Allongement du temps QT
Événements indésirables médicamenteux
|Démangeaison de la peau|
Variantes ✨Pour une évaluation intensive des variantes par ordinateur, veuillez choisir l'abonnement standard payant.
Explications concernant les substances pour les patients
Nous n'avons pas de mise en garde supplémentaire concernant l'association de abarelix et de nilotinib. Veuillez également consulter les informations pertinentes des spécialistes.
Les changements d'exposition rapportés correspondent aux changements de la courbe concentration-temps plasmatique [ AUC ]. Nous ne prévoyons aucun changement dans l'exposition à la abarelix, lorsqu'il est associé à la nilotinib (100%). Nous ne prévoyons aucun changement dans l'exposition à la nilotinib, lorsqu'il est associé à la abarelix (100%).
Les paramètres pharmacocinétiques de la population moyenne sont utilisés comme point de départ pour calculer les changements individuels d'exposition dus aux interactions.
La biodisponibilité de la abarelix est inconnue. La demi-vie terminale [ t12 ] est assez longue (jusqu'à 316.8 heures) et des taux plasmatiques constants [ Css ] ne sont atteints qu'après plus de 1267.2 heures. La liaison aux protéines [ Pb ] est 100 % forte. Le métabolisme via les cytochromes est actuellement encore en cours d'études.
La nilotinib a une faible biodisponibilité orale [ F ] de 100 %, c'est pourquoi la concentration plasmatique maximale [Cmax] a tendance à changer fortement avec une interaction. La demi-vie terminale [ t12 ] est de 16 heures et des taux plasmatiques constants [ Css ] sont atteints après environ 64 heures. La liaison aux protéines [ Pb ] est 100 % forte. Le métabolisme se fait principalement via CYP3A4 et le transport actif s'effectue notamment via PGP.
|Effets sérotoninergiques a||0||Ø||Ø|
Note: À notre connaissance, ni la abarelix ni la nilotinib n'augmentent l'activité sérotoninergique.
|Kiesel & Durán b||0||Ø||Ø|
Notation: À notre connaissance, ni la abarelix ni la nilotinib n'augmentent l'activité anticholinergique.
Allongement du temps QT
Note: En association, la abarelix et la nilotinib peuvent potentiellement déclencher des arythmies ventriculaires de type torsades de pointes.
Effets indésirables généraux
|Effets secondaires||∑ fréquence||aba||nil|
|Démangeaison de la peau||37.0 %||n.a.||37.0|
|La nausée||29.5 %||n.a.||29.5|
|Lipase élevée||28.0 %||n.a.||28.0|
|Mal de crâne||27.5 %||n.a.||27.5|
|La diarrhée||23.5 %||n.a.||23.5|
Constipation (23%): nilotinib
Vomissements (22%): nilotinib
Douleur abdominale (15.5%): nilotinib
Hémorragie gastro-intestinale (4%): nilotinib
Toux (22%): nilotinib
Rhinopharyngite (21%): nilotinib
Pneumonie (9.9%): nilotinib
Arthralgie (21%): nilotinib
Myalgie (17.5%): nilotinib
Faiblesse musculaire (5.5%): nilotinib
Sueurs nocturnes (19.5%): nilotinib
Alopécie (12%): nilotinib
Anémie (15.5%): nilotinib
Leucopénie (5.5%): nilotinib
Neutropénie (5.5%): nilotinib
Hémorragie (1.4%): nilotinib
Hypophosphatémie (12.5%): nilotinib
Hypokaliémie (9%): nilotinib
Hyponatrémie (4%): nilotinib
Œdème périphérique (12%): nilotinib
Infarctus du myocarde: nilotinib
Asthénie (11.5%): nilotinib
Hémorragie intracrânienne (5.5%): nilotinib
Accident vasculaire cérébral: nilotinib
Accident ischémique transitoire: nilotinib
Hyperglycémie (9%): nilotinib
Hypertriglycéridémie (5.5%): nilotinib
Hyperbilirubinémie (6.5%): nilotinib
ALT élevé (4%): nilotinib
AST élevé (2%): nilotinib
Phosphatase alcaline élevée: nilotinib
Sur la base de vos réponses et des informations scientifiques, nous évaluons le risque individuel d'effets secondaires indésirables. Ces recommandations sont destinées à conseiller les professionnels et ne se substituent pas à la consultation d'un médecin. Dans la version d'essai (alpha), le risque de toutes les substances n'a pas encore été évalué de manière concluante.
