QTcF Interval Research Articles

Effect of small angiokinase inhibitor nintedanib (BIBF 1120) on QT interval in patients with previously untreated, advanced renal cell cancer in an open-label, phase II study

Some targeted anticancer agents are associated with serious ventricular tachyarrhythmias, which may be predicted by electrocardiographic evaluation of drug-related QT prolongation. We studied the effects of nintedanib (BIBF 1120; an oral, triple angiokinase inhibitor targeting vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptors) on the QT interval in patients with renal cell carcinoma (RCC) participating in an open-label phase II trial. Treatment-naïve, adult patients with unresectable/metastatic, clear cell RCC received nintedanib 200 mg twice daily. QT intervals were evaluated at baseline (day -1), on day 1 (after the first dose), and on day 15 (steady state) by 12-lead electrocardiograms (ECGs) performed in triplicate. Pharmacokinetic sampling was also undertaken. Among 64 evaluable patients, the upper limits of the 2-sided 90 % confidence intervals for the adjusted mean time-matched changes in QTcF interval (corrected for heart rate by Fridericia's method) from baseline to day 1 and 15 (primary ECG endpoint) were well below the regulatory threshold of 10 ms at all times. No relationship between nintedanib exposure and change from baseline in QTcF was seen. Nintedanib was generally well tolerated with no drug-related cardiovascular adverse events. Nintedanib administered at 200 mg twice daily was not associated with clinically relevant QT prolongation.

P.2.b.020 Safety and tolerability of levomilnacipran SR in major depressive disorder: results from an open-label, 48-week extension study

The QT interval is the most widely used surrogate marker for predicting TdP; however, several alternative surrogate markers, such as Tpeak–Tend (TpTe) and a quantitative T-wave morphology combination score (MCS) have emerged. This study investigated the cardiac effects of sertindole and quetiapine using the QTc interval and newer surrogate markers. Data were derived from a 12 week randomized double-blind study comparing flexible dosage of sertindole 12–20 mg and quetiapine 400–600 mg in patients with schizophrenia. ECGs were recorded digitally at baseline and after 3, 6 and 12 weeks. Between group effects were compared by using a mixed effect model, whereas assessment within group was compared by using a paired t-test. Treatment with sertindole was associated with QTcF and QTcB interval prolongation and an increase in MCS, T-wave asymmetry, T-wave flatness and TpTe. The mean increase in QTcF from baseline to last observation was 12.1 ms for sertindole (p<0.001) and −0.5 ms for quetiapine (p=0.8). Quetiapine caused no increase in MCS, T-wave asymmetry, T-wave flatness or TpTe compared to baseline. In the categorical analysis, there were 11 patients (9.6%) receiving quetiapine who experienced more than 20 ms QTcF prolongation compared with 36 patients (33.3%) in the sertindole group. Sertindole (12–20 mg) was associated with moderate QTc prolongation and worsening of T-wave morphology in a study population of patients with schizophrenia. Although, quetiapine (400–600 mg) did not show worsening of repolarization measures some individual patients did experience significant worsening of repolarization. Clinical Trials NCT00654706.

The cardiovascular safety profile of escitalopram

The cardiovascular effects of escitalopram were examined in a large group of participants in double-blind, randomized, placebo-controlled studies. Escitalopram (n=3298) was administered at doses between 5 and 20mg/day. Patients were treated in acute (8–12 weeks) and long-term (24 weeks) studies. Assessment of cardiovascular safety included heart rate, blood pressure (BP), treatment-emergent adverse events (TEAEs) and electrocardiograms (ECGs). In the short-term, there was a small, but statistically significant 2 beats per minute decrease in heart rate with escitalopram compared with placebo. The difference compared to placebo in systolic or diastolic BP was not clinically or statistically significant. Valid ECG assessments at both baseline and last assessment were available for 2407 escitalopram patients and 1952 placebo patients. Escitalopram–placebo differences in mean changes in ECG values were not clinically meaningful. The mean difference to placebo in the corrected QT [Fridericia's (QTcF)] interval was 3.5ms (all escitalopram doses); 1.3ms (escitalopram 10mg) and 1.7ms (escitalopram 20mg) (p=0.2836 for 10 versus 20 mg). One out of 2407 escitalopram patients had a QTcF interval >500ms and a change from baseline >60ms. The incidence and types of cardiac-associated adverse events were similar between patients treated for 8–12 weeks with placebo (2.2%) or escitalopram (1.9%) and for 24 weeks with placebo (2.7%) or escitalopram (2.3%). Analyses of data from long-term studies and studies of the elderly showed similar results. In conclusion, these data demonstrate that escitalopram, like other SSRIs, has a statistically significant effect on heart rate and no clinically meaningful effect on ECG values, BP, with a placebo-level incidence of cardiac-associated adverse events.

