title: Pharmacokinetics, adverse effects and tolerability of a novel analogue of human pancreatic polypeptide, PP 1420.
abstract: OBJECTIVE
  The objectives of this phase 1 study were to confirm the tolerability of single ascending subcutaneous doses of PP 1420 in healthy subjects, to assess its adverse effects and to investigate the drug's pharmacokinetics and dose proportionality.
  
  
  METHODS
  This was a double-blind, placebo-controlled, randomized study. There were three dosing periods. Each subject (n= 12) was randomized to receive one dose of placebo and two ascending doses of PP 1420, given as a subcutaneous injection. Blood samples were taken over 24 h to assess pharmacokinetics. Standard safety and laboratory data were collected. The primary endpoint was the tolerability of PP 1420. The secondary endpoint was exposure to PP 1420 as assessed by C(max) and AUC(0,∞).
  
  
  RESULTS
  PP 1420 was well tolerated by all subjects with no serious adverse effects. Following single subcutaneous doses of PP 1420 at 2, 4 and 8 mg to male subjects, C(max) was reached at a median t(max) of approximately 1 h post dose (range 0.32-2.00 h). Thereafter, plasma concentrations of PP 1420 declined with geometric mean apparent terminal elimination t(1/2) ranging from 2.42-2.61 h (range 1.64-3.95 h) across all dose levels.
  
  
  CONCLUSIONS
  Subcutaneous PP 1420 was well tolerated in healthy human subjects at single doses between 2-8 mg, with no tolerability issues arising. Where observed, adverse events were not serious, and there was no evidence of a dose-relationship to frequency of adverse events. The results therefore support the conduct of clinical trials to investigate efficacy, tolerability and pharmacokinetics during repeated dosing.
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London W12 0HS, UK.
authors.forename: Tricia M
authors.initials: TM
authors.lastname: Tan
authors.forename: Benjamin C T
authors.initials: BC
authors.lastname: Field
authors.forename: James S
authors.initials: JS
authors.lastname: Minnion
authors.forename: Joyceline
authors.initials: J
authors.lastname: Cuenco-Shillito
authors.forename: Edward S
authors.initials: ES
authors.lastname: Chambers
authors.forename: Sagen
authors.initials: S
authors.lastname: Zac-Varghese
authors.forename: Charlie J
authors.initials: CJ
authors.lastname: Brindley
authors.forename: Shahrul
authors.initials: S
authors.lastname: Mt-Isa
authors.forename: Francesca
authors.initials: F
authors.lastname: Fiorentino
authors.forename: Deborah
authors.initials: D
authors.lastname: Ashby
authors.forename: Ian
authors.initials: I
authors.lastname: Ward
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Ghatei
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Bloom
mesh_terms: D000293:Adolescent; D000328:Adult; D001066:Appetite / Q000187:drug effects*; D001067:Appetite Depressants / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000517:prevention & control*; D010191:Pancreatic Polypeptide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D017476:Receptors, Neuropeptide Y / Q000819:agonists*; D006113:United Kingdom; D055815:Young Adult
chemical_list: D001067:Appetite Depressants; C571723:PP 1420; D017476:Receptors, Neuropeptide Y; C109491:neuropeptide Y4 receptor; D010191:Pancreatic Polypeptide