Pharmacokinetics and Pharmacodynamics of Eltrombopag in Healthy Japanese Males

Abstract

The pharmacokinetics and pharmacodynamics of eltrombopag, a thrombopoietin receptor agonist developed for idiopathic thrombocytopenic purpura, were investigated in healthy Japanese adult males after single and repeat doses of eltrombopag in two clinical studies. In the first study, subjects received a single oral dose of eltrombopag tablets at 30, 50, 75 and 100 mg and placebo in the fasted state. In the second study, each subject received single and once daily for 10 days repeat doses of eltrombopag(25, 50 or 75 mg)or placebo tablets. Plasma eltrombopag concentrations and platelet counts were measured in both studies. AUC and Cmax were proportional to dose within the range of 30-100 mg. ／ The AUC0−24 values after repeat doses of eltrombopag 25, 50 and 75 mg were 56, 130 and 161 mg・hr／mL, respectively, increasing nearly proportionally to the dose increase. The plasma concentration reached steady state in approximately 7 days after starting the repeat dose, and the change in pharmacokinetics caused by repeat dose was small. The AUC values obtained after single and repeat dose in Japanese subjects were nearly twofold higher than those previously reported in non-Japanese subjects(predominantly white). No significant changes in platelet count were observed after single oral doses up to 100 mg of eltrombopag. When 25, 50 and 75 mg were administered once daily for 10 days, the maximum increase in platelet count from the baseline was 54％, 72％ and 90％, respectively, showing a dose-dependent increase. These increases were higher as compared with the previously reported increases in platelet count observed after 30, 50 and 75 mg were administered once daily for 10 days to non-Japanese healthy adults. The increase in platelet count from baseline became higher with increasing AUC in Japanese healthy adults. These results suggest that the difference in platelet count increase between Japanese and non-Japanese is probably associated with the observed inter-ethnic difference in AUC. Eltrombopag might be used at a lower dosage in Japanese than in non-Japanese to attain similar degrees of platelet count increase.

Efficacy and safety of eltrombopag in Japanese patients with chronic liver disease and thrombocytopenia: a randomized, open-label, phase II study

“…An inter-ethnic difference in the pharmacokinetics of eltrombopag has been observed between East Asian and non-Asian patients with ITP, as well as between East Asian and non-Asian healthy volunteers [21]; in our study, the AUC 0– τ in Japanese patients receiving 37.5 mg of eltrombopag once daily was estimated to be 236 μg h/mL, which is similar to that seen in non-East Asian patients with CLD receiving 75 mg once daily in a previous study [26]. Although the mechanisms underlying an inter-ethnic difference in the pharmacokinetics of eltrombopag remain unclear, a common difference between East Asian and Caucasian ethnic groups is body weight [27]. Because the clearance of eltrombopag increased with body weight [21] and because the body weight of East Asian patients is lower than that of Caucasian patients in general, body weight differences could account for the differences in serum levels of eltrombopag seen between the two groups.…”

“…A pharmacogenetic study has also been performed to investigate a relationship between gene polymorphisms and inter-ethnic differences; however, the responsible polymorphism has not been identified (data not shown). Eltrombopag is a substrate of several drug-metabolizing enzymes, including cytochrome P450 (CYP) 1A2, CYP2C8, uridine diphosphate-glucuronosyltransferase (UGT) 1A1, and UGT1A3, and the agent is also a substrate of breast cancer resistance protein [27]. Because the activities of these enzymes are known to have inter-ethnic differences [28, 29], it is possible that multiple factors, including genetic differences in metabolizing enzymes and transporters, may be involved in the observed difference [27].…”

Eltrombopag in severe aplastic anaemia: a guide to its use in the EU

“…In healthy volunteers, eltrombopag dose-dependently increased platelet counts, which returned to baseline after the drug was discontinued, and, unlike thrombopoietin, appeared to have no effect on platelet function, such as aggregation or activation [9][10][11]. In adults with severe aplastic anaemia, eltrombopag therapy for 12 weeks did not affect leukocyte telomere length, modify any T cell subsets or change the elevated thrombopoietin levels present at baseline [7].…”

The role of eltrombopag in the management of hepatitis C virus-related thrombocytopenia

“…It is suggested that low-dose 25 mg once-daily eltrombopag therapy suffices in most patients of Asian origin (compared with in Caucasians, who usually require double this dose) 90. The underlying mechanism accounting for the observed interethnic difference in the pharmacokinetics of eltrombopag is not clear; nonetheless, the most plausible explanation appears to be the difference in the body weight (less in East Asian population compared with the general Caucasian population) 91. Since the clearance of eltrombopag increases with increase in body weight,92 heavy subjects need higher doses to produce an identical therapeutic effect.…”

“…Since the clearance of eltrombopag increases with increase in body weight,92 heavy subjects need higher doses to produce an identical therapeutic effect. Another possible explanation is the known interethnic differences92,93 in the levels of activities of different drug metabolizing enzymes involved in eltrombopag metabolism (eg, CYP1A2, CYP2C8, UGT1A1, and UGT1A3) 91. The predominant route of eltrombopag excretion is via feces (59%) followed by urine (31%).…”