Prolongación del tiempo QT
Eventos adversos de medicamentos
Variantes ✨Para la evaluación computacionalmente intensiva de las variantes, elija la suscripción estándar paga.
Explicaciones de las sustancias para pacientes.
No existen advertencias adicionales para la combinación de abiraterona y azitromicina. Consulte también la información especializada pertinente.
Los cambios informados en la exposición corresponden a los cambios en la curva de concentración plasmática-tiempo [ AUC ]. No detectamos ningún cambio en la exposición a la abiraterona. Actualmente no podemos estimar la influencia de la azitromicina. No esperamos ningún cambio en la exposición a azitromicina, cuando se combina con abiraterona (100%).
Los parámetros farmacocinéticos de la población media se utilizan como punto de partida para calcular los cambios individuales en la exposición debidos a las interacciones.
La abiraterona tiene una biodisponibilidad oral media [ F ] del 100 %, por lo que los niveles plasmáticos máximos [Cmax] tienden a cambiar con una interacción. La vida media terminal [ t12 ] es de 18 horas y se alcanzan niveles plasmáticos constantes [ Css ] después de aproximadamente 72 horas. La unión a proteínas [ Pb ] es muy fuerte al 100 % y el volumen de distribución [ Vd ] es muy grande a 2815 litros, El metabolismo tiene lugar principalmente a través de CYP3A4.
La azitromicina tiene una baja biodisponibilidad oral [ F ] del 100 %, por lo que el nivel plasmático máximo [Cmax] tiende a cambiar fuertemente con una interacción. La vida media terminal [ t12 ] es relativamente extensa a las 72 horas y los niveles plasmáticos constantes [ Css ] sólo se alcanzan después de más de 288 horas. La unión a proteínas [ Pb ] es muy débil al 100 % y el volumen de distribución [ Vd ] es muy grande a 2177 litros. por eso, con una tasa de extracción hepática media de 0,9, tanto el flujo sanguíneo hepático [Q] como un cambio en la unión a proteínas [Pb] son relevantes. El metabolismo no tiene lugar a través de los citocromos comunes y el transporte activo tiene lugar en parte a través de MRP2 y PGP.
|Efectos serotoninérgicos a||0||Ø||Ø|
Clasificación: Según nuestro conocimiento, ni la abiraterona ni la azitromicina aumentan la actividad serotoninérgica.
|Kiesel & Durán b||0||Ø||Ø|
Clasificación: Según nuestro conocimiento, ni la abiraterona ni la azitromicina aumentan la actividad anticolinérgica.
Prolongación del tiempo QT
Clasificación: En combinación, la abiraterona y la azitromicina pueden desencadenar potencialmente arritmias ventriculares del tipo torsades de pointes.
Efectos adversos generales
|Efectos secundarios||∑ frecuencia||abi||azi|
|Edema periférico||20.0 %||20.0||n.a.|
|ALT elevado||13.0 %||13.0||n.a.|
|AST elevado||13.0 %||13.0||n.a.|
|Infección del tracto urinario||10.0 %||10.0||n.a.|
|Dolor abdominal||10.0 %||n.a.||10.0|
Sepsis (5.5%): abiraterona
Síndrome de DRESS: azitromicina
Dolor de cabeza (5%): azitromicina
Visión borrosa (5%): azitromicina
Fibrilación auricular (2.6%): abiraterona
Angina de pecho (1.6%): abiraterona
Miastenia gravis: azitromicina
Pérdida de la audición: azitromicina
Trastorno del gusto: azitromicina
Pustulosis exantemática generalizada: azitromicina
Síndrome de Stevens-Johnson: azitromicina
Necrolisis epidérmica toxica: azitromicina
Hepatitis colestásica: azitromicina
Nefritis tubulointersticial: azitromicina
Con base en sus respuestas e información científica, evaluamos el riesgo individual de efectos secundarios adversos. Estas recomendaciones están destinadas a asesorar a los profesionales y no sustituyen la consulta con un médico. En la versión de prueba restringida (alfa), el riesgo de todas las sustancias aún no se ha evaluado de manera concluyente.
Abstract: Azalide antibiotics, of which azithromycin is the first demonstrated, have different pharmacokinetics from other antibiotics currently used. The bioavailability of the drug is approximately 37%. Extensive and rapid distribution from serum into the intracellular compartments is followed by rapid distribution to the tissues. Tissue concentrations exceed serum concentrations by up to 100-fold following a single azithromycin 500mg dose. Concentration of the drug within phagocytes aids in its ability to combat infections. High concentrations of azithromycin are found in the tonsil, lung, prostate, lymph nodes and liver, with only small concentrations found in fat and muscle. A 500mg dose on day 1, followed by 250mg daily on days 2 to 5, has been demonstrated to maintain azithromycin concentrations at sites of infection and continues to be effective for several days after administration has ceased. The pharmacokinetics of azithromycin make it a drug with diverse therapeutic applications.
