Effect of Obeticholic Acid on Transport of Bile Acids in PBC Examined by 11C-cholyl-sarcosine PET/CT
Condition: Primary Biliary Cirrhosis
MeSH terms: Liver Cirrhosis, Biliary
Study type: Interventional
Phase: Early Phase 1

Summary: 
      This is an investigator-initiated, double-blind crossover study on the mechanism of OCA
      treatment of patients with PBC.

      Hypothesis and significance

      The investigators will test the hypothesis that OCA administration to patients with PBC
      increases hepatobiliary secretion of cholylsarcosine assessed by PET/CT using 11C-labeled
      cholylsarcosine (11C-CSar) as tracer.

      The results of this research project will elucidate the mechanism of the effect of using OCA
      therapeutically in patients with PBC.
    

Detailed description: 
      Background

      Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by
      cholestasis and cirrhosis. Pathogenesis comprises impaired hepatobiliary secretion of bile
      acids to the bile. As a result bile flow reduces and diminished content of bile acids in the
      intestines leads to impaired absorption of lipids and lipid-soluble vitamins, diarrhea,
      general pruritus, and fatigue.

      Bile acids are transported from blood to hepatocytes by the transporter proteins
      Na+-taurocholate co-transporting polypeptide (NTCP) and Organic anion-transporting
      polypeptide (OATP) and secreted from hepatocyte to bile canaliculi by the Bile salt export
      pump (BSEP) and Multidrug resistance protein type 3 (MDR3). Dysfunction of BSEP most probably
      plays a key pathogenic role in PBC.

      Ursodeoxycholic acid (UDCA) is a dihydroxylated bile acid and the only approved drug for
      treatment of PBC today. In most cases UDCA can delay or prevent disease progression. However,
      a subgroup of patients does not respond adequately to UDCA and for these patients new
      therapies are needed.

      BSEP is induced by the nuclear bile acid receptor (BAR), also known as farnesoid X receptor
      (FXR). Obeticholic Acid (INT-747, Intercept) (OCA) is a FXR agonist and induces BSEP.

      OCA administration therefore may increase the hepatobiliary secretion of bile acids, being
      the mechanism behind beneficial therapeutic effects in PBC.

      Cholylsarcosine is a synthetic conjugated bile acid (sarcosine = methyl-glycine) that is
      non-toxic, not metabolized in the gut or liver, and transported by BSEP. The trans-hepatic
      transport of bile acids can be assessed in humans by PET/CT of the liver using 11C-labeled
      cholylsarcosine (11C-CSar) as tracer. 11C-CSar is handled by the liver as a natural bile acid
      in pig studies (1). Studies in humans (2) show that

        -  11C-CSar is taken up avidly by the liver and flow-determined

        -  11C-CSar secretion from hepatocytes to bile is reduced during cholestasis, and

        -  11C-CSar back flux from hepatocytes to blood during cholestasis

      Patients

      8 patients with PBC

        -  who are not responding adequately to treatment with UDCA, defined as ALP > 2 times upper
           normal level during a time period of 6 months

        -  Patients are recruited from Aarhus University Hospital, Department of Hepatology and
           Gastroenterology.

      Paired study design

        -  11C-CSar PET/CT before and after 3 months treatment with OCA or placebo.

      Methods

      PET/CT: Initial low-dose CT for anatomical definition of the PET findings and for attenuation
      correction of PET data. Dynamic 60-min PET recording of the tissue radioactivity
      concentration over time following iv bolus injection of 100 MBq 11C-CSar and iv infusion of
      100 MBq 11C-CSar. During the PET study, ICG is given as a constant iv infusion for
      measurements of hepatic blood flow, used in the kinetic analysis, and blood samples are
      collected from catheters in a radial artery and a liver vein (blood 11C-CSar concentrations
      for kinetic calculations, ICG, and blood gasses for monitoring purposes).

      Liver tests at the time points of the PET/CT study: Plasma ALT, ALP, GGT, bilirubin, bile
      salts, IRN, platelets, hemoglobin, mitochondrial antibodies; ICG clearance.

      Raw data comprise time-courses of the 11C-CSar concentrations in liver tissue and common
      hepatic bile duct (PET recordings) and blood concentrations of 11C-CSar in arterial and liver
      vein blood (blood samples); hepatic blood flow, hepatic venous pressure gradient (HVPG),
      splanchnic oxygen uptake.

      11C-CSar data comprise clearances of 11C-CSar from blood-to-hepatocytes and from
      hepatocytes-to-bile canaliculi, vascular extraction fractions, biliary secretion fraction,
      transit times, etc.
    

Intervention name(s): Obeticholic acid; Placebos
Intervention type(s): Drug; Drug
Intervention description(s): Placebo-controlled
Other intervention name(s): placebo; Obeticholic acid
Intervention MeSH terms: Chenodeoxycholic Acid
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Double blind placebo-controlled crossover
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: Bile Acid Transporter