Oral paltusotine, a nonpeptide selective somatostatin receptor 2 agonist: Mass balance, absolute bioavailability and metabolism in healthy participants

Abstract

Aims: Paltusotine is a novel, nonpeptide, selective somatostatin receptor 2 agonist in development for the treatment of acromegaly and carcinoid syndrome. This study investigated the mass balance, routes of excretion, absolute bioavailability and metabolite profile of orally administered paltusotine.

Methods: In Part A of the two-part, phase 1 study, a single dose (oral solution) of 20 mg paltusotine containing approximately 3.0 MBq (80 μCi) of ¹⁴C-labelled paltusotine was administered to six healthy male participants to evaluate the mass balance and metabolite profile of paltusotine. In Part B, a single dose (oral solution) of paltusotine 20 mg followed approximately 90 min later by a single microtracer intravenous bolus injection of approximately 50 μg paltusotine containing 0.0185 MBq (0.5 μCi) of ¹⁴C-labelled paltusotine was administered to five healthy male participants to assess absolute bioavailability of paltusotine.

Results: The mean absolute bioavailability of paltusotine 20 mg was 69% (90% CI 59-82%). The mean recovery of total radioactivity was 94% (90% in faeces and 3.9% in urine), with excretion primarily via the biliary route. The exposure (AUC_0-inf) ratio of unchanged paltusotine to total reactivity in plasma was 0.75, indicating that there were no abundant circulating metabolites. The geometric mean half-life (t_1/2) for paltusotine in plasma was 26-28 h. Treatment-emergent adverse events associated with paltusotine were mild and transient.

Conclusions: Oral dosing with paltusotine is associated with efficient absorption from the gastrointestinal tract. Most of the administered dose is excreted unchanged. Pharmacokinetic properties of paltusotine are supportive of once-daily dosing.

Keywords: bioavailability; drug metabolism; endocrinology; phase I.

FIGURE 1

Study design. ^aIn Part A, if participants did not meet radioactivity recovery criteria (cumulative recovery in excreta of ≥90% of administered radioactivity with ≤1% of total administered dose recovered on two consecutive days) on Day 8, participants remained at the centre for up to 13 additional days (Day 21) until criteria were met. IV, intravenous.

FIGURE 2

Mean cumulative recovery of ¹⁴C radioactivity in urine, faeces, and combined (total). Data shown are arithmetic means with SE. [Correction added on 27 March 2025, after first online publication: The Figure 2 image has been corrected in this version.]

FIGURE 3

Plasma concentration–time profiles for paltusotine and total radioactivity on linear (A) and semilogarithmic (B) scales after administration of a single oral dose of 20 mg paltusotine containing approximately 3.0 MBq (80 μCi) of ¹⁴C‐paltusotine (n = 6). Data shown are geometric means with 95% CIs. Mean value for total radioactivity was below the lower limit of quantification (3.36 ng‐eq/mL) at 168 h.

FIGURE 4

Plasma concentration–time profiles for paltusotine after oral and IV administration (n = 5; semilogarithmic scale). ^aIV concentration data were adjusted to the 20 mg oral dose. Data shown are geometric means with 95% CIs. Time 0 is the nominal time 0 relative to oral paltusotine and IV ¹⁴C‐paltusotine dosing respectively. IV, intravenous.

FIGURE 5

Proposed metabolic pathways of paltusotine in humans.