Abbott-Levetiracetam - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Abbott-Levetiracetam - Scientific Information

Manufacture: Abbott
Country: Canada
Condition: Epilepsy, Seizures (Convulsions)
Class: Pyrrolidine anticonvulsants
Form: Tablets
Ingredients: Contain the labeled amount of levetiracetam, corn starch, sodium starch glycolate, colloidal silicon dioxide, povidone, talc, magnesium stearate, purified water, hypromellose, polyethylene glycol, titanium dioxide, FD & C blue #2 (250 mg only), ferric oxide yellow (500 mg only), ferric oxide red (750 mg only) and FD & C yellow #6 (750 mg only).

Pharmaceutical Information

Drug Substance

Proper name: Levetiracetam USP
Chemical name: i) 1-pyrrolidineacetamide,-α−Εthyl-2-oxo-, (αs)-.
ii) (-)-(S)- α−Ethyl-2-oxo-1-pyrrolidineacetamide.
iii) 2(S)-(2-oxopyrrolidine –1-yl) butyramide.
Molecular formula and molecular mass: C8H14N2O2 and 170.21 Dalton
Structural formula:
Physicochemical properties:
Physical description: A White to almost white powder
Solubility: Very soluble in water, soluble in acetonitrile and practically insoluble in hexane.
pH and pKa values:
pH : 6.98 ( 1%Aqueous Solution)
pKa : 9.29 (0.1 g in 60ml of DD Water).
The protonation of levetiracetam starts at H0 values between -1 and -2.
Partition co-efficient: Δ log P (log Poctanol – log Pcyclohexane) was calculated at pH 7.4 using phosphate buffered saline and at pH 1.0 using KCl/HCl. The Δ log P at pH 7.4 is 3.65 and at pH 1.0 is 3.10.
Melting Range: 112.0°C to 118.0°C

Clinical Trials

Comparative Bioavailability Studies

A comparative bioavailability study was conducted as a randomized, double blind, two period, single dose, crossover, bioequivalence study using 18 healthy, adult, male human volunteers under fasting conditions. 17 volunteers completed both periods of study which were included in statistical analysis. The rate and extent of absorption of levetiracetam was measured following oral administration of either Abbott-Levetiracetam (levetiracetam) 750 mg Tablets (Abbott Laboratories, Limited) or Keppra 750 mg Tablets (UCB Canada Inc.). The results from measured data are summarized in table 1 as follows:

Table 1: Summary Table of the Comparative Bioavailability Data
Levetiracetam (1 x 750 mg) From measured data uncorrected for potency Geometric Mean Arithmetic Mean (CV %)
Parameter Test * Reference % Ratio of
Geometric
Means**
90% Confidence
Interval
AUCT
(µg*hr/mL)
215.1489
217.7373 (16.14)
210.1749
211.7690 (12.69)
102.16 97.592 - 106.944
AUCI
(µg*hr/mL)
226.0071
228.2524 (14.77)
219.3146
220.8421 (12.31)
102.83 98.674 - 107.152
Cmax
(µg/mL)
25.3262
25.7547 (18.93)
25.3305
26.1165 (26.02)
99.72 92.694 - 107.273
Tmax§
(hr)
0.828 (74.76) 0.843 (63.12)    
T½§
(hr)
7.681 (13.69) 7.608 (11.22)    

*Abbott-Levetiracetam 750 mg, Abbott Laboratories, Limited (Canada).

Keppra® (Levetiracetam Tablets) 750 mg, UCB Canada Inc. (Canada).

§Arithmetic Mean and CV% has been reported for Tmax and T1/2.

**Based on the least squares estimate.

Study Demographics and Trial Design

The efficacy of levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in adults was established in three multicenter, randomized, double-blind, placebo-controlled clinical studies in a total of 904 adult patients who had a history of partial onset seizures with or without secondary generalization.

General Methodology

Patient Population

Patients in these three studies had refractory partial onset seizures for a minimum of 1 (or 2) year(s) prior to enrollment. They had previously taken a minimum number of classical AEDs (either one or two), and at the time of the study were taking a stable dose regimen of at least one AED. During the baseline period, it was required that patients experienced a minimum of 12 partial onset seizures over 12 weeks (Study N132) or 4 partial onset seizures during each 4-week period (Study N051) or 2 partial onset seizures per 4-week period (Study N138).

