A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Rilutek Pharmacology, Pharmacokinetics, Studies, Metabolism - Riluzole
Rilutek Pharmacology, Pharmacokinetics, Studies, Metabolism - Riluzole
CLINICAL PHARMACOLOGY
Mechanism of Action
The etiology and pathogenesis of amyotrophic lateral sclerosis (ALE)
are not known, although a number of hypotheses have been advanced. One
hypothesis is that motor neurons, made vulnerable through either genetic
predisposition or environmental factors, are incured by glutamate. In
some cases of familial ALE the enzyme superoxide dismutase has been found
to be defective.
The mode of action of RILUTEK is unknown. Its pharmacological properties
include the following, some of which may be related to its effect: 1)
an inhibitory effect on glutamate release, 2) inactivation of voltage
dependent sodium channels, and 3) ability to interfere with intracellular
events that follow transmitter binding at excitatory amino acid receptors.
Riluzole has also been shown, in a single study, to delay median time
to death in a transgenic mouse model of ALS. These mice express human
superoxide dismutase bearing one of the mutations found in one of the
familial forms of human ALS.
It is also neuroprotective in various in vivo experimental models
of neuronal injury involving excitotoxic mechanisms. In in vitro
tests, riluzole protected cultured rat motor neurons from the excitotoxic
effects of glutamic acid and prevented the death of cortical neurons induced
by anoxia.
Due to its blockade of glutamatergic neurotransmission, riluzole also
exhibits myoretaxant and sedative properties in animal models at doses
of 30 mg/kg (about 20 times the recommended human daily dose) and anticonvulsant
properties at a dose of 2.5 mg/kg (about 2 times the recommended human
daily dose).
Pharmacokinetics
Riluzole is well-absorbed (approximately 90%), with average absolute
oral bioavailability of about 60% (CV=30%). Pharmacokinetics are linear
over a dose range of 25-100 mg given every 12 hours. A high fat meal decreases
absorption, reducing AUC by about 20% and peak blood levels by about 45%.
The mean elimination half-life of riluzole is 12 hours (CV=35%) after
repeated doses. With multiple-dose administration, riluzole accumulates
in plasma by about 2 fold and steady-state is reached in less than 5 days.
Riluzole is 96% bound to plasma proteins, mainly to albumin and lipoprotein
over the clinical concentration range.
The 50 mg market tablet was equivalent, with respect to AUC, to the tablet
used in the dose ranging clinical trials, while the Cmax was
approximately 30% higher. Both tablets have been used in clinical trials.
However, if doses greater than those recommended are given, it is likely
that higher plasma levels will be achieved, the safety of which has not
been established (see DOSAGE AND ADMINISTRATION).
Metabolism and Elimination
Riluzole is extensively metabolized to six major and a number of minor
metabolites, not all of which have been identified. Some metabolites appear
pharmacologically active in in vitro assays. The metabolism of riluzole
is mostly hepatic and consists of cytochrome P450-dependent hydroxylation
and glucuronidation.
There it marked inter-individual variability in the clearance of riluzole,
probably attributable to variability of CYP1A2 activity, the principal
isozyme involved in N-hydroxylation.
In vitro studies using liver microsomes wshow that hydroxylation of the
primary amine group producing N-hydroxyriluzole is the main metabolic
pathway in human, monkey, dog and rabbit. In humans, cytochrome P450 1A2
is the principal isozyme involved in N-hydroxytation. In vitro
studies predict that CYP2D6, CYP 2C19, CYP 3A4 and CYP 2E1 are unlikely
to contribute significantly to riluzole metabolism in humans. Whereas
direct glucuroconjugation of riluzole (involving the glucurotransferase
isoform UGT-HP4) is very slow in human liver microsomes, N-hydroxyriluzole
is readily conjugated at the hydroxylamine group resulting in the formation
of O- (>90%) and N-glucuronides.
Following a single 150 mg dose of 14C-riluzole to 6 healthy
males, 90% and 5% of the radioactivity was recovered in the urine and
feces respectively over a period of 7 days. Glucuronides accounted for
more than 85% of the metabolites in urine. Only 2% of a riluzole dose
was recovered in the urine as unchanged drug.
Special Populations
The pharmacokinetics of riluzole have not been studied in renally and
hepatically impaired subjects, nor is there information about the effects
of smoking, age and gender on the pharmacokinetics of riluzole but certain
differences in population subsets should be anticipated (see PRECAUTIONS).
Hepatic and Renal Disease: Since riluzole is extensively metabolized
and subsequently excreted in the urine, it is likely that functional hepatic
and renal impairment will reduce the clearance of riluzole and its metabolites
and give higher plasma levels (see PRECAUTIONS
and WARNINGS).
Age: Age-related decreased renal function would be expected to
give higher plasma levels of riluzole and metabolites. However, in controlled
clinical trials, in which approximately 30% of patients were over 65,
there were no differences in adverse events between younger and older
patients (see PRECAUTIONS).
Gender: CYP 1A2 activity has been reported to be lower in women
than in men. Therefore, a gender effect on riluzole kinetics may be expected
in women, resulting in higher blood concentrations of riluzole and its
metabolites (see PRECAUTIONS).
No gender effect on favorable or adverse effects of riluzole was been
in controlled trials, however.
Smoking: Cigarette smoking is known to induce CYP 1A2. Patients
who smoke cigarettes would be expected to eliminate riluzole faster. There
is no information, however, on the effect of, or need for, dosage adjustment
in these patients.
Race: Clearance of riluzole in Japanese subjects native to Japan
was found to be 50% lower as compared to Caucasians after normalizing
for body weight. Although it is not clear if this difference is due to
genetic or environmental factors (e.g., smoking, alcohol, coffee, and
dietary preferences), it is possible that Japanese subjects may possess
a lower capacity (oxidative and/or conjugative) for metabolizing riluzole.
There are no studies, however, of lower doses in Japanese subjects (see
PRECAUTIONS).
Clinical Trials
The efficacy of RILUTEK as a treatment of ALS was established in two
adequate and well-controlled trials in which the time to tracheostomy
or death was longer for patients randomized to RILUTEK than for those
randomized to placebo.
These studies admitted patients with either familial or sporadic ALS,
a disease duration of less than 5 years, and a baseline forced vital capacity
greater than or equal to 60%. In one study, performed in France and Belgium,
155 ALS patients were followed for at least 13 months (maximum duration
18 months) after being randomized to either 100 mg/day (given 50 mg BID)
of RILUTEK or placebo.
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