Electrocardiographic characterization of the QTc interval in patients with advanced solid tumors: pharmacokinetic- pharmacodynamic evaluation of sunitinib.
نویسندگان
چکیده
PURPOSE To evaluate the effects of sunitinib, a multitargeted tyrosine kinase inhibitor, on the QT interval in patients with cancer. EXPERIMENTAL DESIGN Patients received sunitinib loading doses (150-200 mg) on days 3 and 9 and maintenance doses (50 mg/d) on days 4 to 8. Moxifloxacin (day 1), placebo (day 2), and granisetron [with placebo (day 2) or sunitinib (days 3 and 9)] were also administered. Treatment effects were evaluated by time-matched, serial electrocardiograms, and manually overread. RESULTS Twenty-four of 48 patients were QT/PK evaluable. Moxifloxacin produced a time-matched, maximum mean placebo-adjusted corrected QT interval (QT(c)F) of 5.6 ms [90% confidence interval (CI), 1.9-9.3]. Sunitinib QT(c)F changes correlated with exposure, but not T(max). Maximum mean time-matched, placebo-adjusted QT(c)F was 9.6 ms (90% CI, 4.1-15.1) at steady state/therapeutic concentrations (day 3) and 15.4 ms (90% CI, 8.4-22.4) at supratherapeutic concentrations (day 9). No patient had a QT(c)F >500 ms. Concomitant granisetron produced no significant QT(c)F prolongation. Sunitinib-related adverse events were as previously described. CONCLUSIONS Sunitinib has a dose-dependent effect on QT interval. The increased risk of ventricular arrhythmias must be weighed against the therapeutic benefit sunitinib provides to patients with advanced cancer.
منابع مشابه
Cancer Therapy: Clinical Electrocardiographic Characterization of the QTc Interval in Patients with Advanced Solid Tumors: Pharmacokinetic- Pharmacodynamic Evaluation of Sunitinib
Purpose: To evaluate the effects of sunitinib, a multitargeted tyrosine kinase inhibitor, on the QT interval in patients with cancer. Experimental Design: Patients received sunitinib loading doses (150-200 mg) on days 3 and 9 and maintenance doses (50 mg/d) on days 4 to 8. Moxifloxacin (day 1), placebo (day 2), and granisetron [with placebo (day 2) or sunitinib (days 3 and 9)] were also adminis...
متن کاملA phase I first-in-human pharmacokinetic and pharmacodynamic study of serdemetan in patients with advanced solid tumors.
PURPOSE Originally isolated on the basis of its ability to induce p53, serdemetan showed potent activity in various preclinical models, inducing S-phase arrest and apoptosis in TP53 wild-type and mutant tumors. This study evaluated the safety and tolerability of serdemetan, determined the pharmacokinetic and pharmacodynamic profiles, and identified a recommended phase II dose. PATIENTS AND ME...
متن کاملAtrial and Ventricular Electrocardiographic Dromotropic Disturbances in Down Syndrome Patients with Structurally Normal Heart: A Cross-Sectional Study
Background: We designed a cross-sectional study to determine electrocardiographic disorders in Down syndrome patients with congenitally normal hearts in a bid to predict fatal cardiac arrhythmia in the future. Materials and Methods: We investigated 60 children with DS without congenital abnormal hearts. Sixty healthy juveniles were also included in the study as a control group. Physical examina...
متن کاملPharmacodynamic study using FLT PET/CT in patients with renal cell cancer and other solid malignancies treated with sunitinib malate.
PURPOSE To characterize proliferative changes in tumors during the sunitinib malate exposure/withdrawal using 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) positron emission tomography (PET)/computed tomography (CT) imaging. PATIENTS AND METHODS Patients with advanced solid malignancies and no prior anti-VEGF exposure were enrolled. All patients had metastatic lesions amenable to FLT PET/CT imagin...
متن کاملPopulation Pharmacokinetic/Pharmacodynamic Modeling of Sunitinib by Dosing Schedule in Patients with Advanced Renal Cell Carcinoma or Gastrointestinal Stromal Tumor
BACKGROUND Sunitinib is a multi-targeted tyrosine kinase inhibitor used in the treatment of advanced renal cell carcinoma (RCC) and imatinib-resistant/intolerant gastrointestinal stromal tumors (GIST). METHODS A meta-analysis of 10 prospective clinical studies in advanced RCC and GIST was performed to support the development of pharmacokinetic (PK) and PK/pharmacodynamic (PD) models that acco...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Clinical cancer research : an official journal of the American Association for Cancer Research
دوره 15 22 شماره
صفحات -
تاریخ انتشار 2009