Ipragliflozin Does Not Prolong QTc Interval in Healthy Male and Female Subjects: A Phase I Study

BackgroundIpragliflozin, a potent, selective sodium glucose cotransporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus. The International Conference on Harmonisation recommends that the safety investigation of new drugs include characterization of each agent’s effects on the QT/QTc interval. ObjectiveThe goal of this study was to assess the effect on cardiac repolarization (QTc interval) of repeated oral dosing of ipragliflozin at therapeutic (100 mg/d) and supratherapeutic (600 mg/d) levels in healthy subjects. MethodsThis was a double-blind, placebo- and active-controlled, 4-way crossover study. Subjects were randomized to 1 of 4 treatment sequences each including the following 4 treatments: placebo for 7 days; ipragliflozin 100 mg/d for 7 days; ipragliflozin 600 mg/d for 7 days; and active control moxifloxacin 400 mg on day 7 only. The primary assessment of QTc was based on Fridericia’s correction for heart rate (QTcF). Continuous 12-lead ECG interval extraction assessments were conducted on day 7. The least squares mean treatment difference from placebo and corresponding 2-sided 90% CIs were calculated for QTcF up to 14 hours postdose on treatment day 7. Ipragliflozin was deemed unlikely to have a clinically relevant effect on QTcF if the upper bound of the maximum treatment difference from placebo for ipragliflozin across all time points was < 10 ms. Assay sensitivity for QTcF interval prolongation was confirmed if the lower bound of the 2-sided 90% CIs for the mean moxifloxacin QTcF difference from placebo, determined at sampling time closest to average Tmax, was > 5 ms. ResultsA total of 88 subjects were randomized to treatment (n = 22 per sequence; 10 males and 12 females). The largest upper bounds of the 90% CIs of mean treatment differences from placebo were 4.44 and 3.39 ms for ipragliflozin 600 and 100 mg, respectively, in all subjects, indicating no clinically relevant effect on QTcF interval. No specific effects were observed when the data were analyzed according to sex. No subject showed outlier QTcF intervals > 480 ms or a time-matched change from baseline > 60 ms. Moxifloxacin confirmed assay sensitivity for QTcF interval prolongation; the lower bound of the 2-sided 90% CIs at 3 hours postdose was 11.7 ms (> 5 ms). ConclusionsNo clinically meaningful QTc interval prolongation was observed in these healthy subjects who received ipragliflozin doses up to 600 mg/d for 7 days. ClinicalTrials.gov identifier: NCT01232413.

Preladenant, a selective adenosine A2A receptor antagonist, is not associated with QT/QTc prolongation

Preladenant is an orally administered adenosine2A (A2A) receptor antagonist in phase III development for Parkinson's disease treatment. This thorough QT/QTc study evaluated its potential effects on cardiac repolarization. This was a randomized, double-blind, positive- and placebo-controlled, four-period crossover study performed under steady-state exposure of clinical and supratherapeutic doses of preladenant (10 mg BID and 100 mg BID, respectively, for 5 days), moxifloxacin (400 mg on day 5), or placebo in 60 healthy adult volunteers. The potential effect on QTcF was measured by the largest upper bound of 95 % one-sided CIs for the mean changes from time-matched baseline ECG recordings compared with placebo. Plasma preladenant concentrations were also determined on day 5. The QTcF difference for moxifloxacin compared with placebo exceeded 5 ms from 1 to 12 h postdose, establishing assay sensitivity. The QTcF interval was similar between the preladenant and placebo treatment groups: the upper bound of the 95 % one-sided CI for the mean difference in QTcF between preladenant and placebo was less than 10 ms at all time points for the supratherapeutic treatment group (1.3 to 5.7 ms, mean difference: -1.3 to 2.7 ms) and the therapeutic treatment group (0.4 to 4.3 ms, mean difference: -2.1 to 1.5 ms), substantially below the threshold of regulatory concern. The supratherapeutic dose (100 mg BID) provided a Cmax margin of 6.1-fold and AUC margin of 6.9-fold, respectively, compared with 10 mg BID. At clinical and supratherapeutic doses, preladenant is not associated with QTc prolongation.

Lack of effect of bendamustine on Fridericia corrected QT interval (QTcF) in a phase III study of bendamustine-rituximab in advanced indolent non-Hodgkin’s lymphoma (NHL) or mantle cell lymphoma (MCL).

