Introduction
Neuropathic pain is caused by a lesion or disease of the somatosensory
system that results in altered and disordered transmission of sensory
signals into the spinal cord and brain. There are numerous causes of
neuropathic pain including spinal cord injury or other trauma to the
nervous system, peripheral diabetic neuropathy, HIV and herpes virus
infections, autoimmune disorders and
chemotherapy-induced peripheral
neuropathy (CIPN). (Colloca et al., 2017) CIPN has a complex and
multifactorial aetiology and can present as either acute or chronic
neuropathy. For example, acute neuropathy associated with oxaliplatin is
characterised by painful cold hyperalgesia or laryngeal dysaesthesia and
cramps, while chronic oxaliplatin-induced neuropathy is characterised by
numbness in hands and feet which can be functionally disabling. (Saif &
Reardon, 2005; Zajaczkowska, Kocot-Kepska, Leppert, Wrzosek, Mika &
Wordliczek, 2019) The prevalence of chronic oxaliplatin-induced
polyneuropathy is approximately 26–46% at 12 month follow-up.
(Zajaczkowska, Kocot-Kepska, Leppert, Wrzosek, Mika & Wordliczek, 2019)
Depending on the duration and severity of neurosensory toxicity, the
chemotherapy dose may need to be reduced, delayed or the treatment
terminated. (Accord Healthcare Limited, October 2019) Current treatments
for acute, painful neuropathy provide modest benefit at best and
treatment of established chronic neuropathy is largely ineffective.
Thus, effective new treatment approaches for CIPN are needed. (Hou, Huh,
Kim, Kim & Abdi, 2018)
The
sigma1 receptor (σ1R) is a
ligand-operated chaperone at the endoplasmic reticulum which regulates
multiple processes, including modulation of intracellular signalling
cascades related to noxious stimuli, and sensitization and trafficking
of proteins involved in nociception. (Ortiz-Renteria et al., 2018; Pabba
et al., 2014; Vela, Merlos & Almansa, 2015) The σ1R is expressed at
high levels in areas of the central and peripheral nervous system
involved in pain transmission and transduction and neuropathic pain-like
behaviours are attenuated in σ1R -knockout mice. (Bravo-Caparros et al.,
2019; Davis, 2015; Sanchez-Fernandez, Entrena, Baeyens & Cobos, 2017)
MR309 (previously E-52862) is a selective σ1R
antagonist with a high affinity
for human σ1R (Ki=17 nM). (Romero et al., 2012) Data from animal studies
indicate MR309 crosses the blood–brain barrier and binds to σ1R in the
central nervous system (CNS) and support a potential role in the
treatment of neuropathic pain. (Romero et al., 2012) For example, MR309
inhibited formalin-induced nociception, capsaicin-induced mechanical
hypersensitivity and sciatic nerve injury-induced mechanical and thermal
hypersensitivity in a dose-dependent manner. (Bravo-Caparros et al.,
2019; Romero et al., 2012) Knockout animal studies have also implicated
σ1R activation in sensory nerve mitochondrial damage and the development
of neuropathic pain induced by paclitaxel treatment, indicating a
potential role for σ1R antagonists for preventing CIPN. (Nieto et al.,
2014) Indeed, in a model of oxaliplatin-induced neuropathy, MR309
prevented hypersensitivity to cold stimuli, and twice daily (BID)
administration for 1 week increased the antinociceptive effect. (Gris et
al., 2016) Based on preclinical pharmacological studies and animal
neuropathic pain models, σ1R occupancy >75% is needed to
obtain maximal antinociceptive effect. (Romero et al., 2012)
In early clinical trials MR309 was well tolerated by healthy volunteers,
with no serious adverse events (AEs) reported with single doses up to
800 mg, or 400 mg once daily (QD) for 8 days, and some mild-to-moderate
transient CNS effects observed with the highest dose. (Abadias,
Escriche, Vaque, Sust & Encina, 2013) MR309 400 mg QD was also well
tolerated by patients with colorectal cancer receiving oxaliplatin
within a FOLFOX regimen, with preliminary signs of efficacy for
oxaliplatin-induced peripheral neuropathy and hyperexcitability motor
symptoms. (Bruna et al., 2018) A four-week study with MR309 400 mg QD in
patients with chronic post-surgical neuropathic pain (PSNP) for
> 6 months reduced the primary end point (average pain
intensity between baseline and last week of dosing) significantly better
than placebo (EU Clinical Trials Register (EudraCT 2012-000402-30)).
Pharmacokinetic (PK) data in healthy volunteers indicate that MR309 is
absorbed rapidly, and systemic exposure (AUC\(\tau\)) increased
proportionally with ascending dose up to 100 mg QD. At higher doses
extent of exposure increased in a greater than dose proportional manner.
(Abadias, Escriche, Vaque, Sust & Encina, 2013) Based on Cmax, the
estimated therapeutic dose range of MR309 was 100–400 mg. (Abadias,
Escriche, Vaque, Sust & Encina, 2013) Although not investigated to
date, BID dosing might be expected
to result in less fluctuation of MR309 plasma concentrations compared
with QD administration, thereby potentially improving tolerability and
efficacy.
While clinical data are needed to
provide insight into the efficacy of MR309, (Bruna et al., 2018)
pharmacodynamic (PD) markers to guide dose selection for agents
targeting the σ1R pathway are currently
lacking.
[11C]SA-4503
is a selective σ1R positron emission tomography (PET) radioligand
suitable for quantifying σ1R density in the human brain, and has been
used to estimate brain σ1R occupancy in healthy volunteers administered
haloperidol and fluvoxamine. (Ishikawa et al., 2007; Ishiwata et al.,
2006; Mansur et al., 2019) Assessment of the relationship between σ1R
occupancy and the plasma concentration of MR309 will confirm the drug
target interaction in the human brain, and help establish a suitable
dose range for future clinical studies.
Here, we report two exploratory
studies which assessed the
relationship between MR309 given BID and QD and plasma concentration at
steady-state (PK study), and the relationship between plasma exposure of
MR309 and occupancy of σ1R in the brain, using PET with the selective
σ1R radioligand, [11C]SA-4503 (PET study).