Modeling and Experimental Studies of Obeticholic Acid Exposure and the Impact of Cirrhosis Stage

Abstract

Obeticholic acid (OCA), a semisynthetic bile acid, is a selective and potent farnesoid X receptor (FXR) agonist in development for the treatment of chronic nonviral liver diseases. Physiologic pharmacokinetic models have been previously used to describe the absorption, distribution, metabolism, and excretion (ADME) of bile acids. OCA plasma levels were measured in healthy volunteers and cirrhotic subjects. A physiologic pharmacokinetic model was developed to quantitatively describe the ADME of OCA in patients with and without hepatic impairment. There was good agreement between predicted and observed increases in systemic OCA exposure in subjects with mild, moderate, and severe hepatic impairment, which were 1.4-, 8-, and 13-fold relative to healthy volunteers. Predicted liver exposure for subjects with mild, moderate, and severe hepatic impairment were increased only 1.1-, 1.5-, and 1.7-fold. In subjects with cirrhosis, OCA exposure in the liver, the primary site of pharmacological activity along with the intestine, is increased marginally (∼2-fold).

Trial registration: ClinicalTrials.gov NCT01904539 NCT01933503.

© 2016 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1

Physiologic Pharmacokinetic Model Diagram. Similar to other bile acids, OCA is conjugated to glycine and taurine. OCA and its conjugates undergo enterohepatic recirculation. Accounting for differences in hepatic impairment is done by modifying the different flow rates “f,” transport rates “t,” and biotransformation rates “b” at different points throughout the model.

Figure 2

Visual Predictive Check of the Physiologic Pharmacokinetic Model in Healthy Volunteers With Normal Hepatic Function. Blue circles represent observed data points. Solid red line represents median of observed data. Dashed red lines represent the 5th and 95th percentiles of observed data. Solid black line represents predicted median. Gray band represents the 90% prediction interval.

Figure 3

Visual Predictive Check of the Physiologic Pharmacokinetic Model in Subjects With Normal and Impaired Hepatic Function. Blue circles represent observed data points. Solid red line represents median of observed data. Dashed red lines represent the 5th and 95th percentiles of observed data. Solid black line represents predicted median. Gray band represents the 90% prediction interval.

Figure 4

External Validation of the Physiologic Pharmacokinetic Model. (a) Healthy volunteers with normal hepatic function. (b) Subjects with impaired hepatic function. Blue circles represent observed data points. Solid red line represents median of observed data. Dashed red lines represent the 5th and 95th percentiles of observed data. Solid black line represents predicted median. Gray band represents the 90% prediction interval.

Figure 5

Plasma OCA Concentrations are a Poor Surrogate for Liver OCA Concentrations. Systemic exposure of OCA was predicted to be 1.4‐, 8.0‐, and 13‐fold greater in subjects with mild, moderate, and severe hepatic impairment, respectively, based on Child‐Pugh score, than in healthy volunteers, which is consistent with the observed results. Liver exposure of OCA was predicted to be 1.1‐, 1.5‐, and 1.7‐fold greater in subjects with mild, moderate, and severe hepatic impairment, respectively, than in healthy volunteers. n = 8 for observed values. Predicted values were estimated using a 200 replicate simulation from the physiologic pharmacokinetic model of OCA (n = 1,600). Boxplot whiskers represent 1st to 99th percentile.