mirogabalin and Dizziness

Three phase 1 pharmacokinetic (PK)/pharmacodynamics (PD) studies were conducted in healthy men and women to further characterize the safety, tolerability, and PK/PD of mirogabalin administration with or without food and to guide the dose selection and regimen for phase 2 and 3 clinical development. The 3 studies included 2 randomized, double-blind, placebo-controlled, single- and multiple-ascending-dose studies, and 1 open-label, crossover study to evaluate the PK of mirogabalin administered under fasting and fed (high-fat meal) conditions. Forty-eight and 47 healthy volunteers completed the single- and multiple-dose studies, respectively. Thirty subjects were enrolled and completed the food effect study. Mirogabalin was well tolerated in the fed and fasted states. The most frequent treatment-emergent adverse events (TEAEs)-dizziness and somnolence-were expected based on mirogabalin's mechanism of action. Subjects receiving the highest mirogabalin doses (50 and 75 mg single dose) showed greater dizziness and sedation and higher rates of TEAEs than subjects receiving 3-30 mg. After oral administration, mirogabalin was rapidly absorbed (time to maximum concentration, ∼1 hour) and eliminated through urine unchanged (61%-72% urinary excretion). Exposure increased in a dose-proportional manner after single or multiple mirogabalin doses. No significant accumulation occurred with multiple doses over 14 days. After single doses of mirogabalin (15 mg), the bioavailability was considered equivalent in the fed and fasted states, indicating that mirogabalin can be taken without food restrictions. Based on these data, mirogabalin 15 mg twice daily was selected as the highest target dose for further clinical development.

Topics: Administration, Oral; Adult; Analgesics; Bridged Bicyclo Compounds; Calcium Channel Blockers; Calcium Channels; Cross-Over Studies; Dizziness; Dose-Response Relationship, Drug; Fasting; Female; Food-Drug Interactions; Healthy Volunteers; Humans; Male; Metabolic Clearance Rate; Neuralgia; Sleepiness; Young Adult

Mirogabalin (DS-5565) is an α2δ-1 ligand being developed for pain associated with diabetic peripheral neuropathy, fibromyalgia, and postherpetic neuralgia. Nonlinear mixed-effects analyses were performed on average daily pain and on the incidence of the adverse events dizziness and somnolence. These models were used to predict the dose of mirogabalin equivalent to pregabalin and the probability of meaningful reduction in pain compared with placebo and pregabalin. In addition, regimen effects were evaluated for reductions of adverse events. Mirogabalin was estimated to be 17-fold more potent than pregabalin. The effectiveness of 150 mg pregabalin, dosed twice daily, attenuated by week 5. Therefore, the estimated mechanism-based equivalent dose (ED) of 17.7 mg mirogabalin was higher than that predicted to achieve comparable pain reduction. If attenuation of the pregabalin effect is real, mirogabalin doses lower than the ED could yield comparable pain reduction, albeit with less differentiation in pain from placebo. The incidence rate of dizziness and somnolence decreased over time. Twice-daily dosing of mirogabalin was predicted to yield a lower incidence rate of dizziness than once-daily dosing; thus, titration of dosages should reduce adverse event rates. These model results were used to influence phase 3 dosing selection.

Topics: Adult; Aged; Aged, 80 and over; Analgesics; Bridged Bicyclo Compounds; Diabetes Mellitus; Disorders of Excessive Somnolence; Dizziness; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Models, Biological; Neuralgia; Pain Measurement