e19518 Background: Clinical data on the arrhythmogenic potential of bendamustine are limited. Bendamustine and rituximab (BR) are commonly combined, and rituximab concentrations are essentially constant ≥1.5 hours due to its long half-life. This BR single-arm study assessed the effects of bendamustine on QTcF over 1.5 hours in previously untreated adults with advanced indolent NHL or MCL. Methods: Patients in this open-label study were aged ≥18 years with QTc on screening electrocardiogram (ECG) ≤450 ms. Exclusion criteria included low serum potassium or magnesium and history of cardiac conditions with QT prolongation risk. Bendamustine 90 mg/m2 was given on days 1 and 2 and rituximab 375 mg/m2 on day 1 of each 28-day cycle. On day 2 of cycle 1, ECGs and blood sampling were performed ~15 min prior to bendamustine infusion (baseline), at the end of infusion (EOI)/Cmax, and 1 h post-EOI. The primary measure was change in QTcF at EOI. Secondary measures included outlier analyses of QTcF intervals, pharmacokinetic/pharmacodynamic (PK/PD) analysis, and changes in ECG morphology. The ECG analysis included patients with ≥1 ECG at baseline and on treatment. Results: There were 53 enrolled patients (92% white; 60% male; mean age 63.0 y, range 37-84 y; mean body surface area 2.0 m2, range 1.4-2.6 m2). No clinically relevant signal of any bendamustine effect on cardiac repolarization was detected based on the mean change in QTcF from baseline and outlier analyses (Table). In the PK/PD analyses, predicted change in QTcF for bendamustine and its metabolites, M3 and M4, were not significant: 5.4 ms (upper CI 7.6 ms), 6.0 ms (8.8 ms), and 7.1 ms (10.1 ms), respectively, but there were few data. No new ECG morphologic changes were seen. Conclusions: In this small population with previously untreated advanced NHL or MCL, bendamustine was associated with a small increase in mean QTcF that was not clinically meaningful. Support: Teva BPP R&amp;D, Inc. Clinical trial information: NCT01073163. [Table: see text]

Tigecycline does not prolong corrected QT intervals in healthy subjects.

We evaluated the effect of tigecycline (50-mg and 200-mg doses) on corrected QT (QTc) intervals and assessed safety and tolerability in a randomized, placebo-controlled, four-period crossover study of 48 (44 male) healthy volunteers aged 22 to 53 years. Fed subjects received tigecycline (50 mg or 200 mg) or placebo in a blinded fashion or an open-label oral dose of moxifloxacin (400 mg) after 1 liter of intravenous fluid. Serial electrocardiograms were recorded before, and for 96 h after, dosing. Blood samples for tigecycline pharmacokinetics were collected after each recording. QTc intervals were corrected using Fridericia's correction (QTcF). Pharmacokinetic parameters were calculated using noncompartmental methods with potential relationships examined using linear mixed-effects modeling. Adverse events were recorded. The upper limits of the 90% confidence interval for the mean difference between both tigecycline doses and placebo for all time-matched QTcF interval changes from baseline were <5 ms. The tigecycline concentrations initially declined rapidly and then more slowly. In the group given 50 mg of tigecycline, the pharmacokinetic parameters and means were as follows: maximum concentration of drug in serum (C(max)), 432 ng/ml; area under the concentration-time curve from time zero extrapolated to infinity (AUC0-∞), 2,366 ng · h/ml; clearance (CL), 21.1 liters/h; volume of distribution at steady state (V(ss)), 610 liters; and terminal half-life (t(1/2)), 22.1 h. Proportional or similar values were found for the group given 200 mg of tigecycline. Linear mixed-effects modeling failed to show an effect on QTcF values by tigecycline concentrations (P = 0.755). Tigecycline does not prolong the QTc interval in healthy subjects. This study has been registered at ClinicalTrials.gov under registration no. NCT01287793.

A randomized, double-blind, placebo-controlled study to evaluate the effect of repeated oral doses of pazopanib on cardiac conduction in patients with solid tumors.

As tyrosine kinase inhibitors have been associated with cardiotoxicity, we evaluated the effect of pazopanib, an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, on electrocardiographic parameters in patients with cancer. This double-blind, placebo-controlled, parallel-group study randomized patients (N = 96) to moxifloxacin (positive control) or placebo on Day 1 followed by pazopanib or placebo 800 mg/day (fasted) on Days 2-8 and 1,600 mg (with food) on Day 9. Treatment effects were evaluated by baseline-adjusted, time-matched, serial Holter electrocardiograms. Sixty-five patients were evaluable for preplanned analyses. On Day 1, the maximum mean difference in baseline-adjusted, time-matched Fridericia-corrected QT (QTcF) interval in moxifloxacin-treated patients versus placebo was 10.6 ms (90% confidence interval [CI]: 4.2, 17.0). The administration scheme increased plasma pazopanib concentrations approximately 1.3- to 1.4-fold versus the recommended 800 mg once-daily dose. Pazopanib caused clinically significant increases from baseline in blood pressure, an anticipated class effect, and an unexpected reduction in heart rate from baseline that correlated with pazopanib exposure. On Day 9, the maximum mean difference in baseline-adjusted, time-matched QTcF interval in pazopanib-treated patients versus placebo was 4.4 ms (90% CI: -2.4, 11.2). Mixed-effects modeling indicated no significant concentration-dependent effect of pazopanib or its metabolites on QTcF interval. Pazopanib as administered in this study achieved supratherapeutic concentrations, produced a concentration-dependent decrease in heart rate, and caused a small, concentration-independent prolongation of the QTcF interval.

