Allongement du temps QT
Événements indésirables médicamenteux
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 astémizole et de mirabegron. Veuillez également consulter les informations pertinentes des spécialistes.
Les changements d'exposition rapportés correspondent aux changements de la courbe concentration-temps plasmatique [ AUC ]. Nous n'avons détecté aucun changement dans l'exposition à la astémizole. Nous ne pouvons actuellement pas estimer l'influence de la mirabegron. Nous n'avons détecté aucun changement dans l'exposition à la mirabegron. Nous ne pouvons actuellement pas estimer l'influence de la astémizole.
Les paramètres pharmacocinétiques de la population moyenne sont utilisés comme point de départ pour calculer les changements individuels d'exposition dus aux interactions.
La astémizole 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 22 heures et des taux plasmatiques constants [ Css ] sont atteints après environ 88 heures. La liaison aux protéines [ Pb ] est 100 % forte. Le métabolisme a lieu via CYP2D6 et CYP3A4, entre autres.
La mirabegron 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 assez longue (jusqu'à 51 heures) et des taux plasmatiques constants [ Css ] ne sont atteints qu'après plus de 204 heures. La liaison aux protéines [ Pb ] est modérément forte à 71% et le volume de distribution [ Vd ] est très grand à 1670 litres, c'est pourquoi, avec un taux d'extraction hépatique moyen de 0,9, le débit sanguin hépatique [Q] et une modification de la liaison aux protéines [Pb] sont pertinents. Le métabolisme a lieu via CYP2D6 et CYP3A4, entre autres et le transport actif s'effectue en partie via OATP1A2 et PGP.
|Effets sérotoninergiques a||0||Ø||Ø|
Note: À notre connaissance, ni la astémizole ni la mirabegron n'augmentent l'activité sérotoninergique.
|Kiesel & Durán b||0||Ø||Ø|
Notation: À notre connaissance, ni la astémizole ni la mirabegron n'augmentent l'activité anticholinergique.
Allongement du temps QT
Note: En association, la astémizole et la mirabegron peuvent potentiellement déclencher des arythmies ventriculaires de type torsades de pointes.
Effets indésirables généraux
|Effets secondaires||∑ fréquence||ast||mir|
|Infection urinaire||5.7 %||n.a.||5.7|
|Mal de crâne||2.9 %||n.a.||2.9|
|Accident vasculaire cérébral||0.4 %||n.a.||0.4|
|Rétention urinaire||0.0 %||n.a.||0.01|
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: Astemizole is a long-acting, highly selective histamine1-receptor antagonist with minimal central and anticholinergic effects. Comparison studies have shown astemizole to be equal or superior to currently available antihistamines, beclomethasone nasal spray, and cromolyn sodium in relieving allergic symptoms of seasonal and perennial allergic rhinitis. Other uses include treatment of allergic conjunctivitis and chronic urticaria. Astemizole is not as effective for treatment of acute allergic symptoms because of its delayed onset of action. Astemizole and its active metabolite, desmethylastemizole, have long elimination half-lives permitting once-daily dosing. The incidence of sedation is lower than with conventional antihistamines, but increased appetite and weight gain do occur. Astemizole should be useful for both maintenance and prophylactic therapy in patients with chronic allergic conditions who cannot tolerate the sedative or anticholinergic effects of conventional antihistamines.
Abstract: Astemizole is an H1-histamine receptor antagonist with a long duration of action permitting once daily administration. Its efficacy in seasonal and perennial allergic rhinitis has been convincingly demonstrated, and several comparative studies suggest that astemizole is at least as effective as some other H1-histamine receptor antagonists. A few smaller studies have shown beneficial effects on the symptoms of allergic conjunctivitis and chronic urticaria (but not atopic dermatitis). While astemizole appears to share with other H1-histamine receptor antagonists a tendency to increase appetite and cause weight gain after prolonged use, it offers the important advantage of an absence of significant central nervous system depression or anticholinergic effects with usual doses. Thus, astemizole offers a worthwhile improvement in side effect profile over 'traditional' H1-histamine receptor antagonists, especially in patients bothered by the sedative effects of these drugs.
Abstract: An overdose of astemizole predisposes the myocardium to ventricular dysrhythmias, including torsades de pointes. Herein we describe a case of astemizole-induced torsades de pointes ventricular tachycardia and also review previous case reports in the literature. All the patients were young, and dysrhythmias developed only in those with corrected QT intervals greater than 500 ms. Although several mechanisms have been postulated, no clear explanation has been provided for why astemizole promotes myocardial dysrhythmias. Treatment of astemizole-induced torsades de pointes includes discontinuing use of astemizole, intravenous administration of magnesium sulfate and isoproterenol, temporary cardiac pacing, and, when necessary, direct current cardioversion. A cardiac cause of syncope or convulsions must not be overlooked, especially in patients taking H1 antagonists because they often have these symptoms before hospitalization or detection of torsades de pointes (or both).
