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 abirateron et de phénytoïne. Veuillez également consulter les informations spécialisées pertinentes.
|Phénytoïne||1.2 [1.2,1.2] 1||1.2|
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 abirateron. Nous ne pouvons actuellement pas estimer l'influence de la phénytoïne. L'exposition à la phénytoïne augmente à 120%, lorsqu'il est combiné avec la abirateron (120%). L'ASC est comprise entre 120% et 120% selon le
Les paramètres pharmacocinétiques de la population moyenne sont utilisés comme point de départ pour calculer les changements individuels d'exposition dus aux interactions.
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.
La phénytoïne a une biodisponibilité orale élevée [ F ] de 85%, raison pour laquelle les concentrations plasmatiques maximales [Cmax] ont tendance à peu changer pendant une interaction. La demi-vie terminale [ t12 ] est de 13 heures et les taux plasmatiques constants [ Css ] sont atteints après environ 9 999 heures. La liaison aux protéines [ Pb ] est modérément forte à 90% et le volume de distribution [ Vd ] est de 47 litres dans la fourchette moyenne, Étant donné que la substance a un faible taux d'extraction hépatique de 0,9, le déplacement de la liaison aux protéines [Pb] dans le contexte d'une interaction peut augmenter l'exposition. Le métabolisme a lieu via le CYP2C19, CYP2C9 et le CYP2E1, entre autres et le transport actif se fait notamment via PGP.
|Les scores||∑ Points||abi||phé|
|Effets sérotoninergiques a||0||Ø||Ø|
Évaluation: Selon nos connaissances, ni la abirateron ni la phénytoïne n'augmentent l'activité sérotoninergique.
|Les scores||∑ Points||abi||phé|
|Kiesel & Durán b||0||Ø||Ø|
Évaluation: Selon nos résultats, la abirateron n'augmente pas l'activité anticholinergique. L'effet anticholinergique de la phénytoïne est insignifiant.
Extension de temps QT
|Les scores||∑ Points||abi||phé|
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 phénytoïne.
Effets secondaires généraux
|Effets secondaires||∑ la fréquence||abi||phé|
|Œdème périphérique||20.0 %||20.0||n.a.|
|ALT élevé||13.0 %||13.0||n.a.|
|AST élevé||13.0 %||13.0||n.a.|
|Infection urinaire||10.0 %||10.0||n.a.|
|La diarrhée||5.5 %||5.5||n.a.|
|Fibrillation auriculaire||2.6 %||2.6||n.a.|
|Angine de poitrine||1.6 %||1.6||n.a.|
Dermatose bulleuse: phénytoïne
Syndrome de Stevens-Johnson: phénytoïne
Nécrolyse épidermique toxique: phénytoïne
La nausée: phénytoïne
Hypertrophie gingivale: phénytoïne
Déficience de mémoire: phénytoïne
Syndrome de DRESS: phénytoïne
Sur la base de vos
Abstract: Phenytoin is a relatively insoluble weak acid, usually administered as the sodium salt. Bioavailability is dependent upon particle size and problems of generic inequivalence have therefore arisen, particularly in Scandinavia. The drug has a moderately large volume of distribution and is approximately 90% bound to plasma proteins. Clinically important displacement can be caused by bilirubin and several drugs, particularly sodium valproate, which is often combined with phenytoin. Displacement will lower the total serum concentration but will little affect the free drug concentration. The metabolism of phenytoin to the major metabolite, 5-(p-hydroxyphenyl)-5-(phenylhydantoin, is saturable, giving rise to a non linear dose-serum concentration relationship. Therefore, the dose range compatible with a therapeutic serum concentration is narrow within subjects, and monitoring serum concentrations is of particular value in dosage tailoring. In renal failure, the binding of phenytoin to plasma proteins is reduced and therefore a lower range of serum drug concentrations is compatible with therapeutic control. In liver disease, binding may also be impaired but delayed metabolism may occur in addition. During pregnancy the serum concentration may fall progressively as pregnancy advances, probably due to an increased rate of metabolism. Phenytoin readily crosses the placenta, and is metabolised rapidly by the neonate exposed in utero.
