QT time prolongation
Adverse drug events
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Explanations of the substances for patients
We have no additional warnings for the combination of vorinostat and abarelix. Please also consult the relevant specialist information.
The reported changes in exposure correspond to the changes in the plasma concentration-time curve [ AUC ]. We do not expect any change in exposure for vorinostat, when combined with abarelix (100%). We do not expect any change in exposure for abarelix, when combined with vorinostat (100%).
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
The bioavailability, half-life, and volume of distribution of vorinostat are unknown to us.
The bioavailability of abarelix is unknown. The terminal half-life [ t12 ] is rather long at 316.8 hours and constant plasma levels [ Css ] are only reached after more than 1267.2 hours. The protein binding [ Pb ] is 97.5% strong. The metabolism via cytochromes is currently still being worked on.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither vorinostat nor abarelix increase serotonergic activity.
|Kiesel & Durán b||0||Ø||Ø|
Rating: According to our knowledge, neither vorinostat nor abarelix increase anticholinergic activity.
QT time prolongation
Rating: In combination, vorinostat and abarelix can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||vor||aba|
|Taste sense altered||27.9 %||27.9||n.a.|
|Loss of appetite||24.4 %||24.4||n.a.|
|Weight loss||20.9 %||20.9||n.a.|
|Pulmonary embolism||4.7 %||4.7||n.a.|
|Squamous cell carcinoma||3.5 %||3.5||n.a.|
Myocardial infarction: vorinostat
Gastrointestinal hemorrhage: vorinostat
Cerebrovascular accident: vorinostat
Based on your answers and scientific information, we assess the individual risk of undesirable side effects. These recommendations are intended to advise professionals and are not a substitute for consultation with a doctor. In the restricted test version (alpha), the risk of all substances has not yet been conclusively assessed.
Abstract: PURPOSE: This dedicated QTc phase I study, conducted in advanced-stage cancer patients, assessed the effect of a single supratherapeutic dose (800 mg) of vorinostat on the QTc interval. EXPERIMENTAL DESIGN: A randomized, partially blind, placebo-controlled, two-period, crossover study was conducted. Patients (n = 25) received single doses of 800 mg vorinostat and placebo in the fasted state. Holter electrocardiogram monitoring was done before each treatment and for 24 h postdose. Blood samples for vorinostat concentration were collected through 24 h postdose following vorinostat treatment only. Prescribed electrocardiogram and blood sampling times were designed to capture the expected C(max) of vorinostat. RESULTS: Twenty-four of the 25 patients enrolled in the study were included in the QTc analysis. The upper bound of the two-sided 90% confidence interval for the QTcF interval for the placebo-adjusted mean change from baseline of vorinostat was <10 ms at every time point. No patient had a QTcF change from baseline value >30 ms. One patient had QTcF values >450 ms (seen after both vorinostat and placebo administration) and none had values >480 ms. Mean AUC(0-infinity) and C(max) values attained were on the order of approximately 1.93- and approximately 1.41-fold higher, respectively, compared with the 400 mg clinical dose. Based on assessment of clinical and laboratory adverse experiences, single doses of 800 mg vorinostat were generally well tolerated. CONCLUSIONS: Administration of a single supratherapeutic dose of the histone deacetylase inhibitor vorinostat is not associated with prolongation of the QTc interval. A dedicated QTc study in advanced cancer patients is a robust means for assessing risk for ventricular repolarization prolongation.
Abstract: Vorinostat is a histone deacetylase inhibitor used in the treatment of recurrent or persistent cases of cutaneous T-cell lymphoma (CTCL). A retrospective review of 116 patients from phase I and II clinical trials who had a baseline and at least one subsequent ECG revealed that four patients had Grade 2 and one patient had Grade 3 QTc interval prolongation; however, a MEDLINE search found no reported cases of torsades de pointes (TdP) in patients treated with vorinostat. We describe the case of a 49 year-old male with a history of CTCL actively undergoing treatment with vorinostat. During day 1 of hospitalization, he developed a pulseless polymorphic ventricular tachycardia requiring resuscitation. He was found to have a QTc of 826 ms. Following correction of potassium and magnesium, QTc gradually decreased and no further ventricular arrhythmia was noted. Other factors implicated in this case included concurrent sertraline and doxepin therapy (both drugs have been associated with the development of TdP in overdose). The mechanism of development of TdP in this patient is postulated to be related to vorinostat use in combination with hypokalemia and concomitant treatment with medications associated with QTc prolongation. This case highlights the importance of post-market surveillance.