Bile Acid Recycling Inhibitors for Treatment of Pediatric Cholestatic Liver Diseases

Abstract

Provided herein are methods of treating or ameliorating a pediatric cholestatic liver disease by non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric formulation comprising an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. Also provided are methods for treating or ameliorating a pediatric liver disease, decreasing the levels of serum bile acids or hepatic bile acids, treating or ameliorating pruritis, reducing liver enzymes, or reducing bilirubin comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric formulation comprising an ASBTI or a pharmaceutically acceptable salt thereof.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 61 / 553,094, filed Oct. 28, 2011, U.S. Provisional Application No. 61 / 607,487, filed Mar. 6, 2012, U.S. Provisional Application No. 61 / 607,503, filed Mar. 6, 2012, which are incorporated herein by reference in their entirety.BACKGROUND OF THE INVENTION[0002]Pediatric cholestatic liver diseases affect a small percentage of children, but therapy results in significant healthcare costs each year. Currently, many of the pediatric cholestatic liver diseases require invasive and costly treatments such as liver transplantation and surgery. An effective and less invasive treatment that is suitable for the pediatric population is not available.[0003]It is well understood and accepted that the therapeutic needs of children are sufficiently different than those of adults as to require specific studies of medications in children. For example, oral administr...

AI Technical Summary

Benefits of technology

[0013]In certain embodiments, methods provided herein comprise administering compounds that inhibit the ASBT or any recuperative bile salt transporter. In certain embodiments, use of the compounds provided herein reduces or inhibits recycling of bile acid salts in the gastrointestinal tract. In some embodiments, the methods provided herein reduce intraenterocyte bile acids / salts or reduce necrosis and / or damage to intestinal or hepatocellular architecture.

[0050]In some cases, for any of the methods described above, administration of an ASBTI reduces intraenterocyte bile acids / salts in an individual in need thereof. In some embodiments, the methods described herein reduce accumulation of bile acids / salts in ileal enterocytes of an individual in need thereof. In some cases, for any of the methods described above, administration of an ASBTI inhibits transport of bile acids / salts from ileal lumen into enterocytes of an individual in need thereof. In some cases, for any of the methods described above, administration of an ASBTI increases ileal luminal bile acids / salts in an individual in need thereof. In some cases, for any of the methods described above, administration of an ASBTI reduces damage to intestinal (e.g., ileal cells) or hepatocellular (e.g., liver cells) architecture associated with a pediatric cholestatic liver disease or elevated serum or hepatic bile acid concentrations in an individual in need thereof. In some cases, for any of the methods described above, administration of an ASBTI regenerates intestinal lining or liver cells that have been injured by cholestasis and / or by a cholestatic liver disease in an individual suffering from a cholestatic liver disease.

Problems solved by technology

Pediatric cholestatic liver diseases affect a small percentage of children, but therapy results in significant healthcare costs each year.

Currently, many of the pediatric cholestatic liver diseases require invasive and costly treatments such as liver transplantation and surgery.

An effective and less invasive treatment that is suitable for the pediatric population is not available.

For example, oral administration of a solid dosage form of medication is painless and simple for most adult patients, but for the pediatric patient population, swallowing an oral solid dosage form produced for adults can be problematic.

In addition, the drugs used in solid dosages often have an unpleasant taste.

More importantly, oral administration of adult medication targeting cholestatic liver diseases may result in side effects such as diarrhea and intestinal discomfort.

Such problems pose a safety risk and affect compliance.

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