Abstract: 1. In a double-blind crossover study 10 healthy males received either placebo or omeprazole (40 mg day-1) for 9 days, a single dose of phenytoin (300 mg) being taken on the seventh day. 2. Omeprazole significantly increased the area under the curve (0 to 72 h) of phenytoin (mean +/- s.e. mean) from 121.6 +/- 14.0 to 151.4 +/- 13.6 micrograms ml-1 h) (P less than 0.01). 3. The peak concentration, and apparent elimination half-life of phenytoin also tended to be increased though not significantly. 4. The omeprazole-phenytoin interaction observed may be clinically important because of the low therapeutic index associated with phenytoin.
Abstract: Clearance of phenytoin after i.v. injection of 100 mg was studied in six patients before and after 2 weeks daily treatment with 450 mg rifampicin, and in 14 patients with tuberculosis receiving standard treatment with 450 mg rifampicin, 300 mg isoniazid, and 1200 mg ethambutol daily. Acetylator status was measured by urinary acetylated sulphadimidine. Clearance of phenytoin in patients receiving only rifampicin increased from 46.7 ml min-1 +/- 20.6 ml min-1 to 97.8 ml min-1 +/- 33.4 ml min-1 (P less than 0.01), while clearance in patients on three drugs increased from 47.1 +/- 23.4 ml min-1 to 81.3 ml min-1 +/- 41.6 ml min-1 (P less than 0.01). No significant differences were observed between the six fast acetylators and the eight slow acetylators. Phenytoin kinetics were unchanged after further 3 months of combined treatment. Rifampicin is a strong inducer of the elimination of phenytoin. Combined treatment with isoniazid has no counter-acting effect in either fast or slow acetylators.
Abstract: No Abstract available
Abstract: OBJECTIVE: Posaconazole is an extended-spectrum triazole antifungal agent for the treatment and prophylaxis of invasive fungal infections. This randomized, open-label, parallel-group, multiple-dose study was conducted in healthy adult volunteers to assess the potential for a drug interaction between phenytoin and the posaconazole tablet formulation. METHODS: Subjects were randomly assigned for 10 days to one of the following treatments: posaconazole (200 mg once daily), phenytoin (200 mg once daily), or posaconazole (200 mg once daily) and phenytoin (200 mg once daily). Blood samples were collected on days 1 and 10 for pharmacokinetic evaluation of posaconazole and phenytoin concentrations. RESULTS: A total of 36 healthy men enrolled in the study. On day 1, the maximum plasma concentration (C(max)) and area under the concentration-time curve calculated from time 0-24 h post-dose (AUC(0-24)) were unchanged upon co-administration. At steady state (day 10), co-administration of posaconazole with phenytoin resulted in 44% (p = 0.012) and 52% (p = 0.007) decreases in posaconazole C(max) and AUC(0-24), respectively. These decreases in exposure corresponded with a 90% increase in steady-state clearance of orally administered posaconazole. Phenytoin C(max) and AUC(0-24) were not significantly altered upon co-administration of the two agents, 24% increase in C(max) (p = 0.196) and 25% increase in AUC(0-24) (p = 0.212) values, although inter-subject variability was observed within this group. CONCLUSION: Because co-administration of phenytoin and posaconazole significantly reduces posaconazole exposure and increases phenytoin levels in some subjects, concomitant use of these agents should be avoided unless the benefit outweighs the risk.
