title: Joint population pharmacokinetic/pharmacodynamic model for the heart rate effects at rest and at the end of exercise for cilobradine.
abstract: OBJECTIVE
  To develop a semi-mechanistic population pharmacokinetic/pharmacodynamic (PKPD) model for the selective bradycardic agent cilobradine describing simultaneously the heart rate (HR) measured at rest and just after the end of exercise sharing the same set of PKPD parameters.
  
  
  METHODS
  Healthy subjects received cilobradine orally once daily over 2 weeks at 0.25-5 mg doses or placebo. Plasma drug concentrations and HR were measured at rest and following 3 min of exercise over the entire study period. PK and HR data were analyzed using the population approach with NONMEM VII.
  
  
  RESULTS
  Plasma disposition of cilobradine was described with a three compartment model. Cilobradine showed dose proportional and time independent pharmacokinetics. HR response was drug concentration dependent and appeared with a significant delay with respect to PK profiles, a phenomenon modeled using two transit compartments. Perturbation in HR at rest as a consequence of exercise was described assuming that physiological processes controlling cardiac frequency were constantly increased over the period of exercise only.
  
  
  CONCLUSIONS
  The selected model provides a useful modeling tool for cases where the PD response measured is the result of a temporal experimental induced perturbation.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology School of Pharmacy, University of Navarra, Pamplona, 31080, Spain.
authors.forename: Nieves
authors.initials: N
authors.lastname: Vélez de Mendizábal
authors.forename: Alexander
authors.initials: A
authors.lastname: Staab
authors.forename: Hans Günter
authors.initials: HG
authors.lastname: Schäfer
authors.forename: Dirk
authors.initials: D
authors.lastname: Trommeshauser
authors.forename: Christiane
authors.initials: C
authors.lastname: Döge
authors.forename: Matthias
authors.initials: M
authors.lastname: Klüglich
authors.forename: Juliet
authors.initials: J
authors.lastname: Roberts
authors.forename: Iñaki F
authors.initials: IF
authors.lastname: Trocóniz
mesh_terms: D000328:Adult; D001552:Benzazepines / Q000097:blood* / Q000494:pharmacology*; D015444:Exercise; D005260:Female; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010880:Piperidines / Q000097:blood* / Q000494:pharmacology*; D012146:Rest; D055815:Young Adult
chemical_list: D001552:Benzazepines; D010880:Piperidines; C490484:cilobradine