Abstract: No Abstract available
Abstract: A 26 year-old woman was admitted to the hospital two hours after astemizole overdose. Electrocardiograph showed a prolonged QT interval. Torsade de pointes occurred 13 h after ingestion. Plasma levels of astemizole plus hydroxylated metabolites showed an apparent plasma half-life of 17 h. The possible occurrence of torsade de pointes in astemizole overdose, and the long elimination time of astemizole and hydroxylated metabolites, makes it necessary to maintain ECG monitoring until QT interval has returned to normal.
Abstract: AIMS: The aim of this study was to investigate the influence of chronic itraconazole treatment on the pharmacokinetics and cardiovascular effects of single dose astemizole in healthy subjects was studied. METHODS: Twelve male volunteers were taking orally 200 mg twice daily itraconazole or placebo for 14 days with a washout period of 4 weeks in between. Approximately 2 h after the morning dose of itraconazole or placebo on day 11, 10 mg astemizole was orally administered. The plasma concentrations of astemizole and desmethylastemizole were measured by radioimmunoassay up to 504 h after administration; electrocardiograms with analysis of the QTc interval were recorded up to 24 h post administration. RESULTS: Itraconazole treatment did not significantly change the peak concentration of astemizole (0.74 vs 0.81 ng ml-1) but it increased the area under the curve from 0 to 24 h (5.46 to 9.95 ng ml-1 h) and from 0 to infinity (17.4 to 48.2 ng ml-1 h), and the elimination half-life (2.1 to 3.6 days). The systemic bioavailability of desmethylastemizole was also increased. The QTc interval did not increase after astemizole administration and there was no difference in the QTc intervals between the itraconazole and placebo session. CONCLUSIONS: Chronic administration of itraconazole influences the metabolism of single dose astemizole in normal volunteers without changes of cardiac repolarization during the first 24 h after astemizole administration. However, the reduction in astemizole clearance under concomitant administration of itraconazole may result in a marked increase in astemizole plasma concentrations and QTc alterations during chronic combined intake of astemizole with itraconazole.
Abstract: Second-generation histamine H1 receptor antagonists (antihistamines) have been developed to reduce or eliminate the sedation and anticholinergic adverse effects that occur with older H1 receptor antagonists. This article evaluates second-generation antihistamines, including acrivastine, astemizole, azelastine, cetirizine, ebastine, fexofenadine, ketotifen, loratadine, mizolastine and terfenadine, for significant features that affect choice. In addition to their primary mechanism of antagonising histamine at the H1 receptor, these agents may act on other mediators of the allergic reaction. However, the clinical significance of activity beyond that mediated by histamine H1 receptor antagonism has yet to be demonstrated. Most of the agents reviewed are metabolised by the liver to active metabolites that play a significant role in their effect. Conditions that result in accumulation of astemizole, ebastine and terfenadine may prolong the QT interval and result in torsade de pointes. The remaining agents reviewed do not appear to have this risk. For allergic rhinitis, all agents are effective and the choice should be based on other factors. For urticaria, cetirizine and mizolastine demonstrate superior suppression of wheal and flare at the dosages recommended by the manufacturer. For atopic dermatitis, as adjunctive therapy to reduce pruritus, cetirizine, ketotifen and loratadine demonstrate efficacy. Although current evidence does not suggest a primary role for these agents in the management of asthma, it does support their use for asthmatic patients when there is coexisting allergic rhinitis, dermatitis or urticaria.
