1. Pharmacokinetics and ADME Characterization of Intravenous and Oral [14C]-Linerixibat in Healthy Male Volunteers
- Author
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Brandon Swift, Lee Crossman, Graeme Young, Robin L. O'Connor-Semmes, Megan M. McLaughlin, David Kenworthy, David A. Bershas, Matthew Allinder, Jill L. Pirhalla, Mitesh Sanghvi, Maciej J. Zamek-Gliszczynski, Karl M. Thorpe, Jeremy Dennison, Jennypher Mudunuru, and Adrian Pereira
- Subjects
Pharmacology ,CYP3A4 ,Chemistry ,Pharmaceutical Science ,medicine.disease ,Intestinal absorption ,Bioavailability ,Excretion ,Renal Elimination ,Pharmacokinetics ,medicine ,Cholestatic pruritus ,ADME - Abstract
Linerixibat, an oral small molecule ileal bile acid transporter inhibitor under development for cholestatic pruritus in primary biliary cholangitis, was designed for minimal intestinal absorption (site of pharmacological action). This study characterized the pharmacokinetics, absorption, distribution, metabolism, and excretion of [14C]-linerixibat in humans following an intravenous microtracer, concomitant with unlabeled oral tablets, and [14C]-linerixibat oral solution. Linerixibat exhibited absorption-limited flip-flop kinetics: longer oral versus intravenous half-life (6-7 h vs 0.8 h). The short intravenous half-life was consistent with high systemic clearance (61.9 L/h) and low volume of distribution (16.3 L). In vitro studies predicted rapid hepatic clearance via cytochrome P450 (CYP) 3A4 metabolism, which deceptively predicted human hepatic clearance within 1.5-fold. However, linerixibat was minimally metabolized in humans after intravenous administration: ~80% elimination via biliary/fecal excretion (>90-97% as unchanged parent) and ~20% renal elimination by glomerular filtration (>97% as unchanged parent). Absolute oral bioavailability of linerixibat was exceedingly low (0.05%), primarily due to a very low fraction absorbed (0.167%; fgut~100%), with high hepatic extraction ratio (77.0%) acting as a secondary barrier to systemic exposure. Oral linerixibat was almost entirely excreted (>99% recovered radioactivity) in feces as unchanged and unabsorbed linerixibat. Consistent with the low oral fraction absorbed and ~20% renal recovery of intravenous [14C]-linerixibat, urinary elimination of orally administered radioactivity was negligible (
- Published
- 2021