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 lopinavir y telitromicina. 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 lopinavir. Actualmente no podemos estimar la influencia de la telitromicina. No detectamos ningún cambio en la exposición a la telitromicina. Actualmente no podemos estimar la influencia de la lopinavir.
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.
Se desconoce la biodisponibilidad de la lopinavir. Se desconoce la unión a proteínas [ Pb ]. El metabolismo tiene lugar principalmente a través de CYP3A4 y el transporte activo tiene lugar especialmente a través de PGP.
La telitromicina tiene una biodisponibilidad oral media [ F ] del 100 %, por lo que los niveles plasmáticos máximos [Cmax] tienden a cambiar con una interacción. La unión a proteínas [ Pb ] es relativamente débil al 100 % y el volumen de distribución [ Vd ] es muy grande a 218 litros. El metabolismo tiene lugar principalmente a través de CYP3A4 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 lopinavir ni la telitromicina aumentan la actividad serotoninérgica.
|Kiesel & Durán b||0||Ø||Ø|
Clasificación: Según nuestro conocimiento, ni la lopinavir ni la telitromicina aumentan la actividad anticolinérgica.
Prolongación del tiempo QT
Clasificación: En combinación, la lopinavir y la telitromicina pueden desencadenar potencialmente arritmias ventriculares del tipo torsades de pointes.
Efectos adversos generales
|Efectos secundarios||∑ frecuencia||lop||tel|
|Dolor de cabeza||4.0 %||n.a.||4.0|
|Visión borrosa||1.1 %||n.a.||1.1|
|Arritmia ventricular||0.0 %||n.a.||0.0|
|Taquicardia ventricular||0.0 %||n.a.||0.0|
Miastenia gravis: telitromicina
Insuficiencia respiratoria: telitromicina
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: BACKGROUND: This two-way, randomized, single-dose, crossover study determined the pharmacokinetics and absolute oral bioavailability of telithromycin in young and elderly healthy subjects. METHODS: Twelve young (18-40 years) and 12 elderly (>65 years and </=85 years) subjects received a single 800-mg oral dose of telithromycin or an intravenous infusion of 400 mg (young subjects) or 480 mg (elderly subjects) of telithromycin over 2.5 h in two treatment periods, separated by a 1-week washout period. The plasma concentrations and pharmacokinetic parameters of telithromycin and its major metabolite, RU 76363, were determined. Absolute oral bioavailability was calculated using the area under the plasma concentration-time curve (AUC) from zero hours to infinity. RESULTS: The absolute oral bioavailability of telithromycin was 57% in both young and elderly subjects. The AUC for the metabolite was lower after intravenous infusion of telithromycin, indicating first-pass loss following oral administration. Telithromycin was well tolerated in both groups of subjects. CONCLUSIONS: Telithromycin has an absolute oral bioavailability of 57% in young and elderly subjects and is well tolerated.
Abstract: BACKGROUND: Telithromycin is the first member of a new class of antimicrobials-the ketolides. The main objective of this study was to assess the effect of various oral doses of telithromycin on QT interval during single and repeated administrations. METHODS: Seventeen men and 17 women participated in double-blind, placebo-controlled, crossover studies. Of these subjects, 18 (9 men and 9 women) received single and repeated oral doses of telithromycin (800 mg daily), clarithromycin (500 mg twice daily), or placebo (protocol 1). The other 16 subjects received a single oral dose (800 mg, 1600 mg, and 2400 mg) of telithromycin or placebo (protocol 2). At the time of expected telithromycin maximum concentration, several electrocardiographic recordings were obtained at rest and during the course of a submaximal exercise test. QT intervals were measured within a wide range of R-R intervals in each subject. RESULTS: ANOVA showed that telithromycin did not increase QT interval at any dose compared with placebo. The greatest effect observed during any study period was a mean (+/-SD) change in QT-interval duration of 4.2 +/- 15.2 ms (ie, +1.2% +/- 4.0%, P not significant) at R-R = 1000 ms after repeated doses of 800 mg telithromycin. Outlier values (change in Bazett QTc from baseline >60 ms) from resting 12-lead electrocardiograms did not differ across treatment groups, including placebo. CONCLUSIONS: Telithromycin administered as repeated doses of 800 mg (recommended doses) or as single doses of up to 3 times this recommended dose did not increase the QT interval at any heart rate at rest and during effort. Telithromycin did not prolong QT-interval duration when administered to healthy young male and female subjects.
