QT time prolongation
Adverse drug events
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Nilotinib is used to treat Philadelphia chromosome positive chronic myeloid leukemia (Ph + CML). In this blood cancer, the bone marrow produces too many granulocyte-type white blood cells. It is taken orally as a capsule. Nilotinib is an anti-tumor agent from the group of tyrosine kinase inhibitors. It mainly inhibits the BCR-ABL kinase. This is involved in cell reproduction and growth. If it is suppressed, the cancer-modified blood cells die. Common undesirable effects mentioned include nausea, vomiting, diarrhea, headache, changes in the blood count and blood values, infections and skin rashes.
The warnings are checked for the combination of several active substances. For the individual substances, please consult the relevant specialist information.
Since only nilotinib was entered without any further substances, no pharmacokinetic interaction can be detected.
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Nilotinib has a low oral bioavailability [ F ] of 30%, which is why the maximum plasma level [Cmax] tends to change strongly with an interaction. The terminal half-life [ t12 ] is 16 hours and constant plasma levels [ Css ] are reached after approximately 64 hours. The protein binding [ Pb ] is 98% strong. The metabolism mainly takes place via CYP3A4 and the active transport takes place in particular via PGP.
|Serotonergic Effects a||0||Ø|
Rating: According to our knowledge, nilotinib does not increase serotonergic activity.
|Kiesel & Durán b||0||Ø|
Rating: According to our knowledge, nilotinib does not increase anticholinergic activity.
QT time prolongation
Nilotinib can potentially increase QT time, but we do not know about torsades de pointes arrhythmias.
General adverse effects
|Side effects||∑ frequency||nil|
|Elevated lipase||28.0 %||28.0|
Constipation (23%): nilotinib
Vomiting (22%): nilotinib
Abdominal pain (15.5%): nilotinib
Gastrointestinal hemorrhage (4%): nilotinib
Cough (22%): nilotinib
Nasopharyngitis (21%): nilotinib
Pneumonia (9.9%): nilotinib
Arthralgia (21%): nilotinib
Myalgia (17.5%): nilotinib
Muscle weakness (5.5%): nilotinib
Night sweats (19.5%): nilotinib
Alopecia (12%): nilotinib
Anemia (15.5%): nilotinib
Leukopenia (5.5%): nilotinib
Neutropenia (5.5%): nilotinib
Hemorrhage (1.4%): nilotinib
Hypophosphatemia (12.5%): nilotinib
Hypokalemia (9%): nilotinib
Hyponatremia (4%): nilotinib
Peripheral edema (12%): nilotinib
Myocardial infarction: nilotinib
Asthenia (11.5%): nilotinib
Intracranial hemorrhage (5.5%): nilotinib
Cerebrovascular accident: nilotinib
Transient ischemic attack: nilotinib
Hyperglycemia (9%): nilotinib
Hypertriglyceridemia (5.5%): nilotinib
Hyperbilirubinemia (6.5%): nilotinib
Elevated ALT (4%): nilotinib
Elevated AST (2%): nilotinib
Elevated alkaline phosphatase: nilotinib
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: The development of tyrosine kinase inhibitors (TKI) represents a major milestone in oncology. However, their use has been found to be associated with serious toxicities that impinge on various vital organs including the heart. Sixteen TKIs have been approved for use in oncology as of 30 September 2012, and a large number of others are in development or under regulatory review. Cardiovascular safety of medicinal products is a major public health issue that has concerned all the stakeholders. This review focuses on three specific cardiovascular safety aspects of TKIs, namely their propensity to induce QT interval prolongation, left ventricular (LV) dysfunction and hypertension (both systemic and pulmonary). Analyses of information in drug labels, the data submitted to the regulatory authorities and the published literature show that a number of TKIs are associated with these undesirable effects. Whereas LV dysfunction and systemic hypertension are on-target effects related to the inhibition of ligand-related signalling pathways, QT interval prolongation appears to be an off-target class III electrophysiologic effect, possibly related to the presence of a fluorine-based pharmacophore. If not adequately managed, these cardiovascular effects significantly increase the morbidity and mortality in a population already at high risk. Hitherto, the QT effect of most QT-prolonging TKIs (except lapatinib, nilotinib, sunitinib and vandetanib) is relatively mild at clinical doses and has not led to appreciable morbidity clinically. In contrast, LV dysfunction and untreated hypertension have resulted in significant morbidity. Inevitably, dilemmas arise in determining the risk/benefit of a TKI therapy in an individual patient who develops any of these effects following the treatment of the TKI-sensitive cancer. QT interval prolongation, hypertension and LV dysfunction can be managed effectively by using reliable methods of measurement and careful monitoring of patients whose clinical management requires optimisation by a close collaboration between an oncologist and a cardiologist, an evolving subspecialty referred to as cardio-oncology. Despite their potential adverse clinical impact, the effects of TKIs on hypertension and LV function are generally inadequately characterised during their development. As has been the case with QT liability of drugs, there is now a persuasive case for a regulatory requirement to study TKIs systematically for these effects. Furthermore, since most of these novel drugs are studied in trials with relatively small sample sizes and approved on an expedited basis, there is also a compelling case for their effective pharmacovigilance and on-going reassessment of their risk/benefit after approval.
Abstract: Crizotinib (Xalkori®) and nilotinib (Tasigna®) are tyrosine kinase inhibitors approved for the treatment of non-small cell lung cancer and chronic myeloid leukemia, respectively. Both have been shown to result in electrocardiogram rate-corrected Q-wave T-wave interval (QTc) prolongation in humans and animals. Liposomes have been shown to ameliorate drug-induced effects on the cardiac-delayed rectifier K(+) current (IKr, KV11.1), coded by the human ether-a-go-go-related gene (hERG). This study was undertaken to determine if liposomes would also decrease the effect of crizotinib and nilotinib on the IKr channel. Crizotinib and nilotinib were tested in an in vitro IKr assay using human embryonic kidney (HEK) 293 cells stably transfected with the hERG. Dose-responses were determined and the 50% inhibitory concentrations (IC50s) were calculated. When the HEK 293 cells were treated with crizotinib or nilotinib that were mixed with liposomes, there was a significant decrease in the IKr channel inhibitory effects of these two drugs. When isolated, rabbit hearts were exposed to crizotinib or nilotinib, there were significant increases in QTc prolongation. Mixing either of the drugs with liposomes ameliorated the effects of the drugs. Rabbits dosed intravenously (IV) with crizotinib or nilotinib showed QTc prolongation. When liposomes were injected prior to crizotinib or nilotinib, the liposomes decreased the effects on the QTc interval. The use of liposomal encapsulated QT-prolongation agents, or giving liposomes in combination with drugs, may decrease their cardiac liability.
Abstract: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.