Pharmacokinetics and ADME Characterization of Intravenous and Oral [¹⁴C]-Linerixibat in Healthy Male Volunteers

Abstract

Cl renal,iv ; renal clearance; Cl h,iv,blood , hepatic blood clearance; C max , maximum observed plasma concentration; CVb, between participant variability; CYP, cytochrome P450; DDI, drug-drug interaction; DMSO, dimethyl sulfoxide; EDTA, ethylenediaminetetraacetic acid; E h , hepatic extraction ratio; F, absolute oral bioavailability; fa, fraction of linerixibat absorbed; fg, fraction escaping first-pass gut metabolism; F h , first pass liver extraction; GI, gastrointestinal; IBAT, ileal bile acid transporter; IC 50 , half maximal inhibitory concentration; ICRP, International Commission on Radiological Protection; IV, intravenous; IVIVE, in vitro-to-in vivo extrapolation; LC-MS/MS, liquid chromatography with tandem mass spectrometry; LLQ, lower limit of quantification; LSC, liquid scintillation counting; PBC, primary biliary cholangitis; PK, pharmacokinetics; QC, quality control; Qh, hepatic blood flow; SD, standard deviation; t 1/2 , half-life; V ss , volume of distribution; V z , terminal volume

Considerations for Human ADME Strategy and Design Paradigm Shift(s) – An Industry White Paper

“…Interestingly, the data provided by a comprehensive two‐period hADME/ i.v. microtracer design can be pivotal to PBPK model development, 24,25 and has the potential to reduce the need for other clinical pharmacology investigations 26 …”

“…microtracer design can be pivotal to PBPK model development, 24,25 and has the potential to reduce the need for other clinical pharmacology investigations. 26 There are already examples of inclusion of 14 C-labeled drug in very early clinical development, even FTIH, as a routine practice in at least one pharmaceutical company (H.Lundbeck A/S). 7 In this instance, a low radioactive dose (250 nCi -2,500 nCi; 9.25 kBq -92.5 kBq) is administered along with a therapeutically relevant dose, via the intended route of administration.…”

MiR-203 is an anti-obese microRNA by targeting apical sodium-dependent bile acid transporter

“…Elobixibat as an ASBT inhibitor was recently launched in Japan for the treatment of CIC ( Bassotti et al., 2021 ). Linerixibat was a potent and non-absorbable ASBT inhibitor for the treatment of T2D, but was suspended from the development program after the phase II trial ( Zamek-Gliszczynski et al., 2021 ). Despite the successes of ASBT targeting drugs that have been proved in preclinical and clinical studies, less such prodrugs have progressed to market.…”

Investigation of the human metabolism and disposition of the prolyl hydrolase inhibitor daprodustat using IV microtracer with Entero‐Test bile string

“…The inclusion of duodenal bile sampling in human ADME studies is still a relatively rare activity as, historically, bile collection was done using an invasive approach. 23,24 With the advent of a noninvasive approach, such as the bile string devices used in this investigation, along with the insights, it can provide into routes of metabolism and clearance that would otherwise be undiscovered, has meant that this is becoming either routine, as it is at GSK [25][26][27][28] or considered for inclusion more commonly.…”