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

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.