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

Autor: Sebastien Lorenzo, Joel Morganroth, Alice Huntsman-Labed, Yanfeng Wang, Catherine Dutreix, Robert Harrell, Adam del Corral
Rok vydání: 2011
Předmět:
Male
Cancer Research
Moxifloxacin
Pharmacology
Toxicology
Cardiovascular
Tyrosine-kinase inhibitor
chemistry.chemical_compound
Electrocardiography
Clinical trials
Heart Rate
hemic and lymphatic diseases
Medicine & Public Health
Staurosporine
Pharmacology (medical)
Midostaurin
Systemic mastocytosis
Pharmacology/Toxicology
Hematology
medicine.diagnostic_test
Myeloid leukemia
Middle Aged
Long QT Syndrome
Oncology
Cardiology
Quinolines
Female
Original Article
medicine.drug
Fluoroquinolones
Adult
medicine.medical_specialty
Adolescent
medicine.drug_class
Long QT syndrome
Antineoplastic Agents
Young Adult
Double-Blind Method
Internal medicine
medicine
Humans
Protein Kinase Inhibitors
Aza Compounds
business.industry
Pharmaceutical medicine
medicine.disease
chemistry
Pharmacokinetics and drug metabolism
business
Zdroj: Cancer Chemotherapy and Pharmacology
ISSN: 1432-0843
Popis: Purpose Midostaurin (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. Methods This 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. Results The 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. Conclusion Midostaurin demonstrated a good safety profile in healthy volunteers, with no prolonged cardiac repolarization or other changes on the electrocardiogram. Electronic supplementary material The online version of this article (doi:10.1007/s00280-012-1825-y) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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