title: Clinical safety and hypothalamic-pituitary-adrenal axis effects of the arginine vasopressin type 1B receptor antagonist ABT-436.
abstract: BACKGROUND
  Arginine vasopressin type 1B receptor (V1B) receptor antagonism is considered a potential therapeutic for diseases with hypothalamic-pituitary-adrenal (HPA) axis dysregulation.
  
  
  OBJECTIVE
  The aim of the present study was to evaluate the safety and pharmacodynamics of ABT-436, a selective V1B antagonist, in healthy adults.
  
  
  METHODS
  Healthy adults received daily oral doses of ABT-436 in two clinical trials. In a dose escalation trial, nine subjects received each of 100, 500, or 800 mg ABT-436, or placebo, in the morning for 7-14 days. In a crossover trial on two 7-day regimens, 20 subjects received 200 mg ABT-436 each morning or each evening. Pharmacokinetics, measures of basal HPA axis activity, and safety were assessed in both trials.
  
  
  RESULTS
  Mild gastrointestinal intolerance was more common with ABT-436 treatment, compared to placebo, and showed dose dependence. Mean increases and decreases of systolic blood pressure (at different times), and mean pulse increases, were observed in subjects who received 800 mg ABT-436. Mean decreases of plasma adrenocorticotrophic hormone (ACTH), serum cortisol, urine total glucocorticoids, and urine cortisol, compared to placebo, were observed following 7 daily doses of 500 and 800 mg ABT-436. Statistically significant mean differences of plasma ACTH, serum cortisol, and urine total glucocorticoids were observed between morning and evening regimens of 200 mg ABT-436. The largest observed differences were near the times of maximum post-dose ABT-436 plasma concentrations.
  
  
  CONCLUSIONS
  ABT-436 regimens of 200-800 mg once daily (QD) for 7 days attenuated basal HPA axis activity. The results support further evaluation of ABT-436 for treatment of disorders in which HPA axis dysregulation may have an etiologic role.
authors.affiliation: AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA. david.a.katz@me.com.|, 222 West Merchandise Mart Plaza, Suite 1230, Chicago, IL, 60654, USA. david.a.katz@me.com.
authors.forename: David A
authors.initials: DA
authors.lastname: Katz
authors.affiliation: AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Locke
authors.affiliation: AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dutta
authors.affiliation: AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Tracy
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D065092:Antidiuretic Hormone Receptor Antagonists / Q000378:metabolism* / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism*; D017483:Receptors, Vasopressin / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: C000588833:AVPR1b protein, human; D065092:Antidiuretic Hormone Receptor Antagonists; D017483:Receptors, Vasopressin; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone
keywords: ACTH; Antagonist; Cortisol; Glucocorticoid; HPA axis; Receptor; Vasopressin