings were reported in young adult dogs dosed with eslicarbazepine acetate for up to 12 months in duration. A no-effect dose for adverse effects on juvenile dogs was not identified and AUC0-24h-based exposure to eslicarbazepine was less than that at the MRHD at all eslicarbazepine acetate dose levels tested.