title: Phase I, two-way, crossover study to demonstrate bioequivalence and to compare safety and tolerability of single-dose XM17 vs Gonal-f® in healthy women after follicle-stimulating hormone downregulation.
abstract: BACKGROUND
  XM17 is a recombinant human follicle-stimulating hormone (rhFSH) intended mainly for use in controlled ovarian hyperstimulation and the treatment of anovulation. The purpose of the current study was to establish bioequivalence, safety and tolerability of single 300-IU subcutaneous (sc) doses of XM17 to that of the reference follitropin alfa (Gonal-f(®)) in healthy young women.
  
  
  METHODS
  This open-label, Phase I, single-dose, single-center, two-way crossover study was conducted from February to May 2009. Thirty-six women aged 18-39 years were included, with a study duration of ~27 days per participant. After endogenous FSH downregulation with goserelin (3.6 mg) on study Day 0, XM17 and Gonal-f(®) were administered on Days 11 and 19 in random sequence. Frequent serum samples were drawn for standard pharmacokinetics until 168 h postdosing. Laboratory values, adverse events (AEs) and local tolerability were assessed throughout the study period. Primary endpoints included Cmax and AUC0-t. Secondary endpoints included additional pharmacokinetic (PK) parameters, safety and tolerability.
  
  
  RESULTS
  Ratios of XM17 to Gonal-f(®) for Cmax and AUC0-t equaled 1.017 (90 % confidence interval [CI]: 0.958, 1.080) and 1.028 (90 % CI: 0.931, 1.134), respectively, with the CIs contained within the predefined interval (0.8, 1.25). Ratios for AUC0-168h, AUC0-∞ and t1/2 were also ~1, and no difference in tmax was detected. Both XM17 and Gonal-f(®) were well tolerated, with no detectable anti-FSH antibodies, serious AEs or AEs leading to discontinuation or dose reduction.
  
  
  CONCLUSIONS
  PK bioequivalence of single 300-IU sc doses of XM17 to the reference product Gonal-f® was statistically demonstrated. XM17 was well tolerated both systemically and locally.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT02592031 ; date of registration: 28 October, 2015.
authors.affiliation: Merckle GmbH, Member of the Teva Group, Graf-Arco-Str. 3, 89079, Ulm, Germany. andreas.lammerich@ratiopharm.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lammerich
authors.affiliation: Merckle GmbH, Member of the Teva Group, Graf-Arco-Str. 3, 89079, Ulm, Germany. Arnd.Mueller@ratiopharm.de.
authors.forename: Arnd
authors.initials: A
authors.lastname: Mueller
authors.affiliation: Merckle GmbH, Member of the Teva Group, Graf-Arco-Str. 3, 89079, Ulm, Germany. Peter.Bias@ratiopharm.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Bias
mesh_terms: D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D005260:Female; D043373:Follicle Stimulating Hormone, Human / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists; D017273:Goserelin / Q000494:pharmacology; D006801:Humans; D011994:Recombinant Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D013810:Therapeutic Equivalency; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D043373:Follicle Stimulating Hormone, Human; D011994:Recombinant Proteins; C571801:follitropin alfa; D017273:Goserelin; D007987:Gonadotropin-Releasing Hormone