Extension de temps QT
Effets indésirables des médicaments
|Mal de crâne|
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 nifedipine et de abirateron. 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]. L'exposition à la nifedipine augmente à 112%, lorsqu'il est combiné avec la abirateron (112%). Nous n'avons détecté aucune modification de l'exposition à la abirateron. Nous ne pouvons actuellement pas estimer l'influence de la nifedipine.
Les paramètres pharmacocinétiques de la population moyenne sont utilisés comme point de départ pour calculer les changements individuels d'exposition dus aux interactions.
La nifedipine a une biodisponibilité orale moyenne [ F ] de 54%, raison pour laquelle les concentrations plasmatiques maximales [Cmax] ont tendance à changer avec une interaction. La demi-vie terminale [ t12 ] est assez courte à 2 heures et des taux plasmatiques constants [ Css ] sont atteints rapidement. La liaison aux protéines [ Pb ] est modérément forte à 95% et le volume de distribution [ Vd ] est de 54 litres, c'est pourquoi, à 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 le CYP1A2 et le CYP3A4, entre autres et le transport actif se fait notamment via BCRP.
La abirateron a une biodisponibilité orale moyenne [ F ] de 50%, raison pour laquelle les concentrations plasmatiques maximales [Cmax] ont tendance à changer avec une interaction. La demi-vie terminale [ t12 ] est de 18 heures et les taux plasmatiques constants [ Css ] sont atteints après environ 9 999 heures. La liaison aux protéines [ Pb ] est très forte à 99.8% et le volume de distribution [ Vd ] est très important à 2815 litres, Le métabolisme s'effectue principalement via le CYP3A4.
|Les scores||∑ Points||nif||abi|
|Effets sérotoninergiques a||0||Ø||Ø|
Évaluation: Selon nos connaissances, ni la nifedipine ni la abirateron n'augmentent l'activité sérotoninergique.
|Les scores||∑ Points||nif||abi|
|Kiesel & Durán b||0||Ø||Ø|
Évaluation: Selon nos résultats, ni la nifedipine ni la abirateron n'augmentent l'activité anticholinergique.
Extension de temps QT
|Les scores||∑ Points||nif||abi|
La abirateron peut potentiellement augmenter le temps QT, mais nous ne connaissons pas les arythmies des torsades de pointes. Nous ne connaissons aucun potentiel d'allongement de l'intervalle QT pour la nifedipine.
Effets secondaires généraux
|Effets secondaires||∑ la fréquence||nif||abi|
|Œdème périphérique||28.0 %||10.0||20.0|
|Mal de crâne||21.0 %||21.0||n.a.|
|Sensation de chaleur et de bouffées vasomotrices||14.5 %||14.5||n.a.|
|ALT élevé||13.0 %||n.a.||13.0|
|AST élevé||13.0 %||n.a.||13.0|
|Infection urinaire||10.0 %||n.a.||10.0|
La diarrhée (5.5%): abirateron
La nausée: nifedipine
Septicémie (5.5%): abirateron
Fibrillation auriculaire (2.6%): abirateron
Angine de poitrine (1.6%): abirateron
Infarctus du myocarde: nifedipine
Nécrolyse épidermique toxique: nifedipine
Sur la base de vos
Abstract: 1. The effects of age on the pharmacology of nifedipine were investigated in 11 young and six elderly normotensive volunteers. 2. Following 2.5 mg of nifedipine i.v. the plasma clearance of nifedipine was 348 +/- 83 (s.d.) ml min-1 in the elderly compared with 519 +/- 125 ml min-1 in the young (P less than 0.05) and the AUC in the elderly was significantly greater at 125 +/- 28 ng ml-1 h compared with 83.9 +/- 19 ng ml-1 h (P less than 0.05). The Vss was similar in both age groups. 3. Following 10 mg oral sustained release nifedipine the AUC was 281 +/- 64 ng ml-1 h in the elderly compared with 136 +/- 56 ng ml-1 h in the young (P less than 0.002) and Cmax in the elderly was significantly greater at 36.8 +/- 11.8 ng ml-1 compared with 22.3 +/- 5.8 ng ml-1 (P less than 0.05). The trend towards an increased bioavailability in elderly subjects (36%) was supported by a significantly lower nitropyridine metabolite/nifedipine ratio in the elderly. 4. Absorption rate limited kinetics of the sustained release formulation were indicated by the prolonged t1/2 compared with i.v. administration. In the elderly t1/2 (oral) was significantly greater than in the young (elderly 6.7 +/- 2.2 h, young 3.8 +/- 1.4 h, P less than 0.05). 5. Haemodynamic changes in the young were confined to a tachycardia following i.v. administration. In the elderly, supine BP fell significantly following both oral and i.v. nifedipine while the heart rate remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Two studies of the pharmacokinetics and pharmacodynamics of intravenous nifedipine infusion were performed: the first, a randomised double-blind crossover study of nifedipine and its vehicle in eight subjects, the second a dose ranging study in nine subjects. Nifedipine pharmacokinetics did not vary with dose or duration of infusion up to 8 h, and are similar to those reported for other nifedipine preparations. Nifedipine increased heart rate and forearm blood flow and decreased blood pressure after bolus injection but not during prolonged infusion. The vehicle decreased blood pressure and increased forearm blood flow after bolus injection but not during prolonged infusion. It did not affect heart rate. The vehicle's haemodynamic activity has not been previously recognised and is of potential importance in the study of this and similar preparations of calcium antagonists.