Abstract: AIMS: The aims of the present study were to investigate the metabolism of astemizole in human liver microsomes, to assess possible pharmacokinetic drug-interactions with astemizole and to compare its metabolism with terfenadine, a typical H1 receptor antagonist known to be metabolized predominantly by CYP3A4. METHODS: Astemizole or terfenadine were incubated with human liver microsomes or recombinant cytochromes P450 in the absence or presence of chemical inhibitors and antibodies. RESULTS: Troleandomycin, a CYP3A4 inhibitor, markedly reduced the oxidation of terfenadine (26% of controls) in human liver microsomes, but showed only a marginal inhibition on the oxidation of astemizole (81% of controls). Three metabolites of astemizole were detected in a liver microsomal system, i.e. desmethylastemizole (DES-AST), 6-hydroxyastemizole (6OH-AST) and norastemizole (NOR-AST) at the ratio of 7.4 : 2.8 : 1. Experiments with recombinant P450s and antibodies indicate a negligible role for CYP3A4 on the main metabolic route of astemizole, i.e. formation of DES-AST, although CYP3A4 may mediate the relatively minor metabolic routes to 6OH-AST and NOR-AST. Recombinant CYP2D6 catalysed the formation of 6OH-AST and DES-AST. Studies with human liver microsomes, however, suggest a major role for a mono P450 in DES-AST formation. CONCLUSIONS: In contrast to terfenadine, a minor role for CYP3A4 and involvement of multiple P450 isozymes are suggested in the metabolism of astemizole. These differences in P450 isozymes involved in the metabolism of astemizole and terfenadine may associate with distinct pharmacokinetic influences observed with coadministration of drugs metabolized by CYP3A4.
Abstract: BACKGROUND AND OBJECTIVES: Mirabegron is a potent and selective β3-adrenoceptor agonist in development for treatment of overactive bladder. METHODS: Mirabegron pharmacokinetics after single intravenous (i.v.) and oral doses, absolute bioavailability (F), dose proportionality, sex differences and tolerability were assessed in 2 single-dose, open-label, randomized, parallel-group, cross-over studies in healthy men (exploratory Study 1, n = 12) and men and women (Study 2, n = 91). RESULTS: After oral dosing (25 - 150 mg), peak plasma concentrations were attained after ~ 4 h. Mean half-life was around 40 h for both routes of administration. Volume of distribution at steady state was 1,670 l and total clearance was around 57 l/h for i.v. dosing. Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but exposure increased more than proportionally after oral dosing due to increased F (29% for 25 mg to 45% at 150 mg). About 20% of the (absorbed) dose was excreted unchanged into urine. Area under the curve (AUC) was 27% and 64% higher in females than males after i.v. and oral dosing respectively; differences were mostly attributed to body weight, and for oral dosing, also to F. CONCLUSIONS: Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but increased more than proportionally after oral dosing (25 - 150 mg) as a result of increased F. Sex differences in exposure could be explained by body weight and for oral dosing, also by F. Mirabegron was in general well tolerated up to the highest doses studied, 50 mg i.v. and 150 mg oral.
Abstract: Potential effects of the selective β(3)-adrenoceptor agonist mirabegron on cardiac repolarization were studied in healthy subjects. The four-arm, parallel, two-way crossover study was double-blind and placebo- and active (moxifloxacin)-controlled. After 2 baseline ECG days, subjects were randomized to one of eight treatment sequences (22 females and 22 males per sequence) of placebo crossed over with once-daily (10 days) 50, 100, or 200 mg mirabegron or a single 400-mg moxifloxacin dose on day 10. In each period, continuous ECGs were recorded at two baselines and on the last drug administration day. The lower one-sided 95% confidence interval for moxifloxacin effect on QTcI was >5 ms, demonstrating assay sensitivity. According to ICH E14 criteria, mirabegron did not cause QTcI prolongation at the 50-mg therapeutic and 100-mg supratherapeutic doses in either sex. Mirabegron prolonged QTcI interval at the 200-mg supratherapeutic dose (upper one-sided 95% CI >10 ms) in females, but not in males.