Abstract: Macrolides, ketolides and fluoroquinolones as well as other classes of antimicrobial agents have been associated with prolongation of cardiac repolarisation. This effect is most notable with erythromycin, clarithromycin, gatifloxacin, moxifloxacin, levofloxacin and telithromycin. All of these agents produce a blockage of the HERG channel dependent potassium current in myocyte membranes resulting in a prolonged QTc interval which may give rise to polymorphic ventricular tachycardia, Torsades de Pointes or ventricular fibrillation. The risk of malignant arrhythmias is increased by concomitant usage with Type Ia or III anti-arrhythmic agents or with other drugs that prolong the QTc interval or have competitive metabolic routes. Electrolyte disturbances or underlying cardiac disease also increase the risk of ventricular arrhythmias. The best clinical outcome indicator is the incidence of the associated arrhythmias. The rough rank order of risk with these agents, albeit with limited and incomplete data, is in decreasing order; erythromycin, clarithromycin, gatifloxacin, levofloxacin and moxifloxacin. Telithromycin outcomes for associated arrhythmia are yet to be determined. The essential point is that the overall risk of ventricular arrhythmias is very small with these agents but can be reduced further by avoiding their usage for patients with other multiple risk factors for Torsades de Pointes.
Abstract: AIMS: Telithromycin belongs to ketolides, a new class of macrolide antibiotics. Macrolides are known to have the potential to prolong QT interval duration. Previous studies have shown that telithromycin did not induce significant QT interval prolongation in healthy subjects compared with placebo. The main objective of this study was to demonstrate the absence of amplification of QT interval prolongation induced by sotalol, when telithromycin and sotalol were co-administered. The secondary objective was to correlate the QT interval changes induced by the study drugs to plasma concentrations during the elimination phase. METHODS: Twenty-four women received sotalol (160 mg) together with placebo or telithromycin (800 mg) in a two-period, double-blind, randomized study. Electrocardiograms were recorded at rest. Comparison of maximal corrected QT interval (QTc(max)) with sotalol in the presence or absence of telithromycin was performed. The relation between sotalol concentration and QTc was studied using linear regression. RESULTS: Mean difference (95% CI) between QTc(max) with sotalol-placebo and QTc(max) with sotalol-telithromycin was -15.5 ms (-27.7 to -3.2 ms). QTc(max) interval prolongation was lower (P < 0.05) with sotalol-telithromycin than with sotalol-placebo, in relation to decreased sotalol plasma concentrations. Regression analysis showed that the relationship between sotalol plasma concentration and QTc interval duration was not modified by telithromycin co-administration. CONCLUSION: Our results do not support a potential synergistic effect on QT interval prolongation between sotalol and telithromycin. The decrease of mean QTc interval in subjects taking telithromycin and sotalol may be explained by a decrease of sotalol concentration.
