title: A first-in-human study of PDC31 (prostaglandin F2α receptor inhibitor) in primary dysmenorrhea.
abstract: OBJECTIVE
  What is the safe and pharmacodynamically active dose range for PDC31 (prostaglandin F2α receptor inhibitor) in patients with primary dysmenorrhea (PD)?
  
  
  CONCLUSIONS
  The 1 mg/kg/h dose of PDC31 appears to be safe and potentially effective in reducing intrauterine pressure (IUP) and pain associated with excessive uterine contractility when given as a 3-h infusion in patients with PD.
  
  
  BACKGROUND
  PDC31 has previously been shown to reduce the duration and strength of PGF2α-induced contractions in human uterine myometrial strip models and to delay delivery in animal models of preterm labor.
  
  
  METHODS
  This was a prospective, multi-center, dose-escalating first-in-human Phase I study conducted from March 2011 to June 2012. A total of 24 women with PD were enrolled and treated with one of five doses (0.01, 0.05, 0.15, 0.3, 0.5 and 1 mg/kg/h) of PDC31 given as a 3-h infusion. Patients were observed for a further 24 h.
  
  
  METHODS
  This study was conducted at four hospitals in Europe in non-pregnant, menstruating women with PD. Women with PD (n = 24) received PDC31 infused over 3 h within 8-10 h of the onset of menstruation. IUP and pain monitoring through the visual analog scale (VAS) was assessed prior to, during and following the infusion. Patients were observed for dose-limiting toxicities and other adverse events. Pharmacokinetic samples were also taken to profile the drug.
  
  
  RESULTS
  A 3-h infusion of PDC31 was safe up to and including doses of 1 mg/kg/h. Most adverse events were mild (n = 15; 83.3%) and not considered associated with PDC31 (n = 14; 77.8%). PDC31 infusion decreased uterine activity based on IUP and pain (VAS) scores. IUP was decreased by 23% over all dose levels, reaching a minimum at 135-150 min. There appeared to be a dose-dependent effect on IUP, with the high dose group (1 mg/kg/h) showing the largest decrease in IUP. There was a statistically significant linear dose-effect and concentration-effect relationship for several IUP parameters over the evaluation period of 60-180 min. A dose differentiating effect on pain was seen with the two highest doses. PDC31 demonstrated uncomplicated, linear pharmacokinetics with a terminal half-life of ∼2 h.
  
  
  CONCLUSIONS
  This was a first-in-human study and exposure to PDC31 was limited for safety reasons. As such, pharmacodynamic parameters were assessed at a two-sided Type I error of 20%, an appropriate level for the exploratory nature of this study without a placebo control arm. This limited the chance of false positive findings to one in five.
  
  
  CONCLUSIONS
  Like PD, preterm labor is associated with prostaglandin-mediated uterine contractions; therefore, the findings of this study support further development of PDC31 as a treatment for both PD and preterm labor.
  
  
  BACKGROUND
  This work was funded by PDC Biotech GmbH, Vienna, Austria. B.B., R.M.L., L.W., R.J.S., K.J.B. and C.F.S. received reimbursement for the conduct of this study from PDC Biotech GmbH. W.H., M.S. and R.P.S. are paid consultants for PDC Biotech GmbH. P.G. is a paid consultant and shareholder of PDC Biotech GmbH.
  
  
  BACKGROUND
  NCT01250587 at www.clinicaltrials.gov.
authors.affiliation: Department of Gynecological Endocrinology and Reproductive Medicine, Innsbruck Medical University, Innsbruck 6020, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Böttcher
authors.affiliation: Department of Obstetrics and Gynecology, University of Mainz, Mainz 55131, Germany.
authors.forename: R M
authors.initials: RM
authors.lastname: Laterza
authors.affiliation: Department of Gynecological Endocrinology and Reproductive Medicine, Innsbruck Medical University, Innsbruck 6020, Austria.
authors.forename: L
authors.initials: L
authors.lastname: Wildt
authors.affiliation: Department of Obstetrics and Gynecology, University of Mainz, Mainz 55131, Germany.
authors.forename: R J
authors.initials: RJ
authors.lastname: Seufert
authors.affiliation: Department of Gynecological Endocrinology, Clinic of Gynecology, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany.
authors.forename: K J
authors.initials: KJ
authors.lastname: Buhling
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna 1090, Austria.
authors.forename: C F
authors.initials: CF
authors.lastname: Singer
authors.affiliation: PDC Biotech GmbH, Vienna 1010, Austria.
authors.forename: W
authors.initials: W
authors.lastname: Hill
authors.affiliation: PDC Biotech GmbH, Vienna 1010, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Griffin
authors.affiliation: Department of Clinical Pharmacology, Medical University Vienna, Vienna 1090, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Jilma
authors.affiliation: SciAn Services Limited, Toronto, Canada M8X 1X3.
authors.forename: M
authors.initials: M
authors.lastname: Schulz
authors.affiliation: Division of General Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN 46202, USA rogpsmit@iupui.edu.
authors.forename: R P
authors.initials: RP
authors.lastname: Smith
mesh_terms: D000328:Adult; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004412:Dysmenorrhea / Q000188:drug therapy*; D005260:Female; D006801:Humans; D010455:Peptides / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D011446:Prospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D010455:Peptides; C519378:THG113.31 peptide
keywords: intrauterine pressure monitoring; menstrual pain; primary dysmenorrhea; prostaglandin F2α receptor inhibitor