Mirogabalin (DS-5565) is a gabapentinoid supplied as the benzenesulfonate salt (mirogabalin besylate). It is under clinical investigation for neuropathic pain indications such as diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia. Mirogabalin is pharmacologically distinct from older gabapentinoids because of its high selectivity for the α2δ-1 subunit of voltage-gated calcium channels.

Smaller sample sizes are available: Mirogabalin Besylate, 100 mg

Mirogabalin works by influencing several key systems relevant to neuronal signaling:

• Voltage-Gated Calcium Channels: Mirogabalin binds selectively to the α2δ-1 and α2δ-2 subunits of voltage-gated calcium channels. The measured dissociation half-life is ~11.1 hours at α2δ-1 and ~2.4 hours at α2δ-2, compared with ~1.4 hours at both subunits for pregabalin. These kinetics likely underlie some functional differences versus older gabapentinoids. (Domon et al., 2018)
• Indirect GABA Modulation: While not a direct GABA agonist, Mirogabalin may increase functional expression or trafficking of δ subunit-containing GABA_A receptors in the cerebellum and hippocampus (Domon et al., 2018; Kim et al., 2021).
• Neuronal Excitability: By binding to α2δ subunits, mirogabalin modulates neuronal calcium entry and reduces hyperexcitable signaling seen in preclinical neuropathic pain models (Domon et al., 2018).

Mechanism of Action

High α2δ-1 selectivity combined with slower dissociation at α2δ-1 produces prolonged engagement of that site while limiting α2δ-2 binding. This profile plausibly separates analgesic-related effects from some central adverse effects seen with older gabapentinoids. (Domon et al., 2018; Kim et al., 2021)

Observed Effects

• Relative Potency: In preclinical and clinical settings, mirogabalin demonstrates approximately 17-fold higher potency than pregabalin. Analgesic equivalence estimates: 17.7 mg ≈ 300 mg pregabalin; 30 mg ≈ 600 mg pregabalin. (Hutmacher et al., 2016; Domon et al., 2018; Kim et al., 2021)
• Tolerability: Early human studies report mainly dose-dependent, transient dizziness and somnolence. Renal clearance significantly influences exposure and tolerability. (Brown et al., 2018)
• Functional Selectivity: The differential binding kinetics and high α2δ-1 selectivity make it a useful tool in research exploring calcium channel modulation and indirect inhibitory signaling.

Pharmacokinetics

• Absorption: Rapidly absorbed, Tmax ≈ 1 hour (Brown et al., 2018).
• Clearance & Distribution: Mean clearance and volume of distribution consistent across doses (Brown et al., 2018).
• Elimination Half-life: 3.0–4.9 hours (Brown et al., 2018).
• Subunit Dissociation: α2δ-1 ≈ 11.1 h; α2δ-2 ≈ 2.4 h (Brown et al., 2018; Domon et al., 2018)
• Cytochrome: Mirogabalin did not meaningfully inhibit major CYP enzymes or P-gp/BCRP in vitro.

Approval

Mirogabalin is marketed in Japan as Tarlige and is available in 2.5, 5, 10, and 15 mg free-mirogabalin doses (TARLIGE label).

Notes: These dosage conversions are estimates based on extrapolated data. Gabapentin equivalence calculated using pregabalin:gabapentin ratio of 1:6 (Toth C, 2010). Informal anecdotal reports regarding Mirogabalin Besylate suggest that the dose equivalence between Mirogabalin Besylate and Pregabalin may be approximately 5.7 to 7.5:1. These figures are provided for reference purposes only.

Citations

1. Domon Y, Arakawa N, Inoue T, Matsuda F, Takahashi M, Yamamura N, Kai K, Kitano Y. Binding Characteristics and Analgesic Effects of Mirogabalin, a Novel Ligand for the α2δ Subunit of Voltage-Gated Calcium Channels. J Pharmacol Exp Ther. 2018;365(3):573–582. doi: 10.1124/jpet.117.247551.
2. Brown K, Mendell J, Ohwada S, Hsu C, He L, Warren V, Dishy V, Zahir H. Tolerability, pharmacokinetics, and pharmacodynamics of mirogabalin in healthy subjects: Results from phase 1 studies. Pharmacol Res Perspect. 2018;6(5):e00418. doi: 10.1002/prp2.418.
3. Hutmacher MM, Frame B, Miller R, Truitt K, Merante D. Exposure-response modeling of average daily pain score, and dizziness and somnolence, for mirogabalin (DS-5565) in patients with diabetic peripheral neuropathic pain. J Clin Pharmacol. 2016;56(1):67–77. doi: 10.1002/jcph.567.
4. Kim JY, Abdi S, Huh B, Kim KH. Mirogabalin: Could it be the next generation gabapentin or pregabalin? Korean J Pain. 2021;34(1):4–18. doi: 10.3344/kjp.2021.34.1.4.
5. Toth C. Substitution of gabapentin therapy with pregabalin therapy in neuropathic pain due to peripheral neuropathy. Pain Med. 2010;11(3):456–465. doi: 10.1111/j.1526-4637.2009.00796.x.

* TARLIGE product document