title: Bioequivalence and x-ray visibility of a radiopaque etonogestrel implant versus a non-radiopaque implant: a 3-year, randomized, double-blind study.
abstract: BACKGROUND
  The etonogestrel (ENG)-releasing implant is a subdermal progestogen-only contraceptive that provides coverage for up to 3 years. This long-acting hormonal contraceptive has been available in Europe since 1998 and in the US since 2006. To date, localization of non-palpable implants at insertion and before removal has been dependent on ultrasound or magnetic resonance imaging by an experienced clinician. To facilitate localization in rare cases of non-palpable implants using widely available equipment without the need for a specialist, a radiopaque ENG implant has been developed that is detectable by two-dimensional x-ray imaging.
  
  
  OBJECTIVE
  This study aimed to establish whether the radiopaque ENG implant is bioequivalent in situ compared with the original non-radiopaque ENG implant, and to assess x-ray visibility of the radiopaque ENG implant.
  
  
  METHODS
  This was a 3-year, randomized, double-blind, parallel-group study carried out in nine international clinical trial centres. Women aged 18-40 years at the time of screening, with menstrual cycles of a usual length of 24-35 days and a body mass index of between ≥18 and ≤29 kg/m(2) were included. Women were assigned to either the radiopaque or non-radiopaque ENG implant in a 1 : 1 ratio via a block randomization by centre. Bioequivalence testing was performed based on the peak ENG concentration (C(max)), and the area under the curve (AUC) for ENG at 6, 24 and 36 months (AUC(6 mo), AUC(24 mo) and AUC(36 mo)) after insertion. For this purpose, blood sampling for pharmacokinetic determination was performed prior to insertion and for up to 3 years afterwards. Bioequivalence was defined as the 90% confidence interval (CI) of the ratio radiopaque implant/non-radiopaque implant of the geometric means (GMR) within the acceptance range of 0.80-1.25. x-Ray visibility was assessed by two-dimensional x-ray imaging after insertion and before removal of the implant.
  
  
  RESULTS
  The pharmacokinetic profiles of ENG indicated that the radiopaque and non-radiopaque implants were bioequivalent with respect to the geometric mean of C(max) (GMR 1.06; 90% CI 0.91, 1.23), AUC(6 mo) (GMR 1.00; 90% CI 0.91, 1.10), AUC(24 mo) (GMR 0.98; 90% CI 0.88, 1.10) and AUC(36 mo) (GMR 1.00; 90% CI 0.89, 1.11). The radiopaque ENG implant was clearly visible in 50 out of 52 women after insertion and in all 52 women before removal, whereas none of the non-radiopaque implants were visible.
  
  
  CONCLUSIONS
  The radiopaque ENG implant is bioequivalent in situ compared with the original non-radiopaque ENG implant and is clearly visible using x-ray imaging.
  
  
  BACKGROUND
  Registered as ClinicalTrials.gov identifier NCT00620464.
authors.affiliation: Merck Sharpe Dohme Corp. (MSD), Oss, the Netherlands. peter.schnabel@merck.com
authors.forename: Peter
authors.initials: P
authors.lastname: Schnabel
authors.forename: Gabriele S
authors.initials: GS
authors.lastname: Merki-Feld
authors.forename: Alice
authors.initials: A
authors.lastname: Malvy
authors.forename: Ingrid
authors.initials: I
authors.lastname: Duijkers
authors.forename: Ellen
authors.initials: E
authors.lastname: Mommers
authors.forename: Michiel W
authors.initials: MW
authors.lastname: van den Heuvel
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D003271:Contraceptive Agents, Female / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017135:Desogestrel / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004311:Double-Blind Method; D004343:Drug Implants; D006801:Humans; D045167:Progesterone Congeners / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D003271:Contraceptive Agents, Female; D004343:Drug Implants; D045167:Progesterone Congeners; C044815:etonogestrel; D017135:Desogestrel