title: Safety, pharmacokinetics, pharmacogenomics and QT concentration-effect modelling of the SirT1 inhibitor selisistat in healthy volunteers.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 No serious adverse events were reported and no subjects were withdrawn due to adverse events.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.
  
  
  CONCLUSIONS
  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).
authors.affiliation: Siena Biotech SpA, 35, Strada del Petriccio e Belriguardo, 53100, Siena, Italy; La Crocina Pharmaceutical Consultants D.I., Podere La Crocina, 53020, San Giovanni d'Asso, Italy.
authors.forename: Goran
authors.initials: G
authors.lastname: Westerberg
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Chiesa
authors.forename: Claus A
authors.initials: CA
authors.lastname: Andersen
authors.forename: Daniela
authors.initials: D
authors.lastname: Diamanti
authors.forename: Letizia
authors.initials: L
authors.lastname: Magnoni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pollio
authors.forename: Borje
authors.initials: B
authors.lastname: Darpo
authors.forename: Meijian
authors.initials: M
authors.lastname: Zhou
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D002227:Carbazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors*; D059467:Transcriptome / Q000187:drug effects*; D055815:Young Adult
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D002227:Carbazoles; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Huntington's disease; SirT1; concentration−effect modelling; first-in-human; transcriptional profile