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±30 nm, 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±30 nm. 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±30 nm 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.
© 2010 John Wiley & Sons A/S.