Final Results of A Phase 1 Study Investigating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Quizartinib (AC220) Administered Daily to Patients with Relapsed or Refractory Acute Myeloid Leukemia Irrespective of FLT3-ITD Status

AbstractAbstract 1507FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Quizartinib is an oral FLT3 receptor tyrosine kinase (RTK) inhibitor that inhibits both ITD-mutant and wild-type FLT3 and displays efficacy in preclinical models of AML. In this first-in-human study, quizartinib was evaluated in patients with relapsed or refractory AML who were enrolled irrespective of FLT3-ITD status.Quizartinib was administered orally on an intermittent schedule (ID, 14 days on, 14 days off) at 12–450 mg/day or continuously (CD) at 200 or 300 mg/day. A total of 76 patients (61% male; 90% white; median age 60 years [23–86]) received quizartinib; median number of prior treatments was 3 (0–12), including 16% with a prior hematopoietic stem cell transplant. FLT3-ITD status was 22% positive (+) (n=17), 49% negative (−) (n=37), and 29% indeterminate/not tested (ind) (n=22).Plasma inhibitory activity assays using plasma samples collected at trough timepoints showed a high degree of FLT3 inhibition at low dose levels (18 mg/day and higher), indicative of potent in vivo FLT3 inhibition. Marked inhibition of FLT3 phosphorylation was also demonstrated in peripheral blood following administration of quizartinib.Responses were observed in 23/76 patients (30%), with 10 patients (13%) having a best response of any type of complete remission (CR=morphologic leukemia-free state with absolute neutrophil count >1×109/L and platelet count ≥100×109/L, and normal marrow differential with <5% blasts with no Auer rods; CRp=CR with incomplete platelet recovery; CRi=CR with incomplete hematologic recovery). Responses included 2 CR, 3 CRp, 5 CRi, and 13 (17%) partial remissions (PR, same hematologic values as CR but with a decrease of ’50% in % blasts in the bone marrow aspirate to 5% to 25%; a value of <5% blasts was considered a PR if Auer rods were present). Responses were observed at doses as low as 18 mg/day ID. Nine of 17 FLT3-ITD(+) patients responded (53%; 1 CR, 1 CRp, 2 CRi, 5 PR) compared to 5/37 FLT3-ITD(−) patients (14%; 2 CRp, 3 PR) and 9/22 with FLT3-ITD(ind) status (41%; 1 CR, 3 CRi, 5 PR). Median duration of response was 13.3 weeks (95% confidence interval [CI]: 11.0, 29.0 weeks): 9.7 weeks for FLT3-ITD(+) patients (95% CI: 4.1, 29); 23.7 weeks for FLT3-ITD(−) patients (95% CI: 11, not reached); and 12.4 weeks for FLT3-ITD(ind) patients(95% CI: 8, 53). Median overall survival was 14.0 weeks (95% CI: 10.9, 18.6 weeks): 18.3 weeks for FLT3-ITD(+) patients (95% CI: 10.6, 27.1); 9.7 weeks for FLT3-ITD(−) patients (95% CI: 5.6, 14.0); and 18.7 weeks for FLT3-ITD(ind) patients (95% CI: 14.0, 21.1).Quizartinib was generally well tolerated. The most common drug-related AEs (>10% incidence) were nausea (16%), prolonged ECG QT interval (12%), vomiting (11%), and dysgeusia (11%); most were ≤Grade 2. The maximum tolerated dose was 200 mg/day CD. The dose-limiting toxicity was QTcF interval prolongation, which occurred in 38% of subjects at 300 mg/day CD and in 6% at 200 mg/day CD. QTcF interval prolongation was dose dependent, and there were no associated arrhythmias. Grade 3 AEs related to quizartinib occurring in >1 patient were prolonged ECG QT interval (4 patients [5%]), anemia (3 patients [4%]), and fatigue (2 patients [3%]). Two treatment-related Grade 4 AEs (thrombocytopenia and hypoalbuminemia) were reported in 1 patient each (1%).The encouraging efficacy results in both FLT3-ITD(+) and FLT3 ITD(−) patients and an acceptable safety profile in this high-risk population support continued clinical evaluation of quizartinib with lower doses. A recent 333 patient Phase 2 study in a similar population given quizartinib at 200, 135, or 90 mg/day has been completed, and, considering the clinical activity observed at low doses, quizartinib is also being studied in patients with relapsed or refractory AML at 30 and 60 mg/day. Disclosures:Cortes:Novartis: Consultancy. Kantarjian:Ambit Biosciences: Consultancy. Foran:Ambit Biosciences: Consultancy. Ghirdaladze:Ambit Biosciences: Consultancy. Zodelava:Ambit Biosciences: Consultancy. Borthakur:Ambit Biosciences: Consultancy. Gammon:Ambit Biosciences: Employment. Trone:Ambit Biosciences: Employment. Armstrong:Ambit Biosciences: Employment. James:Ambit Biosciences: Employment. Levis:Ambit Biosciences: Consultancy.

