title: Pharmacokinetics and pharmacodynamics of multiple doses of BG00010, a neurotrophic factor with anti-hyperalgesic effects, in patients with sciatica.
abstract: BG00010 is a protein in the glial cell line-derived neurotrophic factor (GDNF) family. It is a selective ligand for the GDNF family receptor alpha-3 (GFRα3) co-receptor that normalizes cellular changes resulting from damage or disease, and potentially alleviates neuropathic pain. The main objectives of this study were to evaluate the pharmacokinetic and safety profiles and to determine the effects on pain of ascending doses of intravenous injections of BG00010 in patients with sciatica.
  
  
  
  This was a randomized, blinded, placebo-controlled multiple-dose study in subjects with sciatica. In Part I (16 patients), four IV dose levels were examined (50, 150, 400, 800 μg kg(-1) ) and in Part II (12 patients), three dose levels were examined (400, 600 and 1200 μg kg(-1) ). Safety and efficacy assessments were used as endpoints.
  
  
  
  The BG00010 concentration-time data indicated relatively low inter-patient variability and there was a dose-dependent (not dose-proportional) increase in serum exposure from 150 to 1200 μg kg(-1) . The effective half-life was between 40 and 60 h. The most frequently occurring adverse events (AEs) reported by patients receiving BG00010 were headache (67-83%), feeling hot (50-100%), and pruritus (42-67%). Most AEs were mild; no serious AEs or AEs leading to discontinuation occurred. Higher dose regimens of BG00010 resulted in greater pain reduction than placebo or lower dose regimens, although a clear dose-response relationship was not seen.
  
  
  
  The pharmacokinetic profile of BG00010 was characterized by low intra-patient variability. These data from a small sample suggest that BG00010 may have a benefit for patients with sciatica.
authors.affiliation: Centre for Human Drug Research (CHDR), Leiden, The Netherlands.
authors.forename: Pieter
authors.identifier: 0000-0002-0193-4732
authors.initials: P
authors.lastname: Okkerse
authors.affiliation: Centre for Human Drug Research (CHDR), Leiden, The Netherlands.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Hay
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Eve
authors.initials: E
authors.lastname: Versage
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Galluppi
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Bernard
authors.initials: B
authors.lastname: Ravina
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Verma
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Williams
authors.affiliation: Biogen, Cambridge, MA, USA.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Aycardi
authors.affiliation: Centre for Human Drug Research (CHDR), Leiden, The Netherlands.
authors.forename: Geert Jan
authors.initials: GJ
authors.lastname: Groeneveld
mesh_terms: D000328:Adult; D000368:Aged; D000700:Analgesics / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy*; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D012585:Sciatica / Q000188:drug therapy*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C490886:ARTN protein, human; D000700:Analgesics; D009419:Nerve Tissue Proteins
keywords: BG00010; neublastin; pharmacodynamics; pharmacokinetics; sciatica