Safety and Pharmacokinetic Assessment of Oral Proglumide in Those with Hepatic Impairment

Abstract

Proglumide is an orally administered cholecystokinin receptor antagonist that was found to improve nonalcoholic steatohepatitis, reverse liver fibrosis, and decrease incidence of hepatocellular carcinoma (HCC) in animal models. The current investigation aimed to test the pharmacokinetics and safety of proglumide in subjects with hepatic impairment compared with healthy controls. In this translational study, subjects with confirmed cirrhosis, Child-Pugh stage A or B, or healthy controls were recruited for a single-dosing study. Baseline urine and blood samples were obtained before administration of proglumide and also collected after ingestion up to 24 h. Drug concentrations measured by mass spectroscopy revealed peak plasma concentrations (Cmax) of 7847, 9721, and 10,635 ng/mL at about 1 h (Tmax) for healthy controls, subjects with Child-Pugh A, and B cirrhosis, respectively. The serum elimination half time was 3 h. Maximum urine drug concentration (Cmax = ~411 µg/mL) was observed at 3 h, and urinary drug concentration declined at 5 h. There were no adverse events reported, and follow-up liver panels in cirrhosis subjects were unchanged or improved. This investigation demonstrated that proglumide is safe and has similar pharmacokinetic properties in subjects with cirrhosis as in healthy controls; therefore, it will be safe to test the efficacy of proglumide as a therapeutic agent in those subjects with cirrhosis or HCC.

Safety and Dosing Study of a Cholecystokinin Receptor Antagonist in Non‐alcoholic Steatohepatitis

“…However, this difference could be due to the fact that more of the Cohort 3 participants had afternoon appointments and their proglumide blood levels had started to decline. We previously showed 28 in participants with cirrhosis and healthy controls, peak blood levels occurred within 1 hour after injections. Once maximum, the drug concentration was reduced to half in about 2.5 hours (C max1/2 ).…”

“…35 We recently completed a pharmacokinetic single‐dose study testing proglumide in participants with Child‐Pugh A and B cirrhosis and found the C max and time to reach maximum plasma concentration (T max ) were comparable to that of healthy controls. 28 Since the current study was the first clinical trial in participants with NASH, we selected a proglumide dose that was lower and a dose higher than the 1,200 mg/day dosing used in earlier peptic ulcer disease studies. Although all three doses were well tolerated in participants with NASH, we observed the greatest decline in ALT and liver stiffness by FibroScan using the highest dose.…”

“…Pharmacokinetic studies performed in rats and human participants showed the metabolism and kinetics in the rats and humans were comparable and that the recommended oral dose of proglumide in people was 400 mg three times daily or 1,200 mg/day 35 . We recently completed a pharmacokinetic single‐dose study testing proglumide in participants with Child‐Pugh A and B cirrhosis and found the C max and time to reach maximum plasma concentration (T max ) were comparable to that of healthy controls 28 . Since the current study was the first clinical trial in participants with NASH, we selected a proglumide dose that was lower and a dose higher than the 1,200 mg/day dosing used in earlier peptic ulcer disease studies.…”

The Role of a Cholecystokinin Receptor Antagonist in the Management of Chronic Pancreatitis: A Phase 1 Trial

“…Hence, the recommendation was to use the 1200 mg per day dose for the current study. Pharmacokinetic studies were also performed with proglumide in healthy controls and in patients with hepatic impairment, which revealed rapid oral absorption and renal excretion [15]. In animal models of chronic pancreatitis, we found that proglumide decreased pancreatic fibrosis and inflammation [16].…”

“…Proglumide was dispensed from the investigational pharmacy at baseline and at the week 4 and week 8 visits and prescribed as one capsule by mouth three times daily for a total daily dose of 1200 mg. The dose and dosing schedule were based upon the results of a prior study involving subjects with metabolic-associated hepatic steatosis [14] and a pharmacokinetic study involving healthy controls and subjects with hepatic impairment [15]. The protocol allowed for the dose to be reduced from 1200 mg/day to 800 mg/day for drug-related side effects.…”