Abstract: Plasma and urine levels of 12 healthy subjects and 30 patients with renal insufficiency of different degrees were examined after oral administration of four 250 mg capsules azithromycin (total daily dose 1,000 mg). The concentrations were determined by cup plate method. The pharmacokinetic parameters were determined model-dependent and noncompartmentally. Neither the area under the plasma concentration curve nor the distribution volume in steady state (16 l/kg body weight) nor the maximal plasma concentration were significantly affected by renal insufficiency. Thus the dosage regimen of azithromycin in renal impairment may (and should) be the same as in patients with normal renal function. The nonrenal clearance is not affected by renal insufficiency, but the concentration of the substance in the tubular lumen (the "tubular load") may be increased.
Abstract: OBJECTIVE: To review the pharmacology, microbiology, chemistry, pharmacokinetics, efficacy, safety, tolerability, dosage, administration, and economic issues of intravenous azithromycin. DATA SOURCES: A MEDLINE search from 1978 to May 1998 of the English-language literature and an extensive review of journals and meeting abstracts was conducted. Due to the lack of published literature concerning the efficacy, safety, and pharmacokinetics of the intravenous formulation of azithromycin, the manufacturer was also contacted and requested to supply information concerning intravenous azithromycin. DATA EXTRACTION: In vitro and preclinical studies were included, as well as data from Phase II and III clinical trials. Efficacy, pharmacokinetic, safety, and tolerability data were also supplemented with information from the manufacturer, due to the lack of published reports. DATA SYNTHESIS: Azithromycin, an azalide subclass of the macrolide antibiotics, is now available as an intravenous formulation. The intravenous form is approved for the treatment of community-acquired pneumonia caused by Chlamydia pneumoniae, Haemophilus influenzae. Legionella pneumophila, Moraxella catarrhalis, Mycoplasma pneumoniae, Staphylococcus aureus (methicillin-sensitive), and Streptococcus pneumoniae, and for the treatment of pelvic inflammatory disease caused by Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma hominis in situations in which intravenous therapy is required. Its spectrum of activity, unique pharmacokinetics, and high and sustained tissue penetration allow for once-daily dosing with monotherapy in many cases. Clinical and bacteriologic response rates as well as the adverse event profile have been similar to or better than comparative agents. CONCLUSIONS: Azithromycin offers advantages over other agents due to its unique pharmacokinetics, high and sustained tissue penetration, and spectrum of activity. This allows for monotherapy and once-daily intravenous dosing for mild-to-moderate community-acquired pneumonia or pelvic inflammatory disease in many instances. Future research should focus on total duration of antibiotic therapy and the need, or lack thereof, for extensive oral antibiotic follow-up.
Abstract: Administration of oral azithromycin, in addition to previously well-tolerated long-term amiodarone therapy, was associated with a marked prolongation of QT interval and increased QT dispersion, both substrates for life-threatening ventricular tachyarrhythmia and torsades de pointes. This is a report of QT prolongation and increased QT dispersion associated with the use of azithromycin. The report assumes an added significance, in view of widespread empirical use of this antibiotic for the treatment of lower respiratory infections and belief of its safety in patients with cardiac diseases. Based on the authors' experience, they would like to emphasize that the combination of azithromycin with other drugs known to prolong QT or causing torsades de pointes be used with caution until the question of the proarrhythmic effect of azithromycin is resolved by further studies.
Abstract: No Abstract available
Abstract: During treatment with azithromycin, a 55 year-old woman developed a newly prolonged QT interval and torsade de pointes in the absence of known risk factors. Female gender and acute renal failure may be considerations in patients treated with azithromycin.
Abstract: Predicting the magnitude of time-dependent metabolic drug-drug (mDDIs) interactions involving cytochrome P-450 3A4 (CYP3A4) from in vitro data requires accurate knowledge of the inactivation parameters of the inhibitor (K(I), k(inact)) and of the turnover of the enzyme (k(deg)) in both the gut and the liver. We have predicted the magnitude of mDDIs observed in 29 in vivo studies involving six CYP3A4 probe substrates and five mechanism based inhibitors of CYP3A4 of variable potency (azithromycin, clarithromycin, diltiazem, erythromycin and verapamil). Inactivation parameters determined anew in a single laboratory under standardised conditions together with data from substrate and inhibitor files within the Simcyp Simulator (Version 9.3) were used to determine a value of the hepatic k(deg) (0.0193 or 0.0077h(-1)) most appropriate for the prediction of mDDIs involving time-dependent inhibition of CYP3A4. The higher value resulted in decreased bias (geometric mean fold error - 1.05 versus 1.30) and increased precision (root mean squared error - 1.29 versus 2.30) of predictions of mean ratios of AUC in the absence and presence of inhibitor. Depending on the k(deg) value used (0.0193 versus 0.0077h(-1)), predicted mean ratios of AUC were within 2-fold of the observed values for all (100%) and 27 (93%) of the 29 studies, respectively and within 1.5-fold for 24 (83%) and 17 (59%) of the 29 studies, respectively. Comprehensive PBPK models were applied for accurate assessment of the potential for mDDIs involving time-dependent inhibition of CYP3A4 using a hepatic k(deg) value of 0.0193h(-1) in conjunction with inactivation parameters determined by the conventional experimental approach.
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: No Abstract available
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.