12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism by which riluzole exerts its therapeutic effects in patients with ALS is unknown.

12.2 Pharmacodynamics

The clinical pharmacodynamics of riluzole has not been determined in humans.

12.3 Pharmacokinetics

A pharmacokinetic study in healthy adult subjects who received riluzole suspension 50 mg under fasting conditions demonstrated similar pharmacokinetics following intragastric administration via feeding tubes and oral administration.

Table 2 displays the pharmacokinetic parameters of riluzole.

Table 2. Pharmacokinetics of Riluzole *
* Unless otherwise stated, information in this table is based on pharmacokinetic studies of riluzole tablets. † Information specific to TIGLUTIK
Absorption
Bioavailability (oral)	Approximately 60%
Dose Proportionality	Linear over a dose range of 25 mg to 100 mg every 12 hours (1/2 to 2 times the recommended dosage)
Food effect †	AUC ↓ 9% and Cmax ↓ 55% (high fat meal)
Time to peak plasma concentration (median) †	0.8 hours
Distribution
Plasma Protein Binding	96% (Mainly to albumin and lipoproteins)
Elimination
Elimination half-life	12 hours (CV=35%) The high individual variability in the clearance of riluzole is potentially attributable to variability of CYP1A2. The clinical implications are not known.
Accumulation	Approximately 2-fold
Metabolism
Fraction metabolized (% dose)	At least 88%
Primary metabolic pathway(s) [in vitro]	Oxidation: CYP1A2 Direct and sequential glucoronidation: UGT-HP4
Active Metabolites	Some metabolites appear pharmacologically active in vitro, but the clinical implications are not known.
Excretion
Primary elimination pathways (% dose)	Feces: 5% Urine: 90% (2% unchanged riluzole)

Specific Populations

Hepatic Impairment

Compared with healthy volunteers, the AUC of riluzole was approximately 1.7-fold greater in patients with mild chronic hepatic impairment (CP score A), and approximately 3-fold greater in patients with moderate chronic hepatic impairment (CP score B). The pharmacokinetics of riluzole have not been studied in patients with severe hepatic impairment (CP score C) [see Use in Specific Populations (8.6)].

Race

The clearance of riluzole was 50% lower in male Japanese subjects than in Caucasian subjects, after normalizing for body weight [see Use in Specific Populations (8.7)].

Gender

The mean AUC of riluzole was approximately 45% higher in female patients than male patients.

Smokers

The clearance of riluzole in tobacco smokers was 20% greater than in nonsmokers. Geriatric Patients and Patients with Moderate to Severe Renal ImpairmentAge 65 years or older and moderate to severe renal impairment do not have a meaningful effect on the pharmacokinetics of riluzole. The pharmacokinetics of riluzole in patients undergoing hemodialysis are unknown.

Drug Interaction Studies

Drugs Highly Bound to Plasma Proteins

Riluzole and warfarin are highly bound to plasma proteins. In vitro, riluzole did not show any displacement of warfarin from plasma proteins. Riluzole binding to plasma proteins was unaffected by warfarin, digoxin, imipramine and quinine at high therapeutic concentrations in vitro.