Pharmacokinetics and Safety of a Single Oral Dose of Mirogabalin in Japanese Subjects With Varying Degrees of Renal Impairment

Abstract

Mirogabalin (DS‐5565) is a novel preferentially selective α2δ‐1 ligand being developed for the treatment of diabetic peripheral neuropathic pain and postherpetic neuralgia. The current multicenter open‐label study determined the effect of varying degrees of renal impairment on the pharmacokinetics and safety of a single dose of mirogabalin 5 mg in Japanese subjects. A total of 30 subjects (6 subjects per renal function category [normal, mild, moderate, or severe impairment; and end‐stage renal disease (ESRD)]) were enrolled and completed the study. The AUClast increased with severity of renal impairment; the geometric least‐squares mean ratios of AUClast compared with subjects with normal renal function were 1.3, 1.9, 3.6, and 5.3 for patients with mild, moderate, and severe impairment and ESRD, respectively. In accordance with this AUClast increase, apparent total body clearance (CL/F), renal clearance (CLr), and the cumulative percentage of mirogabalin dose excreted into urine all decreased with severity of renal impairment. There were no deaths and no severe treatment‐related adverse events (TEAEs), serious TEAEs, or TEAEs resulting in study discontinuation. Mirogabalin was well tolerated in Japanese subjects with normal renal function and those with mild to severe renal impairment. It was also tolerated in subjects with ESRD but with a higher incidence of TEAEs. The most frequently reported TEAEs were dizziness (ESRD, n = 3), somnolence (ESRD, n = 2), and vomiting (ESRD, n = 2). Based on these data, a mirogabalin dose adjustment will be considered in Japanese subjects with moderate to severe renal impairment and those with ESRD.

Coadministration of probenecid and cimetidine with mirogabalin in healthy subjects: A phase 1, randomized, open‐label, drug–drug interaction study

“…a drug that only affects renal clearance (cimetidine). The increase in mirogabalin exposure with cimetidine is similar to the increase observed in patients with mild renal impairment, for whom mirogabalin dose adjustments are not considered necessary 22. Additionally, since the effect of probenecid on mirogabalin is not significant (>2‐fold), mirogabalin dose adjustments may not be necessary with concomitant probenecid.…”

A Randomized, Placebo‐Controlled, Double‐Blind Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Repeated Doses of Mirogabalin in Healthy Asian Volunteers

“…Mirogabalin is rapidly absorbed, and elimination occurs mainly via renal excretion (61% to 72%) . Owing to its renal elimination, a reduction in the dose of mirogabalin is recommended for patients with moderate or severe renal impairment . Following oral administration of doses ranging from 3 to 75 mg in healthy volunteers, the peak and total exposure to mirogabalin increases proportionally with increasing doses .…”

“…6,7 Owing to its renal elimination, a reduction in the dose of mirogabalin is recommended for patients with moderate or severe renal impairment. 8,9 Following oral administration of doses ranging from 3 to 75 mg in healthy volunteers, the peak and total exposure to mirogabalin increases proportionally with increasing doses. 6 The time of peak plasma concentration of mirogabalin is 1 hour with a mean half-life ranging from 3.0 to 4.9 hours.…”

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Mirogabalin When Coadministered With Lorazepam, Zolpidem, Tramadol, or Ethanol: Results From Drug‐Drug Interaction Studies in Healthy Subjects

“…A predominantly renal route of elimination and minimal metabolism of mirogabalin was reported in animal studies . Due to its renal elimination, a dose reduction of mirogabalin is recommended for patients with moderate or severe renal impairment …”

“…16 Due to its renal elimination, a dose reduction of mirogabalin is recommended for patients with moderate or severe renal impairment. 17,18 In clinical studies, mirogabalin demonstrated promising results in patients with diabetic peripheral neuropathy. A phase 2 study in 452 patients with diabetic peripheral neuropathic pain reported that mirogabalin doses from 15 to 30 mg/day were the most effective and significantly reduced average daily pain scores compared with placebo.…”