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.