Dosing Schedules

After a prospective baseline period of approximately 12 weeks, patients were randomized to placebo, or levetiracetam at 1000 mg, 2000 mg or 3000 mg/day (depending on the study), given as twice daily doses. In all trials, there was a 2 or 4 week titration period, followed by a 12- 14 week maintenance period.

Measure of Efficacy

The primary measure of efficacy was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomized treatment period (titration + maintenance). Secondary efficacy parameters include the 50% and 100% responder rate in partial onset seizure frequency over the entire randomized treatment period. Efficacy results are based on the ITT population with the exception of a few patients lacking evaluable seizure frequency data.

The above trial description applies to all three studies below. Thus for each trial, only primary distinguishing information is stated below.

Study N132

Study N132 was a parallel-group study conducted in the United States comparing placebo, levetiracetam 1000 mg/day, and levetiracetam 3000 mg/day in 95, 98, and 101 randomized patients, respectively. The efficacy for Study N132 is displayed in Table 2.

Table 2: Median Percent Reduction From Baseline In Weekly Frequency Of Partial Onset Seizures In Study N132
  AEDs +
Placebo
AEDs + Levetiracetam
1000 mg/day
AEDs + Levetiracetam
3000 mg/day
N 95 97 101
Median Baseline Seizure
Frequency
1.77 2.53 2.08
Percent reduction in partial
seizure frequency from baseline
6.9% 36.9%* 38.1%*

*P<0.001 versus placebo.

Study N051

Study N051 was a crossover study conducted in Europe comparing placebo, levetiracetam 1000 mg/day, and levetiracetam 2000 mg/day in 112, 106, and 106 randomized patients, respectively.

The first period of the study (Period A) was designed to be analyzed as a parallel-group study. The efficacy results for Period A are displayed in Table 3.

Table 3: Median Percent Reduction From Baseline In Weekly Frequency Of Partial Onset Seizures In Study N051 Period A
  AEDs +
Placebo
AEDs + Levetiracetam
1000 mg/day
AEDs + Levetiracetam
2000 mg/day
N 111 106 105
Median Baseline Seizure
Frequency
2.46 2.82 2.59
Percent reduction in partial
seizure frequency from baseline
1.1% 20.7%* 24.4%*

*P<0.001 versus placebo.

Study N138

Study N138 was a parallel-group study conducted in Europe comparing placebo and levetiracetam 3000 mg/day in 105 and 181 randomized patients, respectively. Table 4 displays the efficacy results for Study N138.

Table 4: Median Percent Reduction From Baseline In Weekly Frequency Of Partial Onset Seizures In Study N138
  AEDs +
Placebo
AEDs + Levetiracetam
3000 mg/day
N 104 180
Median Baseline Seizure Frequency 1.78 1.67
Percent reduction in partial seizure frequency from baseline 7.3% 36.8%*

*P<0.001 versus placebo.

Responder Rates

Each patient is categorized according to their efficacy data: percent reduction from baseline in weekly frequency of partial onset seizures, calculated over the entire randomized treatment period. The percentage of patients who remained on levetiracetam for at least 21 days and achieved ≥50% reduction, or a 100% reduction (seizure free) within each of the three pivotal studies is presented in Table 5.

Table 5: Partial Onset Responder Rate Over The Entire Treatment Period By Randomized
Dose
Percent Reduction AEDs +
Placebo
AEDs +
Levetiracetam
1000 mg/day
AEDs +
Levetiracetam
2000 mg/day
AEDs +
Levetiracetam
3000 mg/day
Study N132
N 95 97 - 101
≥50% 7% 36% - 40%
Seizure free (100%) 0% 3% - 6%
Study N051
N 111 106 105 -
≥50% 6% 21% 34% -
Seizure free (100%) 1% 2% 3% -
Study N138
N 104 - - 180
≥50% 14% - - 39%
Seizure free (100%) 0% - - 7%

Detailed Pharmacology

Preclinical Studies

The pharmacological activity of levetiracetam has been assessed in a variety of animal models of acute seizures and chronic epilepsy. Many studies included standard antiepileptic drugs (AEDs) as comparative agents.