Abstract: Telithromycin is the first ketolide, which is a new class of antibacterial agents related to the macrolides that have structural modifications permitting dual binding to bacterial ribosomal RNA so that activity is retained against Streptococcus pneumoniae with macrolide-lincosamide-streptogramin(B) resistance. Clinical experience in infectious patients has shown that oral telithromycin 800mg once daily for 5-10 days is effective for the treatment of community-acquired upper and lower respiratory tract infections. Absorption of telithromycin in humans is estimated to be > or = 90%. Prior to entering the systemic circulation, telithromycin undergoes first-pass metabolism (mainly by the liver). Its absolute bioavailability is 57% and is unaffected by food. The volume of distribution of telithromycin after intravenous infusion is 2.9 L/kg. Telithromycin is 60-70% bound to serum proteins and has extensive diffusion into a range of target biological tissues, achieving concentrations above its minimum inhibitory concentration (MIC) against key respiratory pathogens throughout the dosing interval. After entering the systemic circulation, telithromycin is eliminated by multiple pathways (7% by biliary and/or intestinal excretion, 13% by renal excretion and 37% by hepatic metabolism). Telithromycin is metabolised via cytochrome P450 (CYP) 3A4 and non-CYP pathways. The identified metabolites show minimal antibacterial activity compared with the parent drug. In healthy subjects receiving telithromycin 800 mg once daily, the peak plasma concentration achieved is 2.27 microg/mL. Plasma concentrations of telithromycin show a biphasic decrease over time, with an initial disposition half-life of 2.9 hours and a terminal elimination half-life of approximately 10 hours after multiple dose administration. Steady-state plasma concentrations are achieved within 2-3 days of once-daily administration. Owing to elimination by multiple pathways there is a small increase in exposure when one of these elimination pathways is impaired, as indicated by the results of studies in special patient populations (e.g. those with hepatic or renal impairment). Dosage reductions may be recommended in patients with severe renal impairment. Inhibition of CYP3A4 by potent inhibitors such as itraconazole and ketoconazole results in a 54% and 95% increase in telithromycin area under the plasma concentration-time curve, respectively. The potential for telithromycin to inhibit the CYP3A4 pathway is similar to that of clarithromycin. The once-daily administration of telithromycin is likely to limit the potential for drug interactions and clinically significant increases in exposure. In phase III clinical trials, the telithromycin 800 mg once-daily dose has been shown to provide close to the maximum antimicrobial activity against S. pneumoniae, Haemophilus influenzae and Staphylococcus aureus in patients with community-acquired pneumonia. In conclusion, telithromycin has a well characterised and reproducible pharmacokinetic profile, with pharmacokinetic/pharmacodynamic relationships supporting an oral dosage regimen of 800 mg once daily.
Abstract: The present study aims to investigate the role of P glycoprotein and multidrug resistance-associated protein (Mrp2) in the transport of telithromycin, a newly developed ketolide antibiotic, in vitro and in vivo. The in vitro experiments revealed that the intracellular accumulation of telithromycin in adriamycin-resistant human chronic myelogenous leukemia cells (K562/ADR) overexpressing P glycoprotein was significantly lower than that in human chronic myelogenous leukemia cells (K562/S) not expressing P glycoprotein. Cyclosporine significantly increased the intracellular accumulation of telithromycin in K562/ADR cells. When telithromycin was coadministered intravenously with cyclosporine in Sprague-Dawley (SD) rats, cyclosporine significantly delayed the disappearance of telithromycin from plasma and decreased its systemic clearance to 60% of the corresponding control values. Hepatobiliary excretion experiments revealed that cyclosporine almost completely inhibited the biliary clearance of telithromycin, suggesting that telithromycin is a substrate of P glycoprotein and a potential substrate of Mrp2. Moreover, the biliary clearance of telithromycin was significantly decreased by 80% in Eisai hyperbilirubinemic mutant rats with a hereditary deficiency in Mrp2, indicating that Mrp2, as well as P glycoprotein, plays an important role in the biliary excretion of telithromycin. When the effect of telithromycin on the biliary excretion of doxorubicin, a substrate of P glycoprotein and Mrp2, was examined in SD rats, telithromycin significantly decreased the biliary clearance of doxorubicin by 80%. Results obtained from this study indicate that telithromycin is a substrate of both P glycoprotein and Mrp2, and these transporters are involved in the hepatobiliary transport of telithromycin.
