Pharmacokinetics and brain sigma 1 (σ1) receptor occupancy of MR309, a
selective σ1 receptor antagonist
Abstract
Background and purpose: Preclinical studies of MR309, a selective sigma1
receptor (σ1R) antagonist, support a potential role in treating
neuropathic pain. We report two studies that provide insight into the
pharmacokinetics (PK) and brain σ1R binding of MR309. Experimental
approach: Steady-state PK of MR309 (400 mg QD and 200 mg BID for 10
days; EudraCT 2015-001818-99 [PK study]) and the relationship
between MR309 plasma exposure and brain σ1R occupancy (EudraCT
2017-000670-11 [PET study]) were investigated in healthy volunteers.
Positron emission tomography (PET) using the σ1R ligand [11C]SA4503
was conducted at baseline, 2h and 8h after a single dose of MR309
(200–800 mg). The relationship between brain σ1R occupancy and MR309
exposure was explored using data-driven model fitting. Key results:
MR309 was well tolerated, brain σ1R occupancy ranged between 30.5% and
74.9% following single-dose MR309 (n=7). MR309 BID provided a plasma PK
profile with less fluctuation than QD dosing (n=16). MR309 200 mg BID
yielded average steady state plasma concentrations between 2000 and 4000
ng/mL in the PK study, which corresponded to an estimated brain σ1R
occupancy of 59–74%. Conclusions and implications: MR309 200 mg BID
dose was below the 75% σ1R occupancy threshold expected to elicit
maximal antinociceptive effect as observed in neuropathic pain models.
Further investigations of MR309 for neuropathic pain will require higher
brain σ1R occupancy, and establish the optimal dose by elucidating the
clinical impact of a broad range of brain σ1R occupancy across different
neuropathic pain indications.