Cetilistat: Pharmacology and Clinical Studies

General Description

Cetilistat is a pancreatic lipase inhibitor that effectively reduces dietary fat absorption, assisting in weight management. Preclinical studies in rats showed that cetilistat elevated fecal excretion of triglycerides and non-esterified fatty acids while reducing body weight gain, indicating its efficacy in fat absorption inhibition. Clinical studies involving healthy volunteers demonstrated that cetilistat significantly increased fecal fat excretion compared to placebo, with higher safety and tolerability compared to orlistat, as the incidence of steatorrhea was markedly lower. This profiles cetilistat as a promising option for managing obesity and improving metabolic health.

Figure 1. Cetilistat

Pharmacology

Mechanism of Action

Cetilistat is a pharmacological agent that functions primarily as a pancreatic lipase inhibitor. Through in vitro studies, cetilistat demonstrated its potency in inhibiting pancreatic lipase activity in both rat and human models, with IC50 values of 54.8 nM and 5.95 nM, respectively. This action is crucial in the management of obesity and related conditions, as pancreatic lipase is the enzyme responsible for the breakdown of dietary fats. By blocking this enzyme, cetilistat effectively reduces the intestinal absorption of fats, leading to a decrease in plasma triglyceride levels, particularly after dietary fat intake. The inhibition of pancreatic lipase by cetilistat is a central aspect of its pharmacological profile, making it a valuable tool in weight management therapies. ¹

In Vivo Efficacy

The efficacy of cetilistat has been assessed in various preclinical in vivo studies, notably in Sprague-Dawley rats. When administered in conjunction with a high-fat diet, cetilistat elicited a significant, dose-dependent increase in fecal excretion of triglycerides and non-esterified fatty acids. Concurrently, there was a notable reduction in body weight gain among the treated groups compared to controls. These results indicate that the actions of cetilistat are directly linked to its ability to inhibit fat absorption rather than limiting food intake. Moreover, measurements of white adipose tissue in several regions revealed a considerable reduction, underscoring the effectiveness of cetilistat in promoting fat loss without adversely affecting liver weight or overall caloric intake. ¹

Clinical Implications and Impact

Cetilistat's influence extends beyond simple weight management, having also shown promise in models of severe biliary acute pancreatitis. In these scenarios, cetilistat, alongside orlistat, contributed to significant reductions in serum lipase and various fatty acids. These findings align with its role as a potent lipase inhibitor, demonstrating that cetilistat can also ameliorate conditions associated with inflammation and organ failure without impacting important parameters related to biliary pancreatitis. The overall profile of cetilistat showcases its multifaceted role in not just lowering fat absorption but also improving metabolic health and reducing obesity-related complications, making it an important pharmacological agent in modern therapeutic strategies. ¹

Clinical Studies

Pharmacodynamics and Efficacy

Cetilistat, a novel pharmaceutical agent, was evaluated in three phase I clinical studies involving 99 healthy male volunteers. Participants were placed on a controlled diet of 2160 Kcal/day, consisting of 30% fat. During these trials, participants received varying doses of cetilistat, ranging from 50 to 300 mg three times daily (t.i.d.) for a period of five consecutive days. A comparative group was administered orlistat at 120 mg t.i.d. Daily fecal fat excretion served as the primary pharmacodynamic endpoint, while secondary endpoints included triglyceride and cholesterol excretion, along with evaluations of plasma lipid levels, such as high-density lipoprotein (HDL) and low-density lipoprotein (LDL). Findings revealed that cetilistat significantly increased mean fecal fat excretion across all tested doses compared to baseline and placebo, with noteworthy increases observed in 67% and 45% of participants. ²

Safety and Tolerability

The safety and tolerability of cetilistat were rigorously assessed throughout the clinical studies. Adverse events noted were primarily mild to moderate in intensity and predominantly gastrointestinal, with steatorrhea being the most common. Notably, cetilistat had an incidence of less than one episode of steatorrhea per subject, a stark contrast to the 4.11 episodes per subject reported in the orlistat group. Importantly, no correlation was found between daily fecal fat excretion and steatorrhea incidence. Additionally, cetilistat demonstrated no clinically significant adverse effects on laboratory parameters or vital signs. The extensive analysis indicated that cetilistat is well tolerated, providing promising insights into its application as an effective treatment option for patients requiring fat absorption management. ²

Reference

1. Gras J. Cetilistat for the treatment of obesity. Drugs Today (Barc). 2013 Dec; 49(12): 755-759.

2. Bryson A, de la Motte S, Dunk C. Reduction of dietary fat absorption by the novel gastrointestinal lipase inhibitor cetilistat in healthy volunteers. Br J Clin Pharmacol. 2009 Mar;67(3):309-315.