Shortening of the QT Interval After Food Can Be Used to Demonstrate Assay Sensitivity in Thorough QT Studies

The effect of food was investigated under conditions of a thorough QT (TQT) study and with confirmation of assay sensitivity by the use of a positive control (400 mg of moxifloxacin). Fifty-five healthy subjects were randomized to treatment and a sequence of fasted and fed baseline electrocardiography days. Subjects received standard breakfast 30 to 10 minutes prior to dosing. Measurement of QT interval was performed automatically with subsequent manual onscreen overreading using electronic calipers. A profound increase in heart rate of 9.4 bpm was observed in the fed condition compared with the fasted condition at 1.5 hours after dose with a corresponding shortening of QT (27 milliseconds); (baseline data). When corrected, QTcF interval was shortened significantly with the maximal effect observed at 2 hours after dose of 8.2 (95% confidence interval, 6-10) milliseconds. A concurrent shortening of the PR interval with a maximum value of 5.6 milliseconds was also observed. The findings of this study demonstrate that food alters the QT-RR relationship and shortens QTc and PR for at least 4 hours after a carbohydrate-rich meal. The findings are of regulatory interest as this study shows that normal physiological causes can shorten QTc significantly and that it could be used as a method to demonstrate assay sensitivity.

M138 A RANDOMISED, DOUBLE-BLIND, PLACEBO- AND POSITIVE-CONTROLLED, PARALLEL-GROUP TRIAL TO INVESTIGATE THE EFFECT OF MULTIPLE ORAL DOSES OF NOMAC/E2 ON QTCF INTERVALS IN HEALTHY WOMEN

International Journal of Gynecology & ObstetricsVolume 119, Issue S3 p. S576-S577 Poster presentations M138 A RANDOMISED, DOUBLE-BLIND, PLACEBO- AND POSITIVE-CONTROLLED, PARALLEL-GROUP TRIAL TO INVESTIGATE THE EFFECT OF MULTIPLE ORAL DOSES OF NOMAC/E2 ON QTCF INTERVALS IN HEALTHY WOMEN P.-J. de Kam, P.-J. de KamSearch for more papers by this authorJ. van Kuijk, J. van KuijkSearch for more papers by this authorO. Lillin-de Vries, O. Lillin-de VriesSearch for more papers by this authorT. Post, T. PostSearch for more papers by this authorT. Thomsen, T. ThomsenSearch for more papers by this authorF. Beligotti, F. BeligottiSearch for more papers by this author P.-J. de Kam, P.-J. de KamSearch for more papers by this authorJ. van Kuijk, J. van KuijkSearch for more papers by this authorO. Lillin-de Vries, O. Lillin-de VriesSearch for more papers by this authorT. Post, T. PostSearch for more papers by this authorT. Thomsen, T. ThomsenSearch for more papers by this authorF. Beligotti, F. BeligottiSearch for more papers by this author First published: 22 October 2012 https://doi.org/10.1016/S0020-7292(12)61332-0AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume119, IssueS3Abstracts of XX FIGO World Congress of Gynecology and ObstetricsOctober 2012Pages S576-S577 RelatedInformation

507 - Phase I, Open-Label, Randomized, Crossover Study Evaluating the Effects of Linifanib on Qtc Intervals in Patients with Solid Tumors

