PGX6115: Genetic Effects on Different eltrombopag Exposure between Asians and Whites

Trial description: Eltrombopag is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Clinical studies investigating the utility of eltrombopag to increase platelet counts in patients suffering from thrombocytopenia occurring in a number of other disease indications are ongoing. In all studies evaluated, population pharmacokinetic (PK) analyses have shown that subjects of East Asian ancestry (i.e., Japanese, Chinese, Taiwanese, and Koreans) and South East Asian ancestry (i.e., Thais) achieve higher plasma eltrombopag exposure values as compared to white subjects receiving the same dose of eltrombopag. Across population PK analyses, East/South East Asian ancestry was associated with 50 to 110% (1.5 to 2.1-fold) higher plasma eltrombopag dose-normalized AUC (NAUC) values compared to non-East/South East Asian subjects. GlaxoSmithKline (GSK) reported no statistically significant genetic effects (polymorphisms in an ADME [absorption, distribution, metabolism and excretion] panel with 135 gene regions) that could explain the differences in plasma eltrombopag exposure (AUC) between East Asian and white subjects in an initial pharmacogenetic (PGx) investigation that included 150 healthy volunteers (40 East Asian and 110 white) and 54 patients with ITP (11 East Asian and 43 white). Due to a small sample size, this initial experiment had less than 50% statistical power to detect genetic effects which could account for differences in plasma eltrombopag exposure between East Asians and whites. In particular, this initial genetic investigation had only a small number of East Asian subjects for whom PK data was available. GSK proposed an additional investigation into genetic effects on plasma eltrombopag exposure differences between East Asian and white subjects with a larger cohort of subjects with chronic hepatitis C virus (HCV) and chronic liver disease (CLD) enrolled in eltrombopag clinical studies. Multiple factors are likely responsible for the higher exposures observed in East Asians than in whites because no single metabolic or transporter pathway has been shown to account for the majority of eltrombopag metabolism and disposition. However, some pharmacokinetic determinants of eltrombopag metabolism and disposition have been identified in vitro. These include Cytochrome P450s (CYP1A2 and CYP2C8), UDPglucuronosyltransferases (UGT1A1 and UGT1A3), and the transporter BCRP (ABCG2). Subjects of East Asian (n=161) and white (n=239) ancestries enrolled in the clinical studies TPL104054, TPL111913, TPL103922 and TPL108390, who received open-label eltrombopag, had dose normalized AUC (NAUC) data collected while on study, and provided written informed consent for PGx research and a blood sample which was successfully genotyped for one or more of the genetic markers under study were included in the study. Genetic markers from genes UGT1A1, UGT1A3, CYP1A2, CYP2C8, and ABCG2 sufficient to accurately interrogate key functional star (*) alleles within each gene were determined and genotyped. These were analyzed for association with NAUC to investigate inter-population variability in eltrombopag exposure between East Asians and in Whites.