Midostaurin does not prolong cardiac repolarization defined in a thorough electrocardiogram trial in healthy volunteers

Abstract

PurposeMidostaurin (PKC412) is a multitargeted tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 receptor (FLT3), c-KIT, and other receptors. Midostaurin is active in patients with acute myeloid leukemia and systemic mastocytosis. Although no substantive risk for cardiac abnormalities has been observed with midostaurin in clinical studies thus far, some TKIs have been shown to affect cardiac repolarization. Here we evaluated midostaurin’s effect on cardiac repolarization.MethodsThis phase I study evaluated the effect of midostaurin (75 mg twice daily for 2 days; 75 mg once on day 3) on the heart rate–corrected QT (QTc) interval in a parallel design with active (moxifloxacin) and placebo control arms in healthy volunteers.ResultsThe maximum mean QTc change from baseline corrected using Fridericia’s correction (QTcF) for midostaurin compared with placebo was 0.7 ms at 24 h post dose on day 3. The highest upper bound of the 1-sided 95% CI was 4.7 ms, which excluded 10 ms, demonstrating a lack of QTcF prolongation effect. Assay sensitivity was demonstrated by modeling the moxifloxacin plasma concentration versus QTcF change from baseline, which showed a clear positive increase in QTcF with increasing moxifloxacin plasma concentrations, as expected based on previous studies. In the 4-day evaluation period, a minority of participants (34.6%) experienced an adverse event; 97.0% were grade 1. No grade 3 or 4 adverse events were reported.ConclusionMidostaurin demonstrated a good safety profile in healthy volunteers, with no prolonged cardiac repolarization or other changes on the electrocardiogram.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-012-1825-y) contains supplementary material, which is available to authorized users.

Tafenoquine at therapeutic concentrations does not prolong fridericia‐corrected QT interval in healthy subjects

“…The slope describing the relationship between QTcF interval versus moxifloxacin concentrations was 3.1 ms/μg mL –1 , consistent with that observed in other thorough QT studies and confirming an exposure–response effect of moxifloxacin on QTcF. 29 – 31 As moxifloxacin exposure was considerably lower in this study than reported in the literature, 30 PK/PD modeling was conducted to assess the predicted effect of higher moxifloxacin concentrations on ΔΔQTcF. One thousand datasets were simulated based on doubling the individual concentrations at each time point in the original dataset so as to be similar to those in the typical range observed in other studies reported in the literature.…”

“…Administration of moxifloxacin with food decreased both the rate and extent of absorption as evidenced by the lower C max and AUC values for moxifloxacin in comparison to literature values for moxifloxacin obtained in the fasted state. 29 …”

“…One thousand datasets were simulated based on doubling the individual concentrations at each time point in the original dataset so as to be similar to those in the typical range observed in other studies reported in the literature. 29 The design of these simulated datasets was the same as the study reported here. Estimates of ΔΔQTcF were generated for seven selected time points between 0 and 6 hours post-final dose (Table 4 ).…”

Midostaurin: A New Oral Agent Targeting FMS‐Like Tyrosine Kinase 3‐Mutant Acute Myeloid Leukemia

“…26 In a phase I study of midostaurin in healthy young volunteers, midostaurin was not shown to cause prolongation of cardiac repolarization. 35…”

Synthesis and Cytotoxicity of N12-Ethyl Substituted Indolocarbazole Derivatives

“…随后药物化学家对其进行结构改造, 多个衍 生物已经作为抗肿瘤药物进入了临床研究 [19] . 多靶点 的蛋白激酶抑制剂 PKC-412 [20] 可以有效抑制人白血病 细胞的增殖 [21] , 在临床 I 期研究中表现出了安全性和有 效性 [22] . 临床 II 期研究结果表明, PKC-412 对 FMS 样酪 氨酸激酶 3 (Flt-3)突变型和野生型的急性骨髓性白血病 受试者均有效 [23] .…”