Riluzole

Although the pathogenesis of ALS is not completely elucidated, it is suggested that glutamate (the primary excitatory neurotransmitter in the central nervous system) plays a role for cell death in the disease.

Riluzole is proposed to act by inhibiting glutamate processes. The mode of action is unclear.

The pharmacokinetics of riluzole have been evaluated in healthy male volunteers after single oral administration of 25 to 300 mg and after multiple-dose oral administration of 25 to 100 mg bid. Plasma levels increase linearly with the dose and the pharmacokinetic profile is dose-independent. With multiple dose administration (10 day-treatment at 50 mg riluzole bid), unchanged riluzole accumulates in plasma by about 2 fold and steady-state is reached in less than 5 days.

Absorption

Riluzole is rapidly absorbed after oral administration with maximal plasma concentrations occurring within 60 to 90 minutes (C_max = 173 ± 72 (sd) ng/ml). About 90% of the dose is absorbed and the absolute bioavailability is 60 ± 18%.

The rate and extent of absorption is reduced when riluzole is administered with high-fat meals (decrease in C_max of 44%, decrease in AUC of 17%).

Distribution

Riluzole is extensively distributed throughout the body and has been shown to cross the blood brain barrier. The volume of distribution of riluzole is about 245 ± 69 L (3.4 L/kg). Riluzole is about 97% protein bound and it binds mainly to serum albumin and to lipoproteins.

Biotransformation

Unchanged riluzole is the main component in plasma and is extensively metabolised by cytochrome P450 and subsequent glucuronidation. In vitro studies using human liver preparations demonstrated that cytochrome P450 1A2 is the principal isoenzyme involved in the metabolism of riluzole. The metabolites identified in urine are three phenolic derivatives, one ureido-derivative and unchanged riluzole.

The primary metabolic pathway for riluzole is initial oxidation by cytochrome P450 1A2 producing N-hydroxy-riluzole (RPR112512), the major active metabolite of riluzole. This metabolite is rapidly glucuronoconjugated to O- and N-glucuronides.

Elimination

The elimination half-life ranges from 9 to 15 hours. Riluzole is eliminated mainly in the urine. The overall urinary excretion accounts for about 90% of the dose. Glucuronides accounted for more than 85% of the metabolites in the urine. Only 2% of a riluzole dose was recovered unchanged in the urine.

Special populations

Impaired renal function

There is no significant difference in pharmacokinetic parameters between patients with moderate or severe chronic renal insufficiency (creatinine clearance between 10 and 50 ml.min^-1) and healthy volunteers after a single oral dose of 50 mg riluzole.

Older people

The pharmacokinetic parameters of riluzole after multiple dose administration (4.5 days of treatment at 50 mg riluzole bid) are not affected in the older people (>70 years).

Impaired hepatic function

The AUC of riluzole after a single oral dose of 50 mg increases by about 1.7 fold in patients with mild chronic liver insufficiency and by about 3 fold in patients with moderate chronic liver insufficiency.

Race

A clinical study conducted to evaluate the pharmacokinetics of riluzole and its metabolite N-hydroxyriluzole following repeated oral administration twice daily for 8 days in 16 healthy Japanese and 16 Caucasian adult males showed in the Japanese group a lower exposure of riluzole (C_max 0.85 [90% CI 0.68-1.08] and AUC_inf. 0.88 [90% CI 0.69-1.13]) and similar exposure to the metabolite. The clinical significance of these results is not known.

Riluzole did not show any carcinogenicity potential in either rats or mice.

Standard tests for genotoxicity performed with riluzole were negative. Tests on the major active metabolite of riluzole gave positive results in two in vitro tests. Intensive testing in seven other standard in vitro or in vivo assays did not show any genotoxic potential of the metabolite. On the basis of these data, and taking into consideration the negative studies on the carcinogenesis of riluzole in the mouse and rat, the genotoxic effect of this metabolite is not considered to be of relevance in humans.

Reductions in red blood cell parameters and/or alterations in liver parameters were noted inconsistently in subacute and chronic toxicity studies in rats and monkeys. In dogs, haemolytic anaemia was observed.

In a single toxicity study, the absence of corpora lutea was noted at a higher incidence in the ovary of treated compared to control female rats. This isolated finding was not noted in any other study or species.

All these findings were noted at doses which were 2-10 times higher than the human dose of 100 mg/day.

In the pregnant rat, the transfer of ¹⁴C-riluzole across the placenta to the foetus has been detected. In rats, riluzole decreased the pregnancy rate and the number of implantations at exposure levels at least twice the systemic exposure of humans given clinical therapy. No malformations were seen in animal reproductive studies.

In lactating rats, ¹⁴C-riluzole was detected in milk.