POPULATION PHARMACOKINETICS OF RILUZOLE IN PATIENTS WITH AMYOTROPHIC-LATERAL-SCLEROSIS

Objectives: To characterize the population pharmacokinetic of riluzole in patients with amyotrophic lateral sclerosis (ALS). Methods: One hu ndred patients with ALS who were participating in a multicenter phase III dose-ranging trial of riluzole were sampled on 179 visits. The sam pling strategy (two samples per visit) was varied across patients to d efine the population kinetic profile (full screen). Riluzole plasma le vels were determined by HPLC, and the data were analyzed by nonlinear mixed-effect modeling (NONMEM program) with use of a one-compartment s tructural model. The model incorporated interoccasion (visit-to visit) variability. Results: In the basic one-compartment pharmacokinetic mo del, interindividual variability in plasma clearance (51.4%) was highe r than intraindividual (visit-to-visit) variability (28.0%), indicatin g uniform pharmacokinetic behavior during long-term therapy. Riluzole clearance was independent of dosage (25 to 100 mgtwice daily), treatme nt duration (up to 10 months), age, and renal function; gender and smo king were the most important patient covariates, with hepatic function having lesser influence. Typical value of clearance was 51.4 L/hr for a nonsmoking male patient. It was 32% lower in women than in men and 36% lower in nonsmokers than in smokers. Gender-and smoking-related va riations in riluzole exposure at the recommended dosage (50 mg twice d aily) were within the range of exposures achieved (with no untoward ef fect) in this dose-ranging study. Conclusion: The pharmacokinetics of riluzole has been characterized in patients during long-term therapy. Riluzole clearance is independent of dose and treatment duration. With in-patient variability is low. Gender and smoking status are the main covariates to explain interpatient variability.