Safety, pharmacokinetics, pharmacogenomics and QT concentration-effect modelling of the SirT1 inhibitor selisistat in healthy volunteers

Abstract

Aim: Selisistat (SEN0014196), a first-in-class SirT1 inhibitor, is being developed as a disease-modifying therapy for Huntington's disease. This first-in-human study investigated the safety, pharmacokinetics and pharmacogenomics of single and multiple doses of selisistat in healthy male and female subjects.

Method: In this double-blind, randomized, placebo-controlled study, seven cohorts of eight subjects received a single dose of selisistat at dose levels of 5, 25, 75, 150, 300 and 600 mg and four cohorts of eight subjects were administered 100, 200 and 300 mg once daily for 7 days. Blood sampling and safety assessments were conducted throughout the study.

Results: Selisistat was rapidly absorbed and systemic exposure increased in proportion to dose in the 5-300 mg range. Steady-state plasma concentrations were achieved within 4 days of repeated dosing. The incidence of drug related adverse events showed no correlation with dose level or number of doses received and was comparable with the placebo group. No serious adverse events were reported and no subjects were withdrawn due to adverse events. There were no trends in clinical laboratory parameters or vital signs. No trends in heart rate or ECG parameters, including the QTc interval and T-wave morphology, were observed. There were no findings in physical or neurological examinations or postural control. Transcriptional alteration was observed in peripheral blood.

Conclusion: Selisistat was safe and well tolerated by healthy male and female subjects after single doses up to 600 mg and multiple doses up to 300 mg day(-1).

Trial registration: ClinicalTrials.gov NCT01521832.

Keywords: Huntington's disease; SirT1; concentration−effect modelling; first-in-human; transcriptional profile.

© 2014 The British Pharmacological Society.

Figures

Figure 1

Mean selisistat plasma concentration vs. time following single doses between 5 and 600 mg. , 5 mg; , 25 mg; , 75 mg; , 150 mg; , 300 mg; , 600 mg; , 300 mg; female

Figure 2

(A) Mean (± SD) selisistat AUC0–24 (μm h) following single doses between 5 and 600 mg in males (•) and females (). The dashed line represents the NOAEL exposure. (B) Mean (± SD) selisistat AUC(0,24 h) (μm h) following repeated doses between 100 and 300 mg once daily in males (•) and females (). The dashed line represents the NOAEL exposure

Figure 3

(A, B) Projected and observed QTc effect after single doses of selisistat across plasma concentrations. The model based estimate (solid black line) with 90% CI (grey shaded area) is shown across the range of plasma concentrations observed in the SAD (A) and MAD (B) study. The horizontal red line shows the plasma concentration divided into deciles and the vertical, red bars show the observed ΔΔQTcF with 90% CI within each plasma concentration decile (plotted at the median concentration of each decile). As shown by the upper bound of the 90% CI, a drug-induced effect on the QTc interval exceeding 10 ms could be excluded at all observed plasma concentrations after single or multiple dose administration