LAUSR

Study Objectives: Tolperisone is a centrally acting muscle relaxant being developed in the US as a treatment for acute and painful symptoms of neck and low back muscle spasms. This study explores the impact of tolperisone on driving simulation endpoints, sedation, and cognition compared to placebo (PBO) and cyclobenzaprine (CYC). The CYC half-life is long (>19 hours) and accumulated over the 3 days of the trial. Tolperisone has a Tmax of 1 hour, and a 2to 3-hour half-life. Methods: This was a 3-way, randomized, blinded, crossover study of tolperisone in 31 healthy volunteers. Treatment groups were 450 mg tolperisone administered 3times a day (150 mg TID), 30 mg CYC (10 mg TID), and PBO (TID). Participants spent 3 days of 3 consecutive weeks in the research unit. Dosing occurred in the morning (AM) and at midday (PM) on Days 1-3 and at bedtime on Days 1 and 2. Subjects were administered a DSST followed by 100 km (60 minute) of simulated driving on Day 1 one hour after their midday dose (at drug Tmax), and the morning of Day 2 (pre-dosing) to assess next day residual effects. Tests were the morning of Day 3 (post-dose) to assess the drug at steady-state. Subjects returned to the clinic on Days 7 and 14 to repeat these procedures. Results: For the primary endpoint of Standard Deviation of Lateral Position (SDLP) over 100-km of driving, tolperisone was no different than PBO, whereas CYC showed significant impairment (p1⁄4<0.001). The distribution of SDLP for PBO and tolperisone showed symmetry around zero, while CYC was markedly different; a subset of subjects had a level of impairment associated with increased crash risk, demonstrated by SDLP values above 4.4 cm (consistent with normative Blood Alcohol Concentration (BAC) levels of above 0.05%). Secondary measures confirmed a lack of sedation for tolperisone relative to PBO: Digit Symbol Coding Day 1 p1⁄4 0.84, Day 2 p1⁄4 0.21, Day 3 p1⁄4 0.12; and Karolinska Sleepiness Scale: Day 1 p1⁄4 0.47, Day 2 p1⁄4 0.47, and Day 3 p1⁄4 0.49. Additional measures of driving indicated no impairment for tolperisone versus PBO. Conclusions: Tolperisone 150 mg TID had no impact on various measures of driving, self-reported sleepiness, and cognition, in contrast to CYC 10 mg TID. Data confirms impairment in cognition and driving for healthy subjects taking CYC.