SEARCH

SEARCH BY CITATION

Keywords:

  • adverse effects;
  • obesity;
  • pancreatic polypeptide;
  • pharmacokinetics;
  • phase I trial;
  • tolerability

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Human pancreatic polypeptide (hPP) is a natural pancreatic hormone that suppresses appetite after meals.

• When exogenous hPP is given to healthy human volunteers, it causes a reduction in food intake.

• PP 1420 is a longer acting analogue of hPP that has been developed as a novel treatment for obesity.

WHAT THIS STUDY ADDS

• PP 1420 has been shown to be well tolerated in healthy human volunteers.

• PP 1420 has been shown to have an extended terminal elimination half-life compared with hPP.

AIMS 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 Cmax 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, Cmax was reached at a median tmax 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 t1/2 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.