title: Characterization of anastrozole effects, delivered by an intravaginal ring in cynomolgus monkeys.
abstract: OBJECTIVE
  Is it feasible to deliver anastrozole (ATZ), an aromatase inhibitor (AI), by a vaginal polymer-based drug delivery system in the cynomolgus monkey (Macaca fascicularis) to describe the pharmacokinetic profile?
  
  
  CONCLUSIONS
  The present study showed the effective release of ATZ into the systemic circulation from intravaginal rings in cynomolgus monkeys.
  
  
  BACKGROUND
  ATZ is a marketed drug with well documented pharmacological and safety profiles for oral administration. Aromatase is the key enzyme catalyzing estrogen biosynthesis and is overexpressed in endometriotic lesions. AIs show therapeutic efficacy in endometriosis in exploratory clinical trials.
  
  
  METHODS
  The pharmacokinetics of the in vivo release and the pharmacodynamic activity of ATZ released by intravaginal rings (IVR) were investigated in healthy cycling female cynomolgus monkeys in three different dose groups (n = 5) for one menstrual cycle.
  
  
  METHODS
  IVRs for the cynomolgus monkey, releasing three different doses of ATZ were designed and tested for in vitro/in vivo release for up to 42 days. For pharmacokinetic and pharmacodynamic evaluation, plasma samples were taken once daily from Day 1 to 3 and then every third day until menses occurred (17-42 days).
  
  
  RESULTS
  ATZ was shown to be compatible with the IVR drug delivery system. An average in vivo release of 277 µg/day/animal of ATZ for one menstrual cycle was effective in causing a decrease of systemic estradiol (E₂) levels by ∼30% without inducing counter regulation such as the elevation of FSH or the formation of ovarian cysts.
  
  
  CONCLUSIONS
  The study was limited to three dose groups in which only the highest dose decreased the E₂ level. Hence, additional research with IVRs releasing higher amounts of ATZ is required to define the threshold for an ATZ-dependent ovarian stimulation in cynomolgus monkeys.
  
  
  CONCLUSIONS
  The release rate administered from IVRs is sufficient and in a range that supports feasibility of IVR administration of ATZ as a new approach for long-term therapy of estrogen-dependent diseases such as endometriosis in human.
authors.affiliation: Bayer Healthcare Pharmaceuticals, GDD Research Pharmacokinetics, Müllerstraße 178, 13353 Berlin, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rotgeri
authors.affiliation: Bayer Healthcare Pharmaceuticals, GDD Global Chemical & Pharmac. Development, Bayer Oy, PO Box 415, FI-20101 Turku, Finland.
authors.forename: Henriikka
authors.initials: H
authors.lastname: Korolainen
authors.affiliation: Bayer Healthcare Pharmaceuticals, GDD Global Chemical & Pharmac. Development, Bayer Oy, PO Box 415, FI-20101 Turku, Finland.
authors.forename: Oskari
authors.initials: O
authors.lastname: Sundholm
authors.affiliation: Bayer Healthcare Pharmaceuticals, Global Clinical Development, Müllerstraße 178, 13353 Berlin, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Schmitz
authors.affiliation: Bayer Healthcare Pharmaceuticals, GDD FC/MM Brand Support, Müllerstraße 178, 13353 Berlin, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Fuhrmann
authors.affiliation: Bayer Healthcare Pharmaceuticals, GDD Respiratory & Supplemental Safety, Forschungszentrum Wuppertal - Elberfeld, Aprather Weg 18, 42096 Wuppertal, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Prelle
authors.affiliation: Bayer Healthcare Pharmaceuticals, GDD TRG ONC/GT-GT, Müllerstraße 178, 13353 Berlin, Germany frank.sacher@bayer.com.
authors.forename: Frank
authors.initials: F
authors.lastname: Sacher
mesh_terms: D000282:Administration, Intravaginal; D000077384:Anastrozole; D000818:Animals; D047072:Aromatase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D016503:Drug Delivery Systems / Q000009:adverse effects; D004353:Drug Evaluation, Preclinical; D004343:Drug Implants / Q000009:adverse effects; D004958:Estradiol / Q000097:blood; D005240:Feasibility Studies; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D006207:Half-Life; D007262:Infusions, Intravenous; D008252:Macaca fascicularis; D008597:Menstrual Cycle; D008657:Metabolic Clearance Rate; D009570:Nitriles / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D012995:Solubility; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D047072:Aromatase Inhibitors; D003692:Delayed-Action Preparations; D004343:Drug Implants; D009570:Nitriles; D014230:Triazoles; D000077384:Anastrozole; D004958:Estradiol; D005640:Follicle Stimulating Hormone
keywords: anastrozole; aromatase inhibitor; endometriosis; intravaginal ring