Levetiracetam displayed protection against seizures in animal models of chronic epilepsy involving genetic and kindled animals with spontaneous, recurrent seizures. This contrasts to a lack of anticonvulsant activity in two primary screening tests for AEDs, the maximal electroshock (MES) test, and the maximal pentylenetetrazol (PTZ) test. In general, levetiracetam is devoid of any activity against single seizures induced by maximal stimulation with different chemoconvulsants and only shows a minor anticonvulsant action upon submaximal stimulation and in threshold tests. An exception is the antiseizure protection observed against secondarily generalized activity from focal seizures induced by the chemoconvulsants pilocarpine and kainic acid. The predictive value of these animal models for mechanism of action is uncertain.

In vitro studies show that levetiracetam, at concentrations of up to 10 μM did not appear to result in significant ligand displacement at known receptor sites such as benzodiazepine, GABA (gamma-aminobutyric acid), glycine, NMDA (N-methyl-D-asparate) reuptake sites or second messenger systems. It is unclear whether binding to any of these sites would occur at higher levetiracetam concentrations. Levetiracetam does not appear to modulate neuronal voltage-gated sodium and T-type calcium currents. Levetiracetam partially inhibits N-type calcium currents in neuronal cells.

A binding site for levetiracetam (LEV), that appears to be saturable, has been demonstrated in rat brain [Kd of 62 ± 20 nM and Bmax of 4.5 ± 0.1 pmol/mg protein] and spinal cord [Kd of 52 ± 14 nM and Bmax of 1.6 ± 0.1 pmol/mg protein], using a tritiated derivative of levetiracetam ([3H]ucb 30889). [3H]LEV and [3H]ucb 30889 are structurally related radioligands. [3H]ucb 30889 was preferentially used in binding studies, as it displayed a ten-fold higher affinity than [3H]LEV for their binding sites. In the rat, both radioligands were shown to label the same binding sites. These sites have the same tissue distribution and are almost exclusively restricted to the brain. All sites, in the rat, labeled by [3H]ucb 30889 can be displaced by unlabeled LEV. Experimental data indicate that this binding site labeled by [3H]ucb 30889 appears to be the synaptic vesicle protein SV2A. [3H]ucb 30889 was also suggested to bind to SV2A in human brain [Kd of 53 ± 7 nM and Bmax of 3.6 ± 0.7 pmol/mg protein] and in CHO cells expressing the human recombinant protein. Measurement of [3H]ucb 30889 binding to brain membranes from SV2A knockout mice was 79 ± 9 DPM/assay vs. 933 ± 65 DPM/assay in brain membranes from wild type mice. [3H]ucb 30889 binds to SV2A but not to the related isoforms SV2B and SV2C, expressed in fibroblasts. In Chinese hamster ovary (CHO) cells and tissue from the human cerebral cortex, the binding curves in competition experiments did not reveal the existence of the multiple SV2A binding sites that are observed with [3H]ucb 30889. This indicates that LEV is non-selective or poorly selective with respect to the different SV2A binding sites.

The clinical relevance of these data to humans is unknown.

Toxicology

General Toxicity

The general toxicity of levetiracetam was evaluated after oral administration in acute (mouse, rat, dog and monkey), subacute and chronic (two to 52 weeks or longer in the mouse, rat and dog) studies. Acute (mouse, rat and dog) and two-week (rat and dog) toxicity studies were also conducted using iv administration.

The single-dose studies in mice, rats and dogs indicate a low acute toxicity potential. Lethality was only reached after iv dosing in these studies; although in a subsequent study in mice (micronucleus test), lethality was reached at 10000 mg/kg orally. Oral administration is associated with only transient clinical signs (emesis, salivation, tremors, decreased motor activity, ataxia, tachypnea and side lying). In dogs, emesis is a dose-limiting effect. Repeat administration of levetiracetam is well tolerated. Mortality is observed only following iv administration of 900 mg/kg in rats. In general, clinical signs are minimal across studies and species with the most consistent observations being neuromuscular effects, salivation, and emesis in dogs. In the rodent only, treatment-related changes in the liver and kidney were reported. In the liver, a reversible increase in liver weight and hypertrophy of centrilobular hepatocytes was observed in both sexes in rats and mice. Centrilobular vacuolation associated with lipid deposition occurred in male rats and in mice. Kidney pathology consisting of hyaline droplet nephropathy, exacerbation of chronic progressive nephropathy and associated changes was observed in male rats.

