Hepatic Dysfunction Quantified by HepQuant DuO Outperforms Child‐Pugh Classification in Predicting the Pharmacokinetics of Ampreloxetine

Abstract

HepQuant tests quantify liver function from clearance of deuterium‐ and 13C‐labeled cholates administered either intravenously and orally (SHUNT) or orally (DuO). Hepatic impairment studies have relied on clinical or laboratory criteria like Child‐Pugh classification to categorize the degree of hepatic dysfunction. We compared HepQuant tests with Child‐Pugh classification in predicting the pharmacokinetics of ampreloxetine. Twenty‐one subjects with hepatic impairment (8 Child‐Pugh A, 7 Child‐Pugh B, and 6 Child‐Pugh C), and 10 age‐ and sex‐matched controls were studied. The pharmacokinetics of ampreloxetine were measured after oral administration of a single dose of 10 mg. Disease severity index (DSI), portal‐systemic shunting (SHUNT%), hepatic reserve, and hepatic filtration rates (HFRs) were measured from serum samples obtained after intravenous administration of [24‐13C]‐cholate and oral administration of [2,2,4,4‐2H]cholate. Ampreloxetine plasma exposure (AUC0‐inf) was similar to controls in Child‐Pugh A, increased 1.7‐fold in subjects with Child‐Pugh B, and 2.5‐fold in subjects with Child‐Pugh C and correlated with both Child‐Pugh score and HepQuant parameters. The variability observed in ampreloxetine exposure (AUC0‐inf) in subjects with moderate (Child‐Pugh B) and severe hepatic impairment (Child‐Pugh C) was explained by HepQuant parameters. Multivariable regression models demonstrated that DSI, SHUNT%, and Hepatic Reserve from SHUNT and DuO were superior predictors of ampreloxetine exposure (AUC0‐inf) compared to Child‐Pugh score. HepQuant DSI, SHUNT%, and hepatic reserve were more useful predictors of drug exposure than Child‐Pugh class for ampreloxetine and thus may better optimize dose recommendations in patients with liver disease. The simple‐to‐administer, oral‐only DuO version of the HepQuant test could enhance clinical utility.