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

Abstract

Four randomized, double-blind, placebo-controlled, 4-period drug-drug interaction studies were conducted in healthy subjects to evaluate the pharmacokinetic and pharmacodynamic (PD) interactions between mirogabalin and commonly used central nervous system depressants. Mirogabalin or placebo was administered alone or with single-dose lorazepam, zolpidem, tramadol, ethanol, or interacting drug placebo. Safety was assessed and serial samples for pharmacokinetic parameters were collected for up to 48 hours postdose. PD assessments included body sway (except tramadol), digit symbol substitution test, vertigo symptom scale short form, brief ataxia rating scale, and the Bond and Lader visual analog scale. Coadministration of mirogabalin with any of the 4 drugs did not cause any clinically relevant pharmacokinetic interactions. Peak mirogabalin concentration decreased by 28% (least squares mean ratio, 0.72; 90% confidence interval, [CI] 0.67, 0.76) following tramadol coadministration, and increased by 20% (least squares mean ratio, 1.20; 90%CI, 1.12, 1.28) following ethanol coadministration. Mirogabalin alone had little to no effect on PD parameters, but coadministration of mirogabalin with either lorazepam or ethanol increased the PD effects in body sway and digit symbol substitution test assays. Mirogabalin/lorazepam and mirogabalin/zolpidem increased occurrence of somnolence. Increased incidence of nausea and headache was noted with mirogabalin/tramadol and mirogabalin/ethanol, respectively.

Switching From Pregabalin to Mirogabalin in Patients with Peripheral Neuropathic Pain: A Multi-Center, Prospective, Single-Arm, Open-Label Study (MIROP Study)

“…Mirogabalin is predominantly renally excreted and undergoes minimal in vivo metabolism; thus, the drug-drug interaction risk is considered low. In healthy individuals, concomitant tramadol had little effect on the pharmacokinetics of mirogabalin, nor did it affect the incidences of somnolence or dizziness [17]. In clinical situations, the incidences of somnolence and dizziness have been shown to be higher when pregabalin was used in combination with opioids such as tramadol [18].…”

Clinical pharmacology of lorazepam in infants and children

“…Absorption of oral lorazepam is nearly complete, lorazepam glucuronide is the major metabolite of lorazepam, lorazepam glucuronide concentration exceeds that of lorazepam in blood and urine, and both lorazepam and lorazepam glucuronide are eliminated in the urine [11,12]. Lorazepam interacts with drugs [13][14][15][16][17][18][19][20][21]. Metoprolol causes a small increase in critical flicker fusion threshold with lorazepam [13], lorazepam combined with morphine produces sedation, relief of anxiety, lack of recall, and patient acceptance [14], and lorazepam co-administered with mirogabalin increases somnolence [15].…”

“…The effect of lorazepam in doses of 2 mg and 4 mg combined with morphine 5 mg produces sedation, relief of anxiety, lack of recall, and patient acceptance [14]. Lorazepam combined with mirogabalin increases somnolence [15]. The UGT2B7 genotype affects lorazepam-valproate pharmacodynamic interaction especially in subjects who have homovariant genotypes of UGT2B7 and UGT2B15 [16].…”

A review of a new voltage-gated Ca2+ channel α2δ ligand, mirogabalin, for the treatment of peripheral neuropathic pain

“…Concomitant tramadol administration had little effect on the pharmacokinetics of mirogabalin in healthy adult volunteers [59].…”