Extension de temps QT
Effets indésirables des médicaments
Variantes ✨Pour l'évaluation intensive en calcul des variantes, veuillez choisir l'abonnement standard payant.
Explications pour les patients
Nous n'avons aucun avertissement supplémentaire pour l'association de pazopanib et de cimétidine. Veuillez également consulter les informations spécialisées pertinentes.
Les changements d'exposition mentionnés sont liés aux changements de la courbe concentration plasmatique en fonction du temps [ASC]. Nous n'avons détecté aucune modification de l'exposition à la pazopanib. Nous ne pouvons actuellement pas estimer l'influence de la cimétidine. Nous ne prévoyons aucun changement d'exposition à la cimétidine, lorsqu'il est combiné avec la pazopanib (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 pazopanib a une faible biodisponibilité orale [ F ] de 18%, c'est pourquoi la concentration plasmatique maximale [Cmax] a tendance à changer de manière significative avec une interaction. La demi-vie terminale [ t12 ] est assez longue à 31.4 heures et des taux plasmatiques constants [ Css ] ne sont atteints qu’après plus de 125.6 heures. La liaison aux protéines [ Pb ] est très forte à 99.5%. Le métabolisme a lieu via le CYP1A2, CYP2C8 et le CYP3A4, entre autres.
La cimétidine a une biodisponibilité orale moyenne [ F ] de 65%, raison pour laquelle les concentrations plasmatiques maximales [Cmax] ont tendance à changer avec une interaction. La demi-vie terminale [ t12 ] est assez courte à 1.6333333 heures et des taux plasmatiques constants [ Css ] sont atteints rapidement. La liaison aux protéines [ Pb ] est très faible à 19% et le volume de distribution [ Vd ] est très important à 91 litres. Le métabolisme ne se fait pas via les cytochromes communs et le transport actif s'effectue en partie via BCRP et PGP.
|Les scores||∑ Points||paz||cim|
|Effets sérotoninergiques a||0||Ø||Ø|
Évaluation: Selon nos connaissances, ni la pazopanib ni la cimétidine n'augmentent l'activité sérotoninergique.
|Les scores||∑ Points||paz||cim|
|Kiesel & Durán b||1||Ø||+|
Recommandation: Par mesure de précaution, une attention particulière doit être portée aux symptômes anticholinergiques, en particulier après augmentation de la dose et à des doses dans l'intervalle thérapeutique supérieur.
Évaluation: La cimétidine n'a qu'un effet léger sur le système anticholinergique. Le risque de syndrome anticholinergique avec ce médicament est plutôt faible si la posologie se situe dans la plage habituelle. Selon nos résultats, la pazopanib n'augmente pas l'activité anticholinergique.
Extension de temps QT
|Les scores||∑ Points||paz||cim|
Évaluation: En association, la pazopanib et la cimétidine peuvent potentiellement déclencher des arythmies ventriculaires de type torsades de pointes.
Effets secondaires généraux
|Effets secondaires||∑ la fréquence||paz||cim|
|La diarrhée||55.5 %||55.5||n.a.|
|Phosphatase alcaline élevée||32.0 %||32.0||n.a.|
|Douleur musculo-squelettique||23.0 %||23.0||n.a.|
|Perte d'appétit||22.0 %||22.0||n.a.|
Dyspnée (20%): pazopanib
Hémorragie (17.5%): pazopanib
Mal de crâne (16.5%): pazopanib
Accident ischémique transitoire: pazopanib
Accident vasculaire cérébral: pazopanib
Hypothyroïdie (5.5%): pazopanib
Gynécomastie (4%): cimétidine
Perte de poids: pazopanib
Thromboembolie veineuse (3%): pazopanib
Embolie pulmonaire: pazopanib
Hépatotoxicité (2%): pazopanib
ALT élevé: pazopanib
AST élevé: pazopanib
Pancréatite (1.1%): pazopanib, cimétidine
Hémorragie gastro-intestinale: pazopanib
La nausée: pazopanib
Insuffisance cardiaque: pazopanib
Crise d'hypertension: pazopanib
Sur la base de vos
Abstract: Recently, the use of astemizole and terfenadine, both non-sedating H1-antihistamines, caused considerable concern. Several case reports suggested an association of both drugs with an increased risk of torsades de pointes, a special form of ventricular tachycardia. The increased risk of both H1-antihistamines was associated with exposure to supratherapeutic doses; for terfenadine the risk was also associated with concomitant exposure to the cytochrome P-450 inhibitors ketoconazole, erythromycin and cimetidine. To predict the size of the population that runs the risk of developing this potentially fatal adverse reaction in the Netherlands, the prevalence of prescribing supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was studied. Data were obtained from the PHARMO data base in 1990, a pharmacy-based record linkage system encompassing a catchment population of 300,000 individuals. The results of the study showed that the prescribing of supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was low. Furthermore, the results of a sensitivity analysis showed that the risk of fatal torsades de pointes has to be as high as 1 in 10,000 to cause one death in the Netherlands in one year.