ABSTRACT Background Linifanib (ABT-869) is a novel, orally active and selective inhibitor of VEGF and PDGF family of receptor tyrosine kinases that has shown antitumor activity in multiple types of solid tumors. This study was conducted to evaluate the potential effects of linifanib on QTc prolongation in patients (pts) with advanced solid tumors. Methods Enrolled pts (N = 24; ≥18 years) had measurable disease refractory to standard therapies, ECOG PS 0-1, and adequate organ function. Pts received 2 sequences of regimens of 0.25 mg/kg orally administered linifanib up to a maximum dose of 17.5 mg. Pts received a morning dose on Days 1 and 7 under fasting and fed conditions in a crossover fashion. Serial triplicate ECG recordings were obtained on Day –1, and over 24 hours on Day 1 and 7; single recordings were obtained at screening and study completion or discontinuation. Plasma samples were collected for 72 hours on Day 1 and 7 for pharmacokinetic analysis. Effects of linifanib on cardiac repolarization were analyzed using a linear mixed effects model on time-matched baseline adjusted QTcF intervals. The primary end point was the time-matched difference for on-treatment QTcF from baseline (ΔQTcF). An intersection-union test was performed within the framework of the corresponding linear mixed effects model. The relationship between ΔQTcF and plasma linifanib concentration was explored using a linear mixed effects model. Results In the 24 pts evaluated, baseline QTcF ranged from 360.9 ms to 468.6 ms. After linifanib administration, the mean ΔQTcF ranged from –4.04 ms to 0.73 ms for the fasting regimen, and from –5.94 ms to –1.37 ms for the fed regimen. The upper 95% confidence bound was 4.30 ms (ie, 500 ms or change of >30 ms from baseline. Conclusion At the maximum tolerated dose of 0.25 mg/kg, linifanib had no effect on cardiac repolarization in pts with advanced solid tumors. Disclosure Y. Chiu: Full-time Abbott employee and stockholder. P.M. LoRusso: Patricia LoRusso's institution receives research funding from Abbott. J.L. Ricker: Full-time Abbott employee and stockholder. X. Li: Full-time Abbott employee and stockholder. R. Pradhan: Full-time Abbott employee and stockholder. D.M. Carlson: Full-time Abbott employee and stockholder.

A single supratherapeutic dose of ridaforolimus does not prolong the QTc interval in patients with advanced cancer

PurposeThis dedicated QTc study was designed to evaluate the effect of the mammalian target of rapamycin inhibitor, ridaforolimus, on the QTc interval in patients with advanced malignancies.MethodsWe conducted a fixed-sequence, single-blind, placebo-controlled study. Patients (n = 23) received placebo on day 1 and a single 100-mg oral dose of ridaforolimus on day 2 in the fasted state. Holter electrocardiogram (ECG) monitoring was performed for 24 h after each treatment, and blood ridaforolimus concentrations were measured for 24 h after dosing. The ECGs were interpreted in a blinded fashion, and the QT interval was corrected using Fridericia’s formula (QTcF). After a washout of at least 5 days, 22 patients went on to receive a therapeutic regimen of ridaforolimus (40 mg orally once daily for 5 days per week).ResultsThe upper limit of the two-sided 90 % confidence interval for the placebo-adjusted mean change from baseline in QTcF was <10 ms at each time point. No patient had a QTcF change from baseline >30 ms or QTcF interval >480 ms. Geometric mean exposure to ridaforolimus after the single 100-mg dose was comparable to previous experience with the therapeutic regimen. There appeared to be no clear relationship between individual QTcF change from baseline and ridaforolimus blood concentrations. Ridaforolimus was generally well tolerated, with adverse events consistent with prior studies.ConclusionsAdministration of the single 100-mg dose of ridaforolimus did not cause a clinically meaningful prolongation of QTcF, suggesting that patients treated with ridaforolimus have a low likelihood of delayed ventricular repolarization.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-012-1942-7) contains supplementary material, which is available to authorized users.

Cardiac Changes in Horses with Atypical Myopathy

Atypical myopathy (AM) is an acute, fatal rhabdomyolysis in grazing horses that mainly affects skeletal muscles. Postmortem examinations have shown that myocardial damage also occurs. Limited information is available on the effect of AM on cardiac function in affected and surviving horses. To describe electrocardiographic and echocardiographic changes associated with AM in the acute stage of the disease and after follow-up. Horses (n = 12) diagnosed with AM in which cardiac ultrasound examination and ECG recording were available. All horses underwent clinical examinations, serum biochemistry, electrocardiography, and echocardiography. Four surviving horses underwent the same examinations after 2-10 weeks. All but 1 horse had increased cardiac troponin I concentrations and 10 horses had ventricular premature depolarizations (VPDs). All horses had prolonged corrected QT (QT(cf) ) intervals on the day of admission and abnormal myocardial wall motion on echocardiography. One of the surviving horses still had VPDs and prolonged QT(cf) at follow-up after 10 weeks. The AM results in characteristic electrocardiographic and echocardiographic changes and may be associated with increased cardiac troponin I concentrations and VPDs. In survivors, abnormal cardiac function still may be found at follow-up after 10 weeks. Additional research in a larger group of horses is necessary to identify the long-term effects of AM on cardiac function.

