Effect of Hepatic or Renal Impairment on Eltrombopag Pharmacokinetics

Abstract

Eltrombopag, an oral, small-molecule, nonpeptide thrombopoietin receptor agonist for the treatment of thrombocytopenia, is highly protein bound and primarily eliminated via metabolism in the liver and gastrointestinal tract. Single-dose eltrombopag pharmacokinetics were evaluated in participants with hepatic or renal impairment given possible changes in systemic exposure due to reduced plasma protein binding or reduced metabolism. All participants received a single 50-mg dose of eltrombopag. The adverse event profile was similar across groups, with headache, nausea, and back pain most frequently reported. Compared with healthy participants, participants with mild, moderate, or severe hepatic impairment had mean increases in AUC(0-∞) of 41%, 93%, and 80%, and participants with mild, moderate, or severe renal impairment had mean decreases in AUC(0-∞) of 32%, 36%, and 60%. There was high pharmacokinetic variability and significant overlap in exposures between participants with hepatic or renal impairment and healthy participants. Results suggest that patients with renal impairment may initiate eltrombopag with the standard 50-mg once-daily starting regimen, whereas patients with moderate or severe hepatic impairment should consider a lower 25-mg once-daily regimen. Patients with hepatic or renal impairment should be closely monitored for platelet response and safety, and eltrombopag doses should be adjusted accordingly.

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

“…2; Table 2). The metabolism of ELT has already been proposed to be important in the hepatic disposition of ELT (Jenkins et al, 2007;Bauman et al, 2010). In addition, biliary excretion accounted for ϳ40% of the overall elimination of ELT ( Fig.…”

“…For example, a clinical trial of ELT in patients with chronic liver disease or hepatitis C-related liver disease has recently been conducted, because thrombocytopenia is often found in conditions involving liver injury. However, the plasma concentration of ELT is greatly increased in patients with such hepatic impairments (Bauman et al, 2010), probably because of reduced hepatic disposition of ELT due to malfunction in the major clearance organ. Hepatic uptake of ELT is temperature-and energy-dependent, saturable, and reduced by various types of transporter inhibitors (Figs.…”

“…6A) was close to the clinical concentration of ELT (C max ϭ 14 M) (Williams et al, 2009). However, because ELT is highly bound to plasma protein (Ͼ99.9%) (Bauman et al, 2010), the unbound concentration of ELT could be much lower in the clinical context. In addition, the maximal unbound concentration in the portal vein after oral administration of ELT was calculated to be at most ϳ0.026 M, according to the equation proposed by Ito et al (1998).…”

“…In particular, unchanged ELT was excreted in feces (20% of the dose), but was not detectable in urine (Bauman et al, 2010). In a phase 1 clinical trial, the pharmacokinetics of ELT after oral administration in healthy volunteers was dose proportional up to 75 mg (Jenkins et al, 2007).…”

“…In a phase 1 clinical trial, the pharmacokinetics of ELT after oral administration in healthy volunteers was dose proportional up to 75 mg (Jenkins et al, 2007). On the other hand, when ELT was administered to patients with mild, moderate, or severe hepatic impairment, the area under the curve (AUC) of ELT was increased by 41, 93, or 80%, respectively, compared with that for healthy subjects (Bauman et al, 2010). Although these results imply that overall elimination of ELT is likely to be mediated by the liver, its pharmacokinetic profile has not yet been clarified in detail.…”