Abstract: No Abstract available
Abstract: On the basis of a single clinical trial in first-line treatment, the atazanavir and ritonavir combination appears to be no more effective than the fixed-dose combination of lopinavir and ritonavir. The adverse effect profiles were slightly different, but atazanavir carries a troubling risk of torsades de pointes.
Abstract: BACKGROUND: Drug-induced torsades de pointes (TdP) is a complex regulatory and clinical problem due to the rarity of this sometimes fatal adverse event. In this context, the US FDA Adverse Event Reporting System (AERS) is an important source of information, which can be applied to the analysis of TdP liability of marketed drugs. OBJECTIVE: To critically evaluate the risk of antimicrobial-induced TdP by detecting alert signals in the AERS, on the basis of both quantitative and qualitative analyses. METHODS: Reports of TdP from January 2004 through December 2008 were retrieved from the public version of the AERS. The absolute number of cases and reporting odds ratio as a measure of disproportionality were evaluated for each antimicrobial drug (quantitative approach). A list of drugs with suspected TdP liability (provided by the Arizona Centre of Education and Research on Therapeutics [CERT]) was used as a reference to define signals. In a further analysis, to refine signal detection, we identified TdP cases without co-medications listed by Arizona CERT (qualitative approach). RESULTS: Over the 5-year period, 374 reports of TdP were retrieved: 28 antibacterials, 8 antifungals, 1 antileprosy and 26 antivirals were involved. Antimicrobials more frequently reported were levofloxacin (55) and moxifloxacin (37) among the antibacterials, fluconazole (47) and voriconazole (17) among the antifungals, and lamivudine (8) and nelfinavir (6) among the antivirals. A significant disproportionality was observed for 17 compounds, including several macrolides, fluoroquinolones, linezolid, triazole antifungals, caspofungin, indinavir and nelfinavir. With the qualitative approach, we identified the following additional drugs or fixed dose combinations, characterized by at least two TdP cases without co-medications listed by Arizona CERT: ceftriaxone, piperacillin/tazobactam, cotrimoxazole, metronidazole, ribavirin, lamivudine and lopinavir/ritonavir. DISCUSSION: Disproportionality for macrolides, fluoroquinolones and most of the azole antifungals should be viewed as 'expected' according to Arizona CERT list. By contrast, signals were generated by linezolid, caspofungin, posaconazole, indinavir and nelfinavir. Drugs detected only by the qualitative approach should be further investigated by increasing the sensitivity of the method, e.g. by searching also for the TdP surrogate marker, prolongation of the QT interval. CONCLUSIONS: The freely available version of the FDA AERS database represents an important source to detect signals of TdP. In particular, our analysis generated five signals among antimicrobials for which further investigations and active surveillance are warranted. These signals should be considered in evaluating the benefit-risk profile of these drugs.
Abstract: Telithromycin is a substrate and an inhibitor of cytochrome P450 3A (CYP3A4), with dose- and time-dependent nonlinear pharmacokinetics (PK). We hypothesized that the time-dependent inhibition (TDI) of CYP3A4 was responsible for the nonlinear PK of telithromycin and then used physiologically based PK (PBPK) modeling and simulation to verify this mechanism. Telithromycin PBPK models integrating in vitro, in silico, and in vivo PK data ruled out the contribution of enzyme/transporter saturation and suggested that TDI is a plausible mechanism for PK nonlinearity. The model successfully predicted the clinical interaction with the CYP3A4 substrate midazolam, as verified by external data not used for the model-building (intravenous (i.v.) and oral (p.o.) midazolam area under the concentration-time curve (AUC) ratio with/without concurrent telithromycin administration: 3.26 and 6.72 predicted vs. 2.20 and 6.11 observed, respectively). Models assuming reversible inhibition failed to predict such strong CYP3A4 inhibition. In the absence of in vitro TDI data, a PBPK model can be used to incorporate TDI mechanisms based on nonlinear PK data to predict clinical drug-drug interactions.