INTRODUCTION
Parkinson’s disease is a relatively common neurodegenerative disorder
characterized by motor symptoms such as poorness and slowness of
movement, tremors and loss of balance. Psychiatric symptoms such as
anxiety and depression as well as other non-motor symptoms are also
common (1 ). Treatments that restore
dopamine deficits in the brain such as levodopa and dopamine agonists
have been used since the 1970s to treat the motor symptoms in
Parkinson’s disease (PD), but are known to after a few years cause
adverse effects such as wearing-off, on-off and dyskinesias
(2 ). It is estimated that within five
years of initiation of standard dopamine replacement therapy in PD,
about 50% of patients (and after 10 years almost all patients) develop
involuntary movements, so called Levodopa (L-dopa) Induced Dyskinesias
(LIDs), in response to their medical treatment
(3 ). LIDs are often the key
complication limiting further dose increases in dopaminergic therapy.
Psychotic symptoms such as hallucinations and delusions are relatively
common in patients with PD, where use of dopaminergic medication and
cognitive impairment are the most important underlying factors
(4) . In a systematic review, the
prevalence of hallucinations alone in patients with PD was between 21%
and 46% (5).
Mesdopetam (formerly IRL790, Mesdopetam x ½ L-Tartrate
(N-[2-(3-Fluoro-5-methylsulfonyl-phenoxy)ethyl]propan-1-amine) is a
novel dopamine D3 receptor antagonist. In experimental animal models,
mesdopetam displays both anti-dyskinetic and antipsychotic properties,
while leaving normal behaviour largely unaffected, indicating a novel
pharmacological profile with potential to alleviate several troubling
complications of therapy commonly seen in the management of PD (6).
Mesdopetam is metabolized to two main metabolites in man; the
dealkylated M1 (IRL902) via CYP450, which is further acetylated by
N-acetyltransferase 2 (NAT2) to M2 (IRL872). Both metabolites are
present in plasma and urine.
The objectives of this first-in-human study were to assess the safety,
tolerability and pharmacokinetics of mesdopetam in healthy male
volunteers after single and multiple oral dosing, including food effect
on the pharmacokinetics after single dosing.