Abstract: Nilotinib (Tasigna; Novartis Pharmaceuticals) is a second-generation BCR-ABL tyrosine kinase inhibitor newly approved for the treatment of imatinib-resistant or imatinib-intolerant Philadelphia chromosome positive (Ph+) chronic myeloid leukemia in chronic phase or accelerated phase. This study evaluated the effect of grapefruit juice on the pharmacokinetics of nilotinib in 21 healthy male participants. All participants underwent 2 study periods during which they received a single oral dose of 400 mg nilotinib with 240 mL double-strength grapefruit juice or 240 mL water in a crossover fashion. Serial blood samples were collected for the determination of serum nilotinib concentrations by a validated liquid chromatography/tandem mass spectrometry assay. Concurrent intake of grapefruit juice increased the nilotinib peak concentration (C(max)) by 60% and the area under the serum concentration-time curve (AUC(0-infinity)) by 29% but did not affect the time to reach C(max) or the elimination half-life of nilotinib. The most common adverse events were headache and vomiting, which were mild or moderate in severity, and their frequency appeared to be similar between 2 treatments. Based on the currently available information about nilotinib and the observed extent of increase in nilotinib exposure, concurrent administration of nilotinib with grapefruit juice is not recommended.
Abstract: Nilotinib (Tasigna), an orally bioavailable second-generation BCR-ABL tyrosine kinase inhibitor, is approved for use in patients with chronic myeloid leukemia in chronic phase and accelerated phase who are resistant or intolerant to prior therapy, including imatinib. Previous in vitro studies indicated that nilotinib metabolism is primarily mediated by CYP3A4. To investigate the effect of CYP3A4 induction and inhibition on nilotinib pharmacokinetics, 2 studies were conducted in healthy volunteers prior to and following treatment with a strong inducer (rifampin) or inhibitor (ketoconazole). In the induction study, administration of rifampin 600 mg once daily for 8 days significantly increased urinary 6β-hydroxycortisol/ cortisol ratio, from a preinduction baseline of 5.8 ± 2.7 to 18.0 ± 10.2 after 8 days of rifampin treatment, confirming an inductive effect on CYP3A4. Nilotinib oral clearance was increased by 4.8-fold, and the maximum serum concentration (C(max)) and area under the serum concentration-time curve (AUC) were decreased by 64% and 80%, respectively, in the induced state compared with baseline. In the inhibition study, ketoconazole 400 mg once daily for 6 days increased the C(max) and AUC of nilotinib by 1.8- and 3-fold, respectively, compared with nilotinib alone. These results indicate that concurrent use of strong CYP3A4 inducers or inhibitors may necessitate dosage adjustments of nilotinib and should be avoided when possible.
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.
Abstract: In adult patients, nilotinib is indicated for chronic myeloid leukemia at an approved oral dose of 300 or 400 mg BID. Physiologically based pharmacokinetic (PBPK) model was developed to describe and supplement limited PK data in the pediatric population ranging from 2 to less than 6 years of age and ultimately inform dosing regimen. An adult Simcyp PBPK model was established and verified with clinical pharmacokinetic data after a single or multiple oral doses of 400 mg nilotinib (230 mg/m). The model was then applied to a pediatric PBPK model, taking account of ontogeny profiles of metabolizing enzymes and pediatric physiological parameters. The model was further verified using observed pediatric PK data in 12- to <18-year-old and from 6- to <12-year-old patients. The PBPK models were able to recover, describe, and supplement the limited nilotinib concentration-time data profile in 2- to <6-year-old patients after a single dose and Cafter BID dosing. The exposure (C, C, and AUC) was predicted to be similar across age groups. PBPK model simulations confirmed that body surface area-normalized dosing regimen of 230 mg/mis considered appropriate for pediatric patients >2 to <18 years of age.