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

Abstract

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 (t(max) 0.75-2.0 h, t(1/2) 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.

Figure 1

(A) Design and subject allocation scheme for study 101. (B) Design and subject allocation scheme for study 102. (C) Design and subject allocation scheme for study 106

Figure 2

VAS scores for study 106. The figure shows mean values of difference from baseline scores at 2 h post-dose for the 10 measured VAS. The VAS pairs of adjectives are shown so the first one corresponds to low scores. An asterisk indicates a significant difference vs. placebo in the linear mixed model analysis, adjusted for the baseline value. Baseline values were similar for all groups and in the range of 40 to 70 for all scales, except for ‘calm-excited’, which ranged from 25 to 35. □, Placebo; , 500 mg; , 600 mg, , 800 mg

Figure 3

(A) Mean plasma concentration of S1RA over a 24 h period after single oral doses of 5–800 mg (linear scale). (B) Mean plasma concentration of S1RA over time after single oral doses of 5–800 mg (logarithmic scale). Study 101: , 5 mg; , 10 mg; , 20 mg; , 40 mg; , 60 mg; , 100 mg; , 140 mg; , 200 mg; , 300 mg; , 400 mg; , 500 mg. Study 106: , 500 mg; , 600 mg; , 800 mg

Figure 4

(A) Individual C_max values of S1RA over the dose range following a single administration. (B) Individual AUC(0,24 h) values of S1RA over the dose range following a single administration. , Power model; , Linearity

Figure 5

Whisker box plot of t_max values of S1RA over the dose range following a single administration

Figure 6

Mean plasma concentration of S1RA over time after multiple oral doses of 50–400 mg once daily for 8 days (logarithmic scale). , 50 mg; , 100 mg; , 200 mg; , 300 mg; , 400 mg