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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • OATP1B1 is important for hepatic uptake of rosuvastatin and BCRP is important for rosuvastatin absorption and elimination. Eltrombopag inhibits OATP1B1 and BCRP in vitro at clinically relevant concentrations. Inhibition of these transporters could change cholesterol-lowering efficacy and increase the risk of exposure-dependent toxicities. To determine if co-administration of eltrombopag with rosuvastatin alters plasma rosuvastatin exposure, an open-label study was conducted in 42 healthy adult subjects. WHAT THIS STUDY ADDS • Concomitant administration of eltrombopag with rosuvastatin was associated with increased rosuvastatin exposure via inhibition of drug transporters. The therapeutic index of HMG Co-A reductase inhibitors may be reduced by the concomitant use of eltrombopag. In subjects taking eltrombopag, a reduced dose of HMG Co-A reductase inhibitors may be needed. AIM Eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist, inhibits the organic anion transporting polypeptide 1B1 (OATP1B1) and breast cancer resistance protein (BCRP) in vitro. OATP1B1 is important for hepatic uptake of rosuvastatin and inhibition of this transporter could reduce cholesterol-lowering efficacy and increase the risk of exposure-dependent toxicities. In contrast, BCRP is an efflux transporter and inhibition of this transporter could increase both hepatic and plasma rosuvastatin concentrations, resulting in increased efficacy and toxicity. To determine if co-administration of eltrombopag with rosuvastatin alters plasma rosuvastatin exposure, an open-label study was conducted in 42 healthy adult subjects. METHODS Subjects received rosuvastatin and eltrombopag orally: day 1, rosuvastatin 10 mg single dose; days 6 to 9, eltrombopag 75 mg once daily; day 10, eltrombopag 75 mg once daily and rosuvastatin 10 mg single dose. Adverse event assessments were performed daily and at the follow-up visit. Plasma samples for pharmacokinetic analysis were collected days 1 to 5 and days 10 to 14. RESULTS Co-administration of eltrombopag with rosuvastatin increased geometric mean (90% confidence interval) plasma rosuvastatin AUC(0,∞) by 55% (42%, 69%) and Cmax by 103% (82%, 126%) in the overall study population, with a larger interaction in the non-Asian compared with Asian subjects. CONCLUSIONS Concomitant administration of eltrombopag with rosuvastatin was associated with increased rosuvastatin exposure. The therapeutic index of HMG Co-A reductase inhibitors may be reduced by the concomitant use of eltrombopag. In subjects taking eltrombopag, a reduced dose of HMG Co-A reductase inhibitors may be needed.

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.

This was a double-blind, placebo-controlled, randomized, parallel, dose-escalation study to assess the pharmacokinetics, platelet response, safety, and tolerability of supratherapeutic doses of eltrombopag (100 mg, 150 mg, and 200 mg once daily) administered for 5 days to 33 healthy adult volunteers. Plasma eltrombopag concentrations accumulated between days 1 and 5, with average increases of 66% to 81% for area under the plasma concentration-time curve from time zero to the end of the 24-hour dosing interval (AUC(0-τ)) and 32% to 45% for maximum observed plasma concentration (C(max)) across doses. After 5 days of dosing, AUC(0-τ) was dose-proportional and C(max) was less than dose-proportional over eltrombopag 100 to 200 mg with slope estimates (90% confidence intervals) of 0.92 (0.45-1.39) and 0.76 (0.29-1.22), respectively. Platelet counts peaked at day 14, and maximum change from baseline platelet count increased dose-dependently, with mean platelet count increases of 14, 67, 107, and 150 Gi/L for placebo and eltrombopag 100 mg, 150 mg, and 200 mg, respectively. There was no notable difference in day 14 mean platelet aggregation between eltrombopag (59 to 74%) and placebo (67%), although this was not tested statistically. There was no notable difference in adverse event frequency across eltrombopag doses. Eltrombopag pharmacokinetics and platelet response were dose-dependent, and doses up to 200 mg/d were well tolerated, with safety profiles similar to placebo.

