title: Can an early phase clinical pharmacology study replace a thorough QT study? Experience with a novel H3-receptor antagonist/inverse agonist.
abstract: OBJECTIVE
  The objective of the present study was to compare the effects of pitolisant on QTcF interval in a single ascending dose (SAD) study and a thorough QT (TQT) study.
  
  
  METHODS
  The SAD study at three dose levels of pitolisant enrolled 24 males and the TQT study at two dose levels 25 males. Both studies intensively monitored ECGs and pitolisant exposure. Effect on QTcF interval was analysed by Intersection Union Test (IUT) and by exposure-response (ER) analysis. Results from the two studies were compared.
  
  
  RESULTS
  In both studies, moxifloxacin effect established assay sensitivity. IUT analysis revealed comparable pitolisant-induced maximum mean (90 % confidence interval (CI)) placebo-corrected increase from baseline (ΔΔQTcF) in both the studies, being 13.3 (8.1; 18.5) ms at 200-mg and 9.9 (4.7; 15.1) ms at 240-mg doses in SAD study and 5.27 (2.35; 8.20) ms at 120-mg dose in TQT study. ER analysis revealed that ER slopes in SAD and TQT studies were comparable and significantly positive (0.031 vs 0.027 ms/ng/mL, respectively). At geometric mean concentrations, bootstrap predicted ΔΔQTcF (90 % CI) were 9.23 (4.68; 14.4) ms at 279 ng/mL (240-mg dose) in the SAD study and 4.97 (3.42; 8.19) ms at 156 ng/mL (120-mg dose) in the TQT study.
  
  
  CONCLUSIONS
  Pitolisant lacked an effect of regulatory concern on QTc interval in both the studies, however analysed, suggesting that the results from the SAD study could have mitigated the need for a TQT study. Our findings add to the growing evidence that intensive ECG monitoring in early phase clinical studies can replace a TQT study.
authors.affiliation: , 8 Birchdale, Gerrards Cross, SL9 7JA, UK. clinical.safety@hotmail.co.uk.
authors.forename: Rashmi R
authors.initials: RR
authors.lastname: Shah
authors.affiliation: Hôpital Bichat, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Maison-Blanche
authors.affiliation: Bioprojet Biotech, Saint Gregoire, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Robert
authors.affiliation: Bioprojet Biotech, Saint Gregoire, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Denis
authors.affiliation: Bioprojet Pharma, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Duvauchelle
mesh_terms: D000328:Adult; D000068456:Clinical Studies as Topic / Q000379:methods; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D017442:Histamine Agonists / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D054828:Histamine H3 Antagonists / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008133:Long QT Syndrome; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D017442:Histamine Agonists; D054828:Histamine H3 Antagonists; D010880:Piperidines; C516975:pitolisant
keywords: Exposure–response analysis; ICH E14; Intersection Union Test; Pitolisant; Single ascending dose study; Thorough QT study