Effects of nintedanib (BIBF 1120) on QTc interval in previously untreated patients with renal cell cancer (RCC): Results from an open-label, phase II study.

e15037 Background: Nintedanib (BIBF 1120), an angiokinase inhibitor of VEGFR 1–3, PDGFR-α/-β, and FGFR 1–3, has shown clinical activity with a good safety profile in patients (pts) with solid tumors in previous Phase II clinical trials. Several classes of targeted agents are associated with QT prolongation, including the multi-targeted tyrosine kinase inhibitors. Here, we prospectively evaluated the cardiac safety of nintedanib, specifically assessing the QT liability in an open-label, randomized, phase II efficacy and safety study of nintedanib vs sunitinib in pts with previously untreated RCC. Methods: Eligible pts (advanced, measurable, unresectable, recurrent RCC, ECOG PS 0–1, chemo-naïve, life expectancy &gt;3 months) were randomized to receive either nintedanib 200 mg bid or sunitinib 50 mg od in a 2:1 ratio. Time-matched electrocardiograms of patients treated with nintedanib were collected over 12 hrs. Primary endpoint was the time-matched change from baseline (Day –1 prior nintedanib dosing) to Day 15 (steady-state) in the QTcF interval (QT interval corrected for heart rate dependency by the Fridericia formula) observed at each timepoint. PK parameters were determined and AEs were reported until Day 15. Results: 64 pts were treated with nintedanib. Estimated mean time-matched changes in the QTcF interval (ms) from baseline to Day 15 ranged from –1.7 (90% CI: –4.9, 1.6) at 2 hrs to 3.1 (90% CI: –0.2, 6.4) at 7 hrs. Upper CIs at all timepoints were &lt;10 ms, the ICH E14 guideline threshold level of regulatory concern. Changes from baseline to Day 1 and changes in QT interval were also within the threshold of 10 ms. No pts showed a QTcF or a QT value &gt;500 ms at baseline, Day 1 or Day 15, and no patient experienced an increase from baseline in QTcF &gt;60 ms on Days 1 and 15. PK/QTc analyses did not indicate any relationship between exposure to nintedanib and a change from baseline in QTcF or the QT interval. The most frequently reported drug-related AEs were nausea (14.1%), diarrhea (12.5%) and vomiting (6.3%). Conclusions: Single and multiple doses of 200 mg nintedanib administered until steady-state did not prolong the QTcF interval compared with baseline in pts with RCC.

Effects of Bilastine on T-wave Morphology and the QTc Interval

The International Conference of Harmonisation (ICH) E14 guideline for thorough QT studies requires assessing the propensity of new non-antiarrhythmic drugs to affect cardiac repolarization. The present study investigates whether a composite ECG measure of T-wave morphology (Morphology Combination Score [MCS]) can be used together with the heart rate corrected QT interval (QTc) in a fully ICH E14-compliant thorough QT study to exclude clinically relevant repolarization effects of bilastine, a novel antihistamine. Thirty participants in this crossover study were randomly assigned to receive placebo, moxifloxacin 400 mg, bilastine at therapeutic and supratherapeutic doses (20 and 100 mg) and bilastine 20 mg co-administered with ketoconazole 400 mg. Resting ECGs recorded at 12 nominal time points before and after treatments were used to determine Fridericia corrected QTc (QTcF) and MCS from the T-wave characteristics: asymmetry, flatness and notching. There were no effects of bilastine monotherapy (20 and 100 mg) on MCS or QTcF at those study times where the bilastine plasma concentrations were highest. MCS changes for bilastine monotherapy did not exceed the normal intrasubject variance of T-wave shapes for triplicate ECG recordings. Maximum QTcF prolongation for bilastine monotherapy was 5 ms or less: 3.8 ms (90% CI 0.3, 7.3 ms) for bilastine 20 mg and 5.0 ms (90% CI 2.0, 8.0 ms) for bilastine 100 mg. There were no indications of bilastine inducing larger repolarization effects on T-wave morphology as compared with the QTcF interval, as evidenced by the similarity of z-score equivalents for placebo-corrected changes in MCS and QTcF values. This study shows that bilastine, at therapeutic and supratherapeutic dosages, does not induce any effects on T-wave morphology or QTcF. These results confirm the absence of an effect for bilastine on cardiac repolarization.

A Thorough QT Study of Teduglutide in Healthy Subjects.

Teduglutide, an analog of the endogenous hormone glucagon-like peptide-2, is currently being developed for the treatment of short bowel syndrome. This study investigated the potential effects of teduglutide on cardiac conduction and repolarization. Seventy-two healthy volunteers underwent 4 treatment periods in randomized order with a single subcutaneous injection of placebo, 5 and 20 mg teduglutide, and a single oral 400-mg dose of moxifloxacin. The primary variable to investigate the effect on cardiac repolarization was the difference between QTcF after administration versus predose. The observed upper bounds of the 95% one-sided confidence intervals were 3.0 ms (5 mg) and 4.5 ms (20 mg). Arithmetic mean curves of QTcF intervals over time of both doses of teduglutide and of placebo were almost superposable. Assay sensitivity for the positive control moxifloxacin was shown. In conclusion, teduglutide at intended therapeutic and supratherapeutic doses had no effect on cardiac repolarization. No safety concerns were identified. Treatment with teduglutide was well tolerated.