These changes are considered to be a male rat-specific pathology associated with α2- microglobulin accumulation in the proximal tubules that is not toxicologically relevant to man. There was no target organ identified in the dog. No lethality, organ failure or other irreversible toxicity was observed after long-term oral treatment up to 1800 mg/kg/day in the rat, 960 mg/kg/day in the mouse and 1200 mg/kg/day in the dog.

Studies in neonatal or juvenile animals do not indicate any greater potential for toxicity compared to adult animals. Investigations involving oral administration of for up to 2 weeks of ucb L057, the major human metabolite, indicate a low potential for toxicity in rats and dogs.

Reproductive Toxicology

No adverse effects on male or female fertility or reproductive performance were observed in rats at doses up to 1800 mg/kg/day.

Administration to rats before mating and throughout pregnancy and lactation was associated with slightly retarded fetal growth and skeletal ossification in utero and slight increase in pup mortality between birth and day 8 postpartum at 1800 mg/kg/day and slightly retarded skeletal ossification at 350 mg/kg/day.

When female rats were administered levetiracetam orally up to 1800 mg/kg/day from day 15 of pregnancy to weaning (day 21 postpartum), no effects were observed on litter parameters, pup survival and development. The dose of 1800 mg/kg/day corresponds to 30-fold the upper recommended daily dose in man on a mg/kg/day basis or 6-fold when calculated on a mg/m2 body surface area basis.

In pregnant rats treated at 400, 1200 and 3600 mg/kg/day from day 6 to 15 of pregnancy, the no adverse effect level for embryo-fetal survival, growth and development is 1200 mg/kg/day. There was a slight increase in the proportion of fetuses with supernumerary ribs (thoracolumbar border) and a marginal reduction in skeletal ossification at 3600 mg/kg/day. This dose was toxic for the mothers. This dose represents 60-fold the upper recommended dose in man on a mg/kg/day basis, or 12-fold on a mg/m2 basis.

In pregnant rabbits, the no-adverse effect level for embryo-fetal survival, growth and development was 200 mg/kg/day, a dose producing adverse effects in the mothers. At the highest dose of 1800 mg/kg/day, a 2.5-fold increase in fetal abnormalities was observed together with marked maternal toxicity. This was not seen in two other studies. The dose of 1800 mg/kg/day corresponds to 30-fold the upper recommended dose in man on a mg/kg/day basis or 11-fold when calculated on a mg/m2 basis.

In a study in pregnant mice, levetiracetam administered at 3000 mg/kg/day from day 6 to 15 of pregnancy produced a slight retardation of growth and skeletal ossification and no effect on survival and morphological development. Plasma levetiracetam concentrations at approximate peak time were 20-fold higher than peak concentrations measured in man after 3000 mg/day.

Carcinogenesis and Mutagenesis

Carcinogenesis

Rats were dosed with levetiracetam in the diet for 104 weeks at doses of 50, 300 and 1800 mg/kg/day. There was no evidence of carcinogenicity. Two studies have been conducted in mice. In one study, mice received levetiracetam in the diet for 80 weeks at doses of 60, 240 and 960 mg/kg/day (high dose is equivalent to 2 times the MRHD on a mg/m2 or exposure basis). In a second study, mice received levetiracetam by oral gavage for 2 years at dose levels of 1000, 2000 and 4000 mg/kg/day. Due to poor survival at the highest dose of 4000 mg/kg/day in this study, the high dose was reduced to 3000 mg/kg/day (equivalent to 12 times the MRHD). In neither study was evidence of carcinogenicity seen.

Mutagenesis

Levetiracetam was not mutagenic in the Ames test or in mammalian cells in vitro in the Chinese hamster ovary/HGPRT locus assay. It was not clastogenic in an in vitro analysis of metaphase chromosomes obtained from Chinese hamster ovary cells or in an in vivo mouse micronucleus assay. The hydrolysis product and major human metabolite of levetiracetam (ucb L057) was not mutagenic in the Ames test or the in vitro mouse lymphoma assay.