title: Estimation of the inter- and intrasubject variability of the diurnal serum cortisol rhythm in healthy male subjects to evaluate the biomarker potential for drug target engagement.
abstract: OBJECTIVE
  Changes in the cortisol diurnal rhythm have been found in neuropsychiatric diseases, including anxiety and depression. The aim of this study was to investigate the reliability and reproducibility of cortisol diurnal rhythm in healthy males, through determination of the inter- and intrasubject variability, to facilitate evaluation of this biomarker for drug target engagement.
  
  
  METHODS
  This open-label, 2-period study design evaluated serum cortisol release over a 24-hour period in 18 healthy males. A cosinor model was used to model the cortisol diurnal rhythm, and the inter- and intrasubject coefficients of variation (CVs) were calculated across the 2 periods.
  
  
  RESULTS
  Three significant cortisol concentration peaks were observed at ~7 AM, 1 PM, and 7 PM. The intersubject CVs (%) for the amplitude, acrophase, and midline estimating statistic of rhythm (MESOR) were 18.2, 19.3, and 16.8, respectively. The intrasubject CVs (%) were 11.2, 7.6, and 6.9, respectively. The inter- and intrasubject CVs (%) for the lunch-induced 1 PM peak and the >dinner-induced 7 PM peak were 22.1, 17.3, 44.7, and 22.1 respectively.
  
  
  CONCLUSIONS
  Assessment of serum cortisol diurnal rhythm suggests that the amplitude, acrophase, and MESOR, but not the meal-induced peaks, have the potential to be a reliable biomarker in drug development targeting the hypothalamic-pituitary-adrenocortical (HPA) axis.
authors.forename: Fanni
authors.initials: F
authors.lastname: Natanegara
authors.forename: Adrienne
authors.initials: A
authors.lastname: Tran
authors.forename: Stephen
authors.initials: S
authors.lastname: Lowe
authors.forename: Lai San
authors.initials: LS
authors.lastname: Tham
authors.forename: Christopher
authors.initials: C
authors.lastname: Chen
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D002940:Circadian Rhythm; D005215:Fasting / Q000097:blood; D064368:Healthy Volunteers; D006801:Humans; D006854:Hydrocortisone / Q000097:blood* / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010913:Pituitary-Adrenal System / Q000187:drug effects* / Q000378:metabolism; D019518:Postprandial Period; D015203:Reproducibility of Results; D012737:Sex Factors; D013997:Time Factors; D055815:Young Adult
chemical_list: D015415:Biomarkers; D006854:Hydrocortisone