Safety, tolerability and pharmacokinetics of single and multiple doses of a novel sigma-1 receptor antagonist in three randomized phase I studies


Dr Mariano Sust MD, Department of Clinical Investigation, ESTEVE Research & Development, Av. Mare de Déu de Montserrat 221, 08041 Barcelona, Spain. Tel: +34 93 446 6000, Fax: +34 93 446 6110, E-mail:



• A novel and highly selective sigma-1 receptor antagonist (S1RA) provides a new approach for pain management. S1RA has shown activity in animal models of neuropathic pain and potentiation of opioid analgesia.


• Phase I studies of single and multiple oral dose administration show that S1RA is safe and well tolerated by healthy subjects. S1RA is rapidly absorbed and its rate and extent of exposure increases with dose.

• The safety, tolerability, pharmacokinetic and pharmacodynamic profiles of S1RA support its further phase II development in different pain indications.

AIM To assess the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy subjects of a novel, highly selective, sigma-1 receptor antagonist (S1RA).

METHODS Three randomized, double-blind, placebo-controlled trials evaluated single oral doses (5–500 mg, study 101; 500–800 mg, study 106) and multiple doses (50–400 mg once daily for 8 days, study 102) of S1RA. Safety and tolerability were assessed by adverse event reporting, clinical laboratory, physical examinations, vital signs and electrocardiography, including Holter monitoring. Pharmacodynamic assessments included computerized cognitive testing. Plasma samples were analyzed using validated HPLC-MS/MS methods.

RESULTS One hundred and seventy-five subjects were enrolled. Single and multiple doses were safe and well tolerated, with no serious adverse events. The most common side effects were headache and dizziness. The highest single doses were associated with some mild to moderate transient CNS effects. The maximum tolerated dose was not reached. There were no clinically significant changes in the electrocardiogram (ECG), 24 h Holter monitoring, or in vital signs and laboratory assessments. Subjective CNS pharmacodynamics evaluations showed no relevant differences vs. placebo. Cognitive testing showed no effects on visual memory, executive function, attention or somnolence, while revealing some transient slowing of response for simple reaction time and choice reaction time at 2 h following the administration of higher doses. A fast absorption, rapid distribution and slow elimination were observed (tmax 0.75–2.0 h, t1/2 compatible with once a day administration) and steady-state was reached. No gender differences were observed.

CONCLUSIONS S1RA exhibited an acceptable safety, tolerability, pharmacodynamic and pharmacokinetic profile in healthy subjects over the dose range studied.