Abstract: Nifedipine, the prototype for the dihydropyridine class of calcium antagonists, has been available for 20 years and its efficacy as a vasodilator and an antihypertensive agent is well recognised. The development of the so-called nifedipine gastrointestinal therapeutic system (GITS), which allows once-daily administration, has modified and improved the overall therapeutic profile of nifedipine to such a significant extent that it might almost be considered a new drug entity. The nifedipine GITS is associated with distinct improvements in terms of patient compliance and convenience, and a reduced incidence of adverse effects. With regard to the care of the elderly, this 'new' drug offers the prospect of a well tolerated and effective treatment without major cost implications.
Abstract: The human ATP-binding cassette transporter, ABCG2, confers resistance to multiple chemotherapeutic agents and also affects the bioavailability of different drugs. [(125)I]Iodoarylazidoprazosin (IAAP) and [(3)H]azidopine were used for photoaffinity labeling of ABCG2 in this study. We show here for the first time that both of these photoaffinity analogues are transport substrates for ABCG2 and that [(3)H]azidopine can also be used to photolabel both wild-type R482-ABCG2 and mutant T482-ABCG2. We further used these assays to screen for potential substrates or modulators of ABCG2 and observed that 1,4-dihydropyridines such as nicardipine and nifedipine, which are clinically used as antihypertensive agents, inhibited the photolabeling of ABCG2 with [(125)I]IAAP and [(3)H]azidopine as well as the transport of these photoaffinity analogues by ABCG2. Furthermore, [(3)H]nitrendipine and bodipy-Fl-dihydropyridine accumulation assays showed that these compounds are transported by ABCG2. These dihydropyridines also inhibited the efflux of the known ABCG2 substrates, mitoxantrone and pheophorbide-a, from ABCG2-overexpressing cells, and nicardipine was more potent in inhibiting this transport. Both nicardipine and nifedipine stimulated the ATPase activity of ABCG2, and the nifedipine-stimulated activity was inhibited by fumitremorgin C, suggesting that these agents might interact at the same site on the transporter. In addition, nontoxic concentrations of dihydropyridines increased the sensitivity of ABCG2-expressing cells to mitoxantrone by 3-5-fold. In aggregate, results from the photoaffinity labeling and efflux assays using [(125)I]IAAP and [(3)H]azidopine demonstrate that 1,4-dihydropyridines are substrates of ABCG2 and that these photolabels can be used to screen new substrates and/or inhibitors of this transporter.
