Pharmacokinetics and Hepatic Uptake of Eltrombopag, a Novel Platelet-Increasing Agent

Abstract

ABSTRACT:Eltrombopag (ELT) is a novel thrombopoietin receptor agonist for the treatment of idiopathic thrombocytopenic purpura. Previous reports indicate that ELT is mainly eliminated in the liver, although its pharmacokinetic profile has not yet been clarified in detail. The purpose of the present study is to investigate the overall elimination mechanism of ELT. After intravenous administration of ELT to rats, approximately 40% of unchanged ELT was excreted into the bile in 72 h, whereas less than 0.02% of the dose was excreted in urine, indicating that liver is the major elimination organ for ELT. The total clearance was much lower than the hepatic blood flow rate and comparable with hepatic uptake clearance obtained from integration plot analysis. Coadministration of rifampicin, an organic anion transporter inhibitor, reduced both total clearance and hepatic uptake clearance of ELT. These results suggest that hepatic uptake is the rate-limiting process in the overall elimination of ELT. To further characterize the uptake mechanism, uptake of ELT by freshly isolated mouse hepatocytes was examined. The ELT uptake showed concentration and energy dependence and was inhibited by various compounds, including not only organic anions but also organic cations. Hepatic uptake clearance in vivo was reduced by coadministration of an organic cation, tetrapentylammonium. Finally, uptake of ELT was observed in human embryonic kidney 293 cells transfected with human hepatic transporters organic anion-transporting polypeptide (OATP) 1B1 and OATP2B1 and organic cation transporter OCT1. These results suggest that multiple transporters, including organic anion transporters and organic cation transporters, are involved in hepatic ELT uptake.

Interaction of Novel Platelet-Increasing Agent Eltrombopag with Rosuvastatin via Breast Cancer Resistance Protein in Humans

“…ELT was dissolved in saline containing 5 mM human serum albumin (HSA) to obtain a final concentration of 0.4 mg/ml and was orally administered by gavage (2 mg/kg body weight). This concentration of albumin fully suppresses nonspecific adsorption of ELT on the experimental apparatus (Takeuchi et al, 2011). Rosuvastatin was prepared in 0.5% hydroxypropyl methylcellulose for oral administration by gavage (10 mg/ 5 ml per kilogram body weight) and in saline containing 5 mM HSA for intravenous administration via the tail vein (4 mg/2 ml per kilogram body weight).…”

“…According to our previous study, hepatic uptake could be the rate-limiting process in the overall elimination of ELT (Takeuchi et al, 2011). Hepatic uptake of ELT is mediated at least in part by organic anion transporting peptide 1B1 (OATP1B1) (Takeuchi et al, 2011), although the contribution of this transporter to hepatic ELT uptake remains to be precisely clarified.…”

“…According to our previous study, hepatic uptake could be the rate-limiting process in the overall elimination of ELT (Takeuchi et al, 2011). Hepatic uptake of ELT is mediated at least in part by organic anion transporting peptide 1B1 (OATP1B1) (Takeuchi et al, 2011), although the contribution of this transporter to hepatic ELT uptake remains to be precisely clarified. Nevertheless, certain drugs such as gemfibrozil, rifampicin, and cyclosporin A are known to interact in a clinically significant way with OATP1B1-mediated hepatic uptake of therapeutic agents in humans (Kalliokoski et al, 2010).…”

“…Allred et al (2011) reported that the plasma concentration of rosuvastatin was increased by concomitant administration of ELT, whereas rosuvastatin did not affect the plasma concentration of ELT. ELT can act as an inhibitor of OATP1B1, at least in gene-transfected cell lines in vitro (Takeuchi et al, 2011). Because rosuvastatin is mainly eliminated from the liver (Martin et al, 2003), and its hepatic uptake process is primarily mediated by OATP1B1 (Kitamura et al, 2008), the interaction by ELT is considered to involve the OATP1B1-mediated hepatic uptake process, although the details remain unclear.…”

Solitary Inhibition of the Breast Cancer Resistance Protein Efflux Transporter Results in a Clinically Significant Drug-Drug Interaction with Rosuvastatin by Causing up to a 2-Fold Increase in Statin Exposure

“…Additionally, inhibition of OATP1B3 is unlikely to play a role since, although eltrombopag (K i = 25.6 mM), darunavir (K i = 4.51 mM), and ezetimibe (K i . 4 mM) are inhibitors, R-value extrapolations indicate their potential for DDI as unlikely (,1.25), and lopinavir is not an inhibitor (De Bruyn et al, 2011Takeuchi et al, 2011;Vildhede et al, 2014). Finally, inhibition of sodium/taurocholate cotransporting peptide (NTCP) can be ruled out as a contributory factor since 1) despite being an NTCP inhibitor in vitro (K i = 25 mM; Dong et al, 2013), ezetimibe is not expected to cause a DDI via this mechanism in vivo (R = 1.00); 2) lopinavir does not inhibit NTCP (Vildhede et al, 2014); and 3) although it is unknown whether the ), and Q ent is the enterocyte blood flow (300 ml/min [ 18 l/h; Agarwal et al, 2013); I inlet max u , maximum unbound liver inlet concentration, calculated as f u  [(C max total ) + (F a  k a  dose/Q h )], where F a is the fraction absorbed (as default taken to be 1.0), k a is the absorption rate constant (as default taken to be 0.1 min 21 ), and Q h is hepatic blood flow (1500 ml/min); K i , absolute inhibition constant (assuming competitive inhibition; equates to IC 50 in these assays as probe substrate concentration used is , ,,, K m ); MW, molecular weight [taken from the drug label accessed via Pharmapendium database (http://www.pharmapendium.com)]; NA, not applicable.…”