SAT628 Effect Of Hepatic Impairment On The Pharmacokinetics, Safety, And Tolerability Of Oral Paltusotine, A Non-peptide, Selective Somatostatin Receptor Subtype 2 Agonist

Disclosure: R. Luo: Employee; Self; Crinetics Pharmaceuticals Inc. A. Casagrande: Employee; Self; Crinetics Pharmaceuticals Inc. S. Oun: Employee; Self; Crinetics Pharmaceuticals Inc. Y. Wang: Employee; Self; Crinetics Pharmaceuticals Inc. R. Struthers: Employee; Self; Crinetics Pharmaceuticals Inc. A. Krasner: Employee; Self; Crinetics Pharmaceuticals Inc. Paltusotine is an investigational oral, once-daily, nonpeptide, small molecule somatostatin receptor type 2 agonist in clinical development for the treatment of acromegaly and neuroendocrine tumors. This multicenter, open-label, phase 1 study assessed the influence of varying degrees of hepatic impairment on the pharmacokinetics (PK), safety, and tolerability of paltusotine. Participants with mild, moderate, and severe hepatic impairment based on Child-Pugh classification and matched healthy participants received a single 20 mg oral dose of paltusotine after an overnight fast of at least 10 hours. Analysis of paltusotine in plasma was performed using a validated liquid chromatography-tandem mass spectrometry method. Geometric mean ratios of PK parameters were calculated from an analysis of variance (primary analysis) with hepatic condition (normal, mild, moderate, severe) as a fixed effect and the log transformed PK parameter as the dependent variable. A sensitivity analysis (matched pairs mixed models for repeated measures) accounted for participant age and BMI. Overall, 36 participants were included (mild [n=8], moderate [n=8], and severe [n=6] hepatic impairment; matched healthy [n=14]). Most participants were male (72.2%); mean age was 57.3 years, and mean BMI was 30.7 kg/m(2). Following single oral administration of 20 mg paltusotine, the mean plasma concentration of paltusotine peaked rapidly, with the median time to maximum concentration ranging from 1.6 to 3.0 hours postdose across all groups. The maximum plasma concentration (C(max)) and total plasma exposure (area under the curve from time 0 extrapolated to infinity [AUC(0-inf)]) of paltusotine were similar across all hepatic impairment groups when compared with healthy participants as indicated by the geometric mean ratio (90% CI) values (participants with mild, moderate, and severe hepatic impairment: C(max): 1.35 [0.79-2.31], 0.76 [0.45-1.31], and 1.05 [0.58-1.90], respectively; AUC(0-inf): 1.00 [0.60-1.66], 0.75 [0.45-1.24], and 0.90 [0.51-1.57], respectively). Results of the sensitivity analysis were consistent with those from the primary analysis. Overall, the most common (≥5% of participants) treatment-emergent adverse events (TEAEs) were diarrhea (16.7%) and headache (5.6%). The incidence of TEAEs was similar across all 4 groups. No participant discontinued the study because of a TEAE, and no serious drug-related TEAEs were reported. In conclusion, the peak and total plasma exposures and safety and tolerability profile of paltusotine were similar across participants with varying degrees of hepatic impairment compared with participants with normal hepatic function. There were no changes in paltusotine plasma exposure that would be considered clinically meaningful or sufficient to warrant dose adjustment for mild, moderate, or severe hepatic impairment. Support: Crinetics Pharmaceuticals. Presentation: Saturday, June 17, 2023