Tolerability, pharmacokinetics, and pharmacodynamics of mirogabalin in healthy subjects: Results from phase 1 studies

Abstract

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.

Results of Mirogabalin Treatment for Diabetic Peripheral Neuropathic Pain in Asian Subjects: A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Study

“…Pregabalin was selected as the active control since both agents target the same voltage-gated calcium channel a 2 d subunit, and because pregabalin is approved in many countries for the treatment of DPNP [13,15]. No upper age limit was placed on this study, since a phase 1 study in elderly subjects showed no Data are given as n (%) Adverse events were coded using the Medical Dictionary for Regulatory Activities version 16.0 BID twice daily, PT preferred term, SOC system organ class notable differences from the results obtained in non-elderly subjects with regard to safety, tolerability, and pharmacokinetics [33]. Nevertheless, despite these elements of study design, mirogabalin produced numeric but not statistically significant improvements compared with placebo, and almost no impact was observed with pregabalin on any measure, likely due to the subjective nature of pain measurement and the difficulty in minimizing the placebo response [34].…”

Mirogabalin—A Novel Selective Ligand for the α2δ Calcium Channel Subunit

“…Mirogabalin was tested in healthy volunteers at doses ranging from 3 to 75 mg [ 23 ]. After oral administration, mirogabalin is quickly absorbed, with a mean time to maximum plasma concentration (T max ) of 0.5–1.5 h after single or repeated doses [ 5 ].…”

“…After oral administration, mirogabalin is quickly absorbed, with a mean time to maximum plasma concentration (T max ) of 0.5–1.5 h after single or repeated doses [ 5 ]. The plasma maximum concentration (C max ) and concentration–time curve (AUC) increased in a dose-dependent manner, whereas the steady-state plasma concentration was achieved by day 3 [ 23 ]. In the fed state, T max is delayed by 0.5 h after taking a 15 mg dose of mirogabalin, and C max is reduced by approximately 18%, but it does not influence its general exposure to any clinically relevant degree [ 23 ].…”

Mirogabalin: could it be the next generation gabapentin or pregabalin?

“…Fed (high-fat meal) or fasting states in healthy volunteers did not affect bioavailability after taking a single dose of mirogabalin 15 mg. No food restriction was needed when taking mirogabalin in a phase 1 study [44].…”