Background/purpose: Eltrombopag is an oral, small molecule, thrombopoietin receptor agonist approved in the United States for the treatment of chronic immune thrombocytopenic purpura and under investigation for treatment of thrombocytopenia due to other etiologies. In vitro studies identified a phototoxic potential for eltrombopag that was not confirmed in subsequent animal studies at exposures up to 11 times the human clinical exposure. A randomized study in healthy men and women was conducted to more fully characterize the photosensitizing potential of a therapeutic dose of eltrombopag (75 mg q.i.d.). Methods: In this placebo-controlled, randomized, parallel group study, the photosensitizing potential of eltrombopag was evaluated in 36 healthy subjects with 12 subjects per group treated for 6 days with eltrombopag 75 mg q.i.d., placebo q.i.d., or positive control ciprofloxacin 500 mg b.i.d. (a mild photosensitizer). The primary endpoint was the photosensitizing potential of eltrombopag in comparison with the placebo on day 6 as measured by the phototoxic index (PI) at 24-h postirradiation, delayed erythema, and the change from baseline in minimum erythemal dose (MED) at 24-h postirradiation. The PI and MED were determined at discrete wavelengths in the ultraviolet (UV) and visible light spectrum from 290 to 430 nm. Results: At wavelengths of 295 ± 5, 300 ± 5, 305 ± 30nm, and solar simulator whole spectrum (SS WS), there were no notable median differences in delayed PI or change from baseline MED at 24-h postirradiation after administration of eltrombopag 75 mg q.i.d., placebo, or ciprofloxacin 500 mg b.i.d. Mild phototoxicity induced by ciprofloxacin 500 mg b.i.d. was observed at wavelengths of 335 ± 30 and 365 ± 30 nm within the UVA region. Following administration of ciprofloxacin, the median difference in delayed PI relative to placebo at wavelengths of 335 ± 30 and 365 ± 30 nm was increased to 0.75 [95% confidence interval (CI), 0.222-2.037] and 1.20 (95% CI, 0.404-1.720), respectively However, there was no evidence that photosensitivity was increased following administration of eltrombopag 75 mg q.i.d. There were no significant differences between median delayed PI following administration of repeat doses of eltrombopag 75 mg q.i.d. and repeat doses of placebo at wavelengths of 335 ± 30 and 365 ± 30nm. Comparing eltrombopag 75 mg q.i.d. with ciprofloxacin 500 mg b.i.d., the median difference in delayed PI for wavelengths of 335 ± 30 and 365 ± 30nm was decreased to - 0.94 (95% CI, - 2.037 to - 0.289) and - 1.38 (95% CI, - 1.882 to - 0.432), respectively With 6 days of treatment, eltrombopag and placebo did not increase the photosensitivity of the skin, while the positive control ciprofloxacin did increase the photosensitivity of skin, resulting in mild phototoxicity. Administration of eltrombopag for 6 days was well tolerated; no deaths, serious adverse events (AEs), or drug-related AEs leading to discontinuation were observed during the study. There were no meaningful differences in AEs reported between the eltrombopag-treated group and either the placebo or ciprofloxacin-treated group. Conclusion: Repeat dosing of eltrombopag 75 mg q.i.d. for 6 days in healthy men and women did not induce photosensitivity at any wavelength tested (UVA, ultraviolet B) in this study. Eltrombopag is well tolerated and does not induce photosensitivity.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Some non-anti-arrhythmic drugs delay cardiac repolarization, which can be measured as an increase in the QT interval. Delays in cardiac repolarization create an electrophysiological environment that favours the development of cardiac arrhythmias, which may lead to torsade de pointes, which can be fatal. As part of the clinical development of eltrombopag, a thorough QTc study was conducted to evaluate the effects of eltrombopag on cardiac repolarization at both therapeutic and supratherapeutic doses and to characterize the relationship between plasma eltrombopag concentrations and change in QTc. WHAT THIS STUDY ADDS This study found no clinically significant QT prolongation for eltrombopag when administered as 50 mg or 150 mg every day for 5 days. There were no safety or tolerability signals of clinical concern. A small incidence of ventricular premature beats was observed, but this was consistent with previously reported incidences in healthy volunteers without apparent heart disease. AIM To evaluate the effect of eltrombopag on cardiac repolarization and to characterize the relationship between plasma eltrombopag concentrations and change in QTc. METHODS This was a double-blind, placebo- and active-controlled, randomized, balanced four-period, crossover study in healthy men and women. Subjects were randomized to receive eltrombopag 50 mg and 150 mg, moxifloxacin 400 mg (positive control) and placebo in one of four sequences. RESULTS Eighty-seven subjects entered the study and 48 completed. There was no prolongation of QTc (Fridericia) following eltrombopag treatment, as the upper limit of the 90% confidence interval (CI) for the time-matched change from baseline in QTcF between drug and placebo (ddQTcF) did not exceed 10 ms for eltrombopag at either dose. Maximum observed mean treatment difference was 2.29 ms (90% CI 0.34, 4.24) for eltrombopag 150 mg at 1 h post-dose and 11.64 ms (90% CI 9.64, 13.64) for moxifloxacin 400 mg at 4 h. Eltrombopag Cmax and AUC(0,24 h) increased in a dose proportional manner between 50 mg and 150 mg after 5 days' dosing. Proportions of subjects with adverse events were similar across treatments (52–66% of subjects). Most withdrawals (26/39 subjects) were due to elevated platelets. Three subjects were withdrawn for ventricular premature beats (one following each active treatment) reported as related to the study drug. CONCLUSIONS No clinically significant QTc prolongation was observed for eltrombopag at therapeutic and supratherapeutic doses.

MSC 2000: Primary 62M10; secondary 62C10. Abstract: The authors consider time series observations with data irregularities such as censoring due to a detection limit. Practitioners commonly disregard censored data cases which often result in biased esti- mates. The authors present an attractive remedy for handling autocorrelated censored data based on a class of autoregressive and moving average (ARMA) models. In particular, they introduce an imputation method well suited for fitting ARMA models in the presence of censored data. They demonstrate the effectiveness of their technique in terms of bias, efficiency, and information loss. They also describe its adaptation to a specific context of meteorological time series data on cloud ceiling height, which are measured subject to the detection limit of the recording device. Analyse de s´ eries chronologiques censur ´