Polyhydroxylated Bile Acid and FXR Agonist Combination Therapy
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Solution Overview
Problem
Current treatments for biliary disorders and cholestatic conditions often involve toxic farnesoid X receptor agonists that can cause adverse effects, and there is a need for a combination therapy that can enhance therapeutic efficacy while reducing toxicity and improving bile flow.
Innovation Solution
A combination therapy comprising a polyhydroxylated bile acid, such as tetrahydroxylated bile acids, and a farnesoid X receptor agonist, like obeticholic acid or tropifexor, administered in subtherapeutic or toxic amounts, to counteract toxicity and enhance therapeutic effects in treating biliary and gastrointestinal disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If farnesoid X receptor agonists are used to treat biliary disorders, then therapeutic efficacy is improved, but toxicity increases causing adverse effects
Solution Approach 1:
The patent uses polyhydroxylated bile acids as intermediary substances that mediate between the FXR agonist and the liver tissue. These compounds act as protective agents that reduce the direct toxic interaction between the agonist and hepatic cells, thereby maintaining therapeutic efficacy while mitigating hepatotoxicity and other adverse effects.
Solution Approach 2:
The invention combines FXR agonists with polyhydroxylated bile acids to create a composite therapeutic formulation. This combination leverages the therapeutic benefits of the agonist while the polyhydroxylated bile acid component provides protective effects, reducing overall toxicity and improving the safety profile of the treatment.
2Reliability
If high doses of farnesoid X receptor agonists are administered to enhance therapeutic effect, then treatment efficacy improves, but adverse effects increase
Solution Approach 1:
The patent modifies the dosing parameters by administering FXR agonists in combination with polyhydroxylated bile acids, which allows for effective therapeutic doses while reducing the incidence and severity of adverse effects. The presence of polyhydroxylated bile acids changes the pharmacological parameters of the combination, improving the therapeutic window.
3Productivity
If bile acid secretion is increased to improve bile flow, then cholestasis is treated, but liver damage occurs due to detergent effects
Solution Approach 1:
The patent introduces polyhydroxylated bile acids with specific local properties (higher hydrophilicity, lower detergent activity) into the bile acid pool. These compounds selectively interact with toxic bile acids at the site of action, reducing their harmful detergent effects on liver cells while maintaining overall bile flow and choleretic activity.
Data Source
AI summary
The present invention relates to, in part, a combination therapy of a polyhydroxylated bile acid and a farnesoid X receptor agonist. The present invention also provides, in part, a pharmaceutical composition comprising a farnesoid X receptor agonist and a polyhydroxylated bile acid in the preparation of a medicament for treating a biliary disorder or a gastrointestinal disorder.