Abstract: BACKGROUND: Anticholinergic drugs are often involved in explicit criteria for inappropriate prescribing in older adults. Several scales were developed for screening of anticholinergic drugs and estimation of the anticholinergic burden. However, variation exists in scale development, in the selection of anticholinergic drugs, and the evaluation of their anticholinergic load. This study aims to systematically review existing anticholinergic risk scales, and to develop a uniform list of anticholinergic drugs differentiating for anticholinergic potency. METHODS: We performed a systematic search in MEDLINE. Studies were included if provided (1) a finite list of anticholinergic drugs; (2) a grading score of anticholinergic potency and, (3) a validation in a clinical or experimental setting. We listed anticholinergic drugs for which there was agreement in the different scales. In case of discrepancies between scores we used a reputed reference source (Martindale: The Complete Drug Reference®) to take a final decision about the anticholinergic activity of the drug. RESULTS: We included seven risk scales, and evaluated 225 different drugs. Hundred drugs were listed as having clinically relevant anticholinergic properties (47 high potency and 53 low potency), to be included in screening software for anticholinergic burden. CONCLUSION: Considerable variation exists among anticholinergic risk scales, in terms of selection of specific drugs, as well as of grading of anticholinergic potency. Our selection of 100 drugs with clinically relevant anticholinergic properties needs to be supplemented with validated information on dosing and route of administration for a full estimation of the anticholinergic burden in poly-medicated older adults.
Abstract: Three open-label, single-dose studies investigated the impact of hepatic or renal impairment on abiraterone acetate pharmacokinetics and safety/tolerability in non-cancer patients. Patients (n = 8 each group) with mild/moderate hepatic impairment or end-stage renal disease (ESRD), and age-, BMI-matched healthy controls received a single oral 1,000 mg abiraterone acetate (tablet dose); while patients (n = 8 each) with severe hepatic impairment and matched healthy controls received 125- and 2,000-mg abiraterone acetate (suspension doses), respectively (systemic exposure of abiraterone acetate suspension is approximately half to that of tablet formulation). Blood was sampled at specified timepoints up to 72 or 96 hours postdose to measure plasma abiraterone concentrations. Abiraterone exposure was comparable between healthy controls and patients with mild hepatic impairment or ESRD, but increased by 4-fold in patients with moderate hepatic impairment. Despite a 16-fold reduction in dose, abiraterone exposure in patients with severe hepatic impairment was about 22% and 44% of the Cmax and AUC∞ of healthy controls, respectively. These results suggest that abiraterone pharmacokinetics were not changed markedly in patients with ESRD or mild hepatic impairment. However, the capacity to eliminate abiraterone was substantially compromised in patients with moderate or severe hepatic impairment. A single-dose administration of abiraterone acetate was well-tolerated.
Abstract: Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data were often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding and the blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate the model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for the terminal elimination half-life (t1/2 , 100% of drugs), peak plasma concentration (Cmax , 100%), area under the plasma concentration-time curve (AUC0-t , 95.4%), clearance (CLh , 95.4%), mean residence time (MRT, 95.4%) and steady state volume (Vss , 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. Copyright © 2016 John Wiley & Sons, Ltd.
Abstract: Two novel oral drugs that target androgen signaling have recently become available for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Abiraterone acetate inhibits the synthesis of the natural ligands of the androgen receptor, whereas enzalutamide directly inhibits the androgen receptor by several mechanisms. Abiraterone acetate and enzalutamide appear to be equally effective for patients with mCRPC pre- and postchemotherapy. Rational decision making for either one of these drugs is therefore potentially driven by individual patient characteristics. In this review, an overview of the pharmacokinetic characteristics is given for both drugs and potential and proven drug-drug interactions are presented. Additionally, the effect of patient-related factors on drug disposition are summarized and the limited data on the exposure-response relationships are described. The most important pharmacological feature of enzalutamide that needs to be recognized is its capacity to induce several key enzymes in drug metabolism. The potency to cause drug-drug interactions needs to be addressed in patients who are treated with multiple drugs simultaneously. Abiraterone has a much smaller drug-drug interaction potential; however, it is poorly absorbed, which is affected by food intake, and a large interpatient variability in drug exposure is observed. Dose reductions of abiraterone or, alternatively, the selection of enzalutamide, should be considered in patients with hepatic dysfunction. Understanding the pharmacological characteristics and challenges of both drugs could facilitate decision making for either one of the drugs.
Abstract: We present a case of a 77 year-old gentleman with previous coronary artery bypass grafting, admitted to hospital with recurrent torsades de pointes (TdP) due to abiraterone-induced hypokalaemia and prolonged QTc. The patient was on abiraterone and prednisone for metastatic prostate cancer. He required multiple defibrillations for recurrent TdP. Abiraterone is a relatively novel drug used in metastatic prostate cancer and we discuss this potential adverse effect and its management in this unusual presentation.