Abstract: Astemizole (Hismanal), an antihistamine agent, has been reported to be associated with ventricular arrhythmias. In this paper we present a case of QT prolongation and torsades de pointes (TdP) in a 77-year-old woman who had been taking astemizole (10 mg/day) for 6 months because of allergic skin disease. At the time of admission, the serum concentration of astemizole and its metabolites was markedly elevated at 15.85 ng/ml, approximately 3 times the normal level. The patient was also taking cimetidine, a known inhibitor of cytochrome P-450 enzymatic activity, and during her admission was diagnosed as having vasospastic angina. To the best of our knowledge, this is the first report of astemizole-induced QT prolongation and TdP in Japan.
Abstract: Renal drug interactions can result from competitive inhibition between drugs that undergo extensive renal tubular secretion by transporters such as P-glycoprotein (P-gp). The purpose of this study was to evaluate the effect of itraconazole, a known P-gp inhibitor, on the renal tubular secretion of cimetidine in healthy volunteers who received intravenous cimetidine alone and following 3 days of oral itraconazole (400 mg/day) administration. Glomerular filtration rate (GFR) was measured continuously during each study visit using iothalamate clearance. Iothalamate, cimetidine, and itraconazole concentrations in plasma and urine were determined using high-performance liquid chromatography/ultraviolet (HPLC/UV) methods. Renal tubular secretion (CL(sec)) of cimetidine was calculated as the difference between renal clearance (CL(r)) and GFR (CL(ioth)) on days 1 and 5. Cimetidine pharmacokinetic estimates were obtained for total clearance (CL(T)), volume of distribution (Vd), elimination rate constant (K(el)), area under the plasma concentration-time curve (AUC(0-240 min)), and average plasma concentration (Cp(ave)) before and after itraconazole administration. Plasma itraconazole concentrations following oral dosing ranged from 0.41 to 0.92 microg/mL. The cimetidine AUC(0-240 min) increased by 25% (p < 0.01) following itraconazole administration. The GFR and Vd remained unchanged, but significant reductions in CL(T) (655 vs. 486 mL/min, p < 0.001) and CL(sec) (410 vs. 311 mL/min, p = 0.001) were observed. The increased systemic exposure of cimetidine during coadministration with itraconazole was likely due to inhibition of P-gp-mediated renal tubular secretion. Further evaluation of renal P-gp-modulating drugs such as itraconazole that may alter the renal excretion of coadministered drugs is warranted.
Abstract: Anticholinergic Drug Scale (ADS) scores were previously associated with serum anticholinergic activity (SAA) in a pilot study. To replicate these results, the association between ADS scores and SAA was determined using simple linear regression in subjects from a study of delirium in 201 long-term care facility residents who were not included in the pilot study. Simple and multiple linear regression models were then used to determine whether the ADS could be modified to more effectively predict SAA in all 297 subjects. In the replication analysis, ADS scores were significantly associated with SAA (R2 = .0947, P < .0001). In the modification analysis, each model significantly predicted SAA, including ADS scores (R2 = .0741, P < .0001). The modifications examined did not appear useful in optimizing the ADS. This study replicated findings on the association of the ADS with SAA. Future work will determine whether the ADS is clinically useful for preventing anticholinergic adverse effects.
