Pharmacokinetic and pharmacodynamic results from a randomized controlled study with the growth hormone secretagogue receptor blocker PF-5190457 in recently abstinent patients with alcohol use disorder

Objective Ghrelin and liver-expressed antimicrobial peptide 2 (LEAP2) act via the growth hormone secretagogue receptor (GHSR), which modulates feeding, alcohol use, and endocrine and immune system function. The GHSR blocker PF-5190457 has potential as a novel pharmacotherapy for alcohol use disorder (AUD). This study aimed to characterize the effects of PF-5190457 on endocrine and immune markers in individuals with AUD. Methods Pre-planned analyses used data from a randomized, double-blind, placebo-controlled, crossover human laboratory study in recently abstinent inpatients with AUD (N=29; 8 females). Participants received PF-5190457 (100 mg twice daily) or matched placebo for 5+ days, separated by 2+ washout days. Blood was collected daily prior to dosing (T1). On days 4+, behavioral testing occurred post-dosing, followed by an additional blood collection ~2 hours post dosing (T2). Pharmacokinetic (PK: PF-5190457 and its active metabolite PF-6870961) and pharmacodynamic (PD: comprehensive panel of endocrine and immune markers) parameters were assessed over the course of dosing days. Additional exploratory analyses examined relationships between PK, PD, and behavioral measures. Results PF-5190457 and PF-6870961 concentrations peaked at T2 and were elevated at T1 under drug vs placebo. LEAP2 levels were reduced under drug vs placebo but rebounded on the first washout day. PF-5190457 dramatically reduced growth hormone (GH) at T2, followed by an elevation of GH at T1 the following day. No other endocrine or immune markers differed significantly between drug and placebo. GH at T1 negatively correlated with the number of calories selected during a cafeteria-like virtual reality buffet experiment under drug, but not placebo conditions. Conclusions GHSR blockade with repeated dosing of PF-5190457 changed LEAP2 and GH concentrations but produced overall negligible effects on the endocrine and immune systems. These results further characterize the ghrelin system in AUD and its potential as a therapeutic target.