A Modeling and Simulation Approach to Characterize Methadone QT Prolongation Using Pooled Data From Five Clinical Trials in MMT Patients

Pharmacokinetic (PK)-pharmacodynamic modeling and simulation were used to establish a link between methadone dose, concentrations, and Fridericia rate-corrected QT (QTcF) interval prolongation, and to identify a dose that was associated with increased risk of developing torsade de pointes. A linear relationship between concentration and QTcF described the data from five clinical trials in patients on methadone maintenance treatment (MMT). A previously published population PK model adequately described the concentration-time data, and this model was used for simulation. QTcF was increased by a mean (90% confidence interval (CI)) of 17 (12, 22) ms per 1,000 ng/ml of methadone. Based on this model, doses >120 mg/day would increase the QTcF interval by >20 ms. The model predicts that 1-3% of patients would have ΔQTcF >60 ms, and 0.3-2.0% of patients would have QTcF >500 ms at doses of 160-200 mg/day. Our predictions are consistent with available observational data and support the need for electrocardiogram (ECG) monitoring and arrhythmia risk factor assessment in patients receiving methadone doses >120 mg/day.

No Effect of a Single Supratherapeutic Dose of Lersivirine, a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor, on Corrected QT Interval in Healthy Subjects

The objective of this study was to investigate the effect of a supratherapeutic dose of lersivirine (LRV) on corrected QT (QTc) interval using Fridericia's equation (QTcF) in healthy subjects. In this randomized, single-dose, placebo- and active-controlled 3-way crossover study, healthy adult males (n = 48) were randomized to receive LRV (2,400 mg), moxifloxacin (400 mg), or placebo for each treatment period. Triplicate 12-lead electrocardiogram measurements were performed, PK samples were collected, and vital signs were measured. Adverse event monitoring and safety laboratory testing were performed. All subjects were white (mean age, 39 years; body mass index [BMI], 25.6 kg/m(2)) and completed the study. Following LRV administration, the upper bound of the 90% confidence interval (CI) for time-matched adjusted mean differences to placebo QTcF at each time point postdose was below the regulatory threshold of 10 ms, satisfying the criteria for a negative thorough QT/QTc study. The highest upper bound of QTcF 90% CI occurred at 6 h for LRV (3.32 ms; 90% CI, 1.47 to 5.17 ms). The study was deemed adequately sensitive as the lower bound of the 90% CI for the adjusted mean QTcF differences between moxifloxacin and placebo at the moxifloxacin historical T(max) of 3 h was >5 ms (15.29 ms; 90% CI, 13.44 to 17.14 ms). There was no statistically significant relationship between LRV exposure and placebo-adjusted change from baseline QTcF or clinically significant changes in QRS complex, pulse rate (PR) interval, heart rate, or blood pressure. LRV (2,400 mg) did not prolong the QTcF interval, and no clinically relevant electrocardiogram or vital sign changes were observed in healthy subjects.

A phase I QTc study of tivozanib in patients with advanced solid tumors.

445 Background: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors-1, -2, and -3 that is currently being tested in a Phase III study in patients with renal cell carcinoma and Phase I/II studies of other solid tumors. Preclinical and retrospective electrocardiogram (ECG) analyses suggest no effect of tivozanib on QTc, although this has not been prospectively assessed according to ICH E14 Cardiac Assessment of New Drugs Guidelines. This open-label, non-randomized, single-arm study prospectively investigated the effect of tivozanib on the QTcF interval and its morphology on the ECG and ECG-pharmacokinetic (PK) relationship in patients with advanced solid tumors. Methods: Patients with advanced solid tumors, an ECOG score ≤1 and life expectancy ≥3 months were eligible. Patients received 1.5 mg of tivozanib orally, once daily for 21 days. Serial blood samples and time-matched, triplicate, 12-lead ECGs were collected on: Day 1 20-30 minutes pre-dose (no blood sample collected), immediately pre-dose, and at 2.5, 4, 5, 6, 8, and 10 hours post dose; Day 2 pre-dose evaluation was taken approximately 24 hours post Day 1 dose; Day 8 (±1 day) pre-dose, and at 2.5, 5, and 8 hours post dose; Day 21 pre-dose and at 2.5, 4, 5, 6, 8, and 10 hours post dose; and Day 22 at approximately 24 hours post Day 21 dose. Additional safety parameters were evaluated by assessing clinical laboratory tests, physical examinations, vital signs, and recording of adverse events. Results: Fifty patients with advanced solid tumors (males, 17; median age, 63 years; 94% white) who received ≥ 1 dose of tivozanib were evaluable. Preliminary data showed that there were no clinically significant changes in QTcF from baseline. Further analysis will be completed, and final safety and ECG-PK modeling will be presented. Conclusions: Preliminary data suggest that tivozanib 1.5 mg/d over a 21-day period does not cause clinically significant QT/QTc prolongation over baseline, suggesting that its safety and PK profile is similar to that observed in previous studies, including ECG evaluation in a monkey telemetry study.