Abstract: BACKGROUND: Adverse effects of anticholinergic medications may contribute to events such as falls, delirium, and cognitive impairment in older patients. To further assess this risk, we developed the Anticholinergic Risk Scale (ARS), a ranked categorical list of commonly prescribed medications with anticholinergic potential. The objective of this study was to determine if the ARS score could be used to predict the risk of anticholinergic adverse effects in a geriatric evaluation and management (GEM) cohort and in a primary care cohort. METHODS: Medical records of 132 GEM patients were reviewed retrospectively for medications included on the ARS and their resultant possible anticholinergic adverse effects. Prospectively, we enrolled 117 patients, 65 years or older, in primary care clinics; performed medication reconciliation; and asked about anticholinergic adverse effects. The relationship between the ARS score and the risk of anticholinergic adverse effects was assessed using Poisson regression analysis. RESULTS: Higher ARS scores were associated with increased risk of anticholinergic adverse effects in the GEM cohort (crude relative risk [RR], 1.5; 95% confidence interval [CI], 1.3-1.8) and in the primary care cohort (crude RR, 1.9; 95% CI, 1.5-2.4). After adjustment for age and the number of medications, higher ARS scores increased the risk of anticholinergic adverse effects in the GEM cohort (adjusted RR, 1.3; 95% CI, 1.1-1.6; c statistic, 0.74) and in the primary care cohort (adjusted RR, 1.9; 95% CI, 1.5-2.5; c statistic, 0.77). CONCLUSION: Higher ARS scores are associated with statistically significantly increased risk of anticholinergic adverse effects in older patients.
Abstract: BACKGROUND: Multi-targeted vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are known to cause cardiac toxicity, but the relative risk (RR) of QTc interval prolongation and serious arrhythmias associated with them are not reported. METHODS: We conducted a trial-level meta-analysis of randomised phase II and III trials comparing arms with and without a US Food and Drug Administration-approved VEGFR TKI (sunitinib, sorafenib, pazopanib, axitinib, vandetanib, cabozantinib, ponatinib and regorafenib). A total of 6548 patients from 18 trials were selected. Statistical analyses were conducted to calculate the summary incidence, RR and 95% CIs. RESULTS: The RR for all-grade and high-grade QTc prolongation for the TKI vs no TKI arms was 8.66 (95% CI 4.92-15.2, P<0.001) and 2.69 (95% CI 1.33-5.44, P=0.006), respectively, with most of the events being asymptomatic QTc prolongation. Respectively, 4.4% and 0.83% of patients exposed to VEGFR TKI had all-grade and high-grade QTc prolongation. On subgroup analysis, only sunitinib and vandetanib were associated with a statistically significant risk of QTc prolongation, with higher doses of vandetanib associated with a greater risk. The rate of serious arrhythmias including torsades de pointes did not seem to be higher with high-grade QTc prolongation. The risk of QTc prolongation was independent of the duration of therapy. CONCLUSIONS: In the largest study to date, we show that VEGFR TKI can be associated with QTc prolongation. Although most cases were of low clinical significance, it is unclear whether the same applies to patients treated off clinical trials.
Abstract: BACKGROUND: Tyrosine kinase inhibitors (TKIs) are associated with prolongation of the QTc interval on the electrocardiogram (ECG). The QTc-interval prolongation increases the risk of life-threatening arrhythmias. However, studies evaluating the effects of TKIs on QTc intervals are limited and only consist of small patient numbers. METHODS: In this multicentre trial in four centres in the Netherlands and Italy we screened all patients who were treated with any TKI. To evaluate the effects of TKIs on the QTc interval, we investigated ECGs before and during treatment with erlotinib, gefitinib, imatinib, lapatinib, pazopanib, sorafenib, sunitinib, or vemurafenib. RESULTS: A total of 363 patients were eligible for the analyses. At baseline measurement, QTc intervals were significantly longer in females than in males (QTcfemales=404 ms vs QTcmales=399 ms, P=0.027). A statistically significant increase was observed for the individual TKIs sunitinib, vemurafenib, sorafenib, imatinib, and erlotinib, after the start of treatment (median ΔQTc ranging from +7 to +24 ms, P<0.004). The CTCAE grade for QTc intervals significantly increased after start of treatment (P=0.0003). Especially patients who are treated with vemurafenib are at increased risk of developing a QTc of ⩾470 ms, a threshold associated with an increased risk for arrhythmias. CONCLUSIONS: These observations show that most TKIs significantly increase the QTc interval. Particularly in vemurafenib-treated patients, the incidence of patients at risk for arrhythmias is increased. Therefore, especially in case of combined risk factors, ECG monitoring in patients treated with TKIs is strongly recommended.
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.