Abstract: BACKGROUND: Mirabegron is a β3-adrenoceptor agonist for the treatment of overactive bladder. There has been little information published or presented about the involvement of cytochrome P450 (CYP) isoenzymes 3A and 2D6 in the metabolism of mirabegron in humans; in vitro data indicate that oxidative metabolism is primarily mediated by CYP3A with a minor role for CYP2D6. OBJECTIVE: To determine to what extent CYP3A and CYP2D6 isoenzymes are involved in mirabegron metabolism. METHODS: Two open-label, randomized, one-sequence crossover drug-drug interaction studies in healthy subjects were conducted to assess the effect of ketoconazole and rifampicin on the pharmacokinetics of mirabegron and two parallel-group studies in healthy subjects with either known confirmed or predicted CYP2D6 phenotype. RESULTS: Co-administration of multiple dosages of 400 mg/day ketoconazole with a single 100 mg mirabegron oral controlled absorption system (OCAS) dose increased mirabegron maximum concentration (C(max)) and area under the curve extrapolated to infinity (AUC∞) to 145 % (90 % confidence interval [CI] 123-172 %] and 181 % (90 % CI 163-201 %), respectively. Co-administration of multiple dosages of 600 mg/day rifampicin with a single 100 mg mirabegron OCAS dose decreased mirabegron C max and AUC∞ to 65 % (90 % CI 50-86 %) and 56 % (90 % CI 49-65 %), respectively, without an effect on terminal elimination half-life (t(½)). The urinary excretion of mirabegron was increased by ketoconazole and decreased by rifampicin, reflecting the AUC changes, whereas renal clearance was not affected. Ketoconazole decreased mirabegron t ½ from 50.9 to 37.6 h suggesting that volume of distribution as well as first-pass effect decreased. Rifampicin did not affect mirabegron t ½, suggesting that it affects first pass through the intestinal wall or liver. Rifampicin greatly increased the ratio to parent drug of the presumed CYP-mediated mirabegron metabolites M8 and M15 by 777 and 646 %. Steady-state mirabegron pharmacokinetic parameters (50 and 100 mg mirabegron OCAS) were similar in 13 CYP2D6 poor, 40 intermediate, and 99 extensive metabolizers, whereas C max and AUC under the dosing interval τ of 24 h (AUCτ) were 30-47 % lower in 10 ultrarapid metabolizers. After administration of 160 mg mirabegron immediate release, C(max) was 14 % and AUC∞ 19 % higher in eight poor metabolizers than in eight extensive metabolizers (phenotyped) with similar t ½. All treatments were well tolerated. CONCLUSIONS: Mirabegron is metabolized by CYP3A and to a minor extent by CYP2D6 in humans. Mirabegron is not considered a sensitive substrate of CYP3A in vivo, as ketoconazole increased mirabegron exposure by less than 2-fold. The effect of CYP2D6 phenotype on mirabegron exposure is small and likely of limited clinical importance.
Abstract: INTRODUCTION: The Holter bin method evaluates QT interval changes in the presence of heart rate changes without correcting the QT interval. However, the method does not allow time-matched comparisons, thus contradicting available guidance and good practice. We report a modification of the methods that allows time-matched comparisons without any heart rate correction. METHODS AND RESULTS: The modified Holter bin method (a) finds matching baseline heart rates for each QT reading on treatment and (b) calculates ΔQT values from the QT intervals on baseline and on treatment that match in heart rates. The difference between ΔQT values on active treatment and placebo provides the ΔΔQT value. The method was compared with the individual correction method in the data of the mirabegron thorough QT study in which supratherapeutic doses of this β3-adrenoceptor agonist led to substantial heart rate changes. The modified Holter bin method reproduced closely the results obtained with the individual heart rate correction. At all time points of the mirabegron study, the differences between the mean ΔΔQT values by the Holter bin method and the individual correction method were below 1 millisecond. Compared to the individual correction, the Holter bin method led to slight increases in the standard deviations of ΔΔQT values, but these were on average below 0.25 millisecond. CONCLUSIONS: The Holter bin methodology can be modified to make it compatible with the available guidance and with good practice of clinical investigations. The results obtained with the modified Holter bin method are practically the same as with individualized heart rate corrected QT intervals. The close correspondence between the 2 methods demonstrates that the present possibilities of comparing QT interval duration in the presence of experiment-induced heart rate differences are not influenced by methodological artifacts.
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: This was the first study to construct a physiologically-based pharmacokinetic (PBPK) model for mirabegron which incorporates the overall elimination pathways of metabolism by cytochrome P450 (CYP) 3A4, uridine 5'-diphosphate-glucuronosyltransferase (UGT) 2B7, and butyrylcholinesterase (BChE) and renal excretion. The objective was to assess the risk of drug-drug interactions (DDIs) by estimating the contribution of each elimination pathway and simulating the magnitude of the DDIs with UGT2B7 inhibitors. A PBPK model for mirabegron was constructed to reproduce the plasma concentration-time curves from a phase 1 study and the magnitude of the DDI with ketoconazole taking into account the overall elimination pathways. The PBPK model was subsequently verified using data from other DDI studies. The constructed PBPK model estimated the contribution for each elimination pathway: 44% and 29% for CYP3A4 and UGT2B7 in the liver, 1.6% for UGT2B7 in the kidney, 3.2% for BChE in plasma, and 22% for renal excretion. Co-administration of probenecid (an UGT2B7 inhibitor) or fluconazole (an UGT2B7 and CYP3A4 inhibitor) was predicted to increase area under the curve for mirabegron to 115% or 174%, respectively. In conclusion, PBPK modeling and simulation revealed a low DDI risk for mirabegron following co-administration with BChE or UGT2B7 inhibitors.