Pharmacokinetics, adverse effects and tolerability of a novel analogue of human pancreatic polypeptide, PP 1420

Abstract

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 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.

Figure 1

Mean plasma concentrations of PP 1420 following single, subcutaneous injections of PP 1420 at 2 mg (filled circles), 4 mg (filled squares) and 8 mg (filled triangles). Plotted on a log scale (y axis). Error bars indicate SD

Figure 2

Relationship between AUC(0,∞) values and dose of PP 1420 following single subcutaneous doses of 2, 4 and 8 mg PP 1420 to male subjects. The dotted line shows the dose-proportional relationship passing through the parameter at the 2 mg dose level. The solid line shows the power function obtained from the linear regression from the log parameter against log dose

Figure 3

Relationship between C_max values and dose of PP 1420 following single subcutaneous doses of 2, 4 and 8 mg PP 1420 to male subjects. The dotted line shows the dose-proportional relationship passing through the parameter at the 2 mg dose level. The solid line shows the power function obtained from the linear regression from the log parameter against log dose

Figure 4

Visual analogue scores (VAS) for gastrointestinal tolerability parameters. VAS depicted as placebo-corrected mean (±SEM) change from baseline after subcutaneous injection of PP1420 at 2 mg (circles), 4 mg (triangles) and 8 mg (inverted triangles)