Therapeutic Equivalence of Ursodeoxycholic Acid Tablets and Ursodeoxycholic Acid Capsules for the Treatment of Primary Biliary Cirrhosis.

Abstract

Primary biliary cirrhosis (PBC) is a chronic cholestatic, progressive inflammatory liver disease with a suspected autoimmunological pathogenesis. The disease is typically diagnosed in women at an age between 30 and 65 years and has a prevalence of up to 1 in 1000 women over the age of 40. The only approved medical therapy for PBC is ursodeoxycholic acid (UDCA) in a recommended dose of 13–15mg/kg/day. UDCA is a hydrophilic dihydroxy bile acid (3a,7bdihydroxy-5b-cholanoic acid). In humans, UDCA accounts for up to 4% of the bile acid pool. Following oral administration, approximately 30–60% of UDCA is absorbed in the gut. After intestinal absorption, UDCA enters the portal circulation and is then taken up by the hepatocytes via specific bile acid transporters. Within the hepatocyte, UDCA is conjugated to glycine or taurine and is subsequently transported into the bile ducts by the bile salt export pump (BSEP). In bile, UDCA concentration peaks 1 3 h following oral administration. In humans, the biological half-life of UDCA is 3.5–5.8 days and the predominant route of elimination is by feces. UDCA exerts its beneficial effects at the level of hepatocytes and cholangiocytes. It stimulates hepatocyte secretion by mostly post-transcriptional mechanisms, including insertion of transporters like BSEP and the anion exchanger AE2. In addition, UDCA exerts antiapoptotic effects in hepatocytes and protects cholangiocytes against endogenous toxic bile acids by modifying micelle formation. UDCA consistently improves the biochemical parameters of cholestasis, delays the histological progression and the time to liver transplantation in patients suffering from PBC. Both, UDCA 250mg capsules and UDCA 500mg tablets (“Ursofalk1”), are registered in Germany and other European countries for the treatment of PBC. UDCA 500mg tablets were developed to facilitate medication intake compared to the standard UDCA 250mg capsule preparations. Tablets are considerably smaller, but contain twice as much active pharmaceutical ingredient compared to the capsule preparation, which might improve the compliance of patients and thereby increase its therapeutic efficacy. Ursofalk tablets were registered in Germany on the basis of bioequivalence studies comparing tmax, Cmax, and AUC values of UDCA between capsules and tablets. Cmax values of UDCA in plasma are probably of only limited clinical relevance for the efficacy and safety of UDCA. Aim of this trial was to assess if the therapeutic efficacy of UDCA 500mg tablets is equivalent to that of UDCA 250mg capsules (both at 14 2mg/kg BW/day once daily) in patients with PBC. Therapeutic efficacy was measured by comparing the liver enzyme parameters alkaline phosphatase (AP), g-glutamyl transferase (gGT), and alanine aminotransferase (ALT) under both treatments. The secondary objectives were to assess the safety Clinical Pharmacology in Drug Development XX(XX) 1–6 © The Author(s) 2013 DOI: 10.1002/cpdd.24