Abstract: AIMS: To assess the role of MDR1 and gamma-aminobutyric acid receptor-gamma 2 sub unit (GABRG2) gene polymorphism in seizure susceptibility in generalized seizure (GS) and febrile seizure (FS) patients and to evaluate MDR1 C3435T gene polymorphism's role in absorption of the anti-epileptic drug, phenytoin (PHT) in a cohort of patients. METHODS: One hundred twenty-seven cases of seizure (86 GS and 41 FS) patients were analyzed for MDR1 C3435T and GABRG2 C588T gene polymorphisms using restriction fragment length polymorphism-polymerase chain reaction. Serum PHT levels were analyzed. RESULTS: The T allele of MDR1 C3435T and GABRG2 C588T gene polymorphism was higher in GS in the Indian population compared with controls. From the data in GS, CT and TT genotype carriers of the MDR1 gene and TT genotype carriers of the GABRG2 gene had more recurrent seizures compared with others. MDR1 T allele carriers in the seizure reoccurrence (SR) group of GS and FS were high compared with the well-controlled seizure group (with no seizures after treatment). TT genotype carriers in SR group were high in FS (with regard to MDR1 gene polymorphism) and GS (with regard to GABRG2 gene polymorphism) compared with a well-controlled seizure group. MDR1 C3435T gene polymorphism affects serum PHT levels (p<0.015). Association of dose PHT ratio and genotype groups of MDR1 C3435T gene polymorphism showed a significant association (p<0.05). MDR1*CC genotype was more common in cases with low serum PHT levels.In addition, it is evident that CT and TT genotype carriers have a high percentage of SR with elevated serum PHT levels. CONCLUSIONS: Our results show that the MDR1 3435T and GABRG2 588T alleles play a role in seizure occurrence. Moreover, the MDR1 3435T allele also affects PHT absorption. We suggest MDR1 C3435T and GABRG2 C588T genotyping would be of value in order to lower the risk of concentration-dependent drug toxicity and for better patient management.
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: P-glycoprotein (P-gp), an ATP-dependant efflux pump transports a wide range of substrates across cellular membranes. Earlier studies have identified drug efflux due to the over-expression of P-gp as one of the causes for the resistance of phenytoin, an anti-epileptic drug (AED). While no clear evidence exists on the specific characteristics of phenytoin association with the human P-gp, this study employed structure-based computational approaches to identify its binding site and the underlying interactions. The identified site was validated with that of rhodamine, a widely accepted reference and an experimental probe. Further, an in silico proof-of-concept for phenytoin interactions and its decreased binding affinity with the closed-state of human P-gp model was provided in comparison with other AEDs. This is the first report to provide insights into the phenytoin binding site and possibly better explain its efflux by P-gp.
Abstract: AIM: Conducting PK studies in pregnant women is challenging. Therefore, we asked if a physiologically-based pharmacokinetic (PBPK) model could be used to predict the disposition in pregnant women of drugs cleared by multiple CYP enzymes. METHODS: We expanded and verified our previously published pregnancy PBPK model by incorporating hepatic CYP2B6 induction (based on in vitro data), CYP2C9 induction (based on phenytoin PK) and CYP2C19 suppression (based on proguanil PK), into the model. This model accounted for gestational age-dependent changes in maternal physiology and hepatic CYP3A, CYP1A2 and CYP2D6 activity. For verification, the pregnancy-related changes in the disposition of methadone (cleared by CYP2B6, 3A and 2C19) and glyburide (cleared by CYP3A, 2C9 and 2C19) were predicted. RESULTS: Predicted mean post-partum to second trimester (PP : T2 ) ratios of methadone AUC, Cmax and Cmin were 1.9, 1.7 and 2.0, vs. observed values 2.0, 2.0 and 2.6, respectively. Predicted mean post-partum to third trimester (PP : T3 ) ratios of methadone AUC, Cmax and Cmin were 2.1, 2.0 and 2.4, vs. observed values 1.7, 1.7 and 1.8, respectively. Predicted PP : T3 ratios of glyburide AUC, Cmax and Cmin were 2.6, 2.2 and 7.0 vs. observed values 2.1, 2.2 and 3.2, respectively. CONCLUSIONS: Our PBPK model integrating prior physiological knowledge, in vitro and in vivo data, allowed successful prediction of methadone and glyburide disposition during pregnancy. We propose this expanded PBPK model can be used to evaluate different dosing scenarios, during pregnancy, of drugs cleared by single or multiple CYP enzymes.
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: 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.
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.