QT time prolongation
Adverse drug events
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Explanations of the substances for patients
We have no additional warnings for the combination of abiraterone and telithromycin. Please also consult the relevant specialist information.
The changes in exposure mentioned relate to changes in the plasma concentration-time curve [AUC]. We did not detect any change in exposure to abiraterone. We cannot currently estimate the influence of telithromycin. Telithromycin exposure increases to 104%, when combined with abiraterone (104%).
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Abiraterone has a mean oral bioavailability [ F ] of 50%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is 18 hours and constant plasma levels [ Css ] are reached after approximately 72 hours. The protein binding [ Pb ] is very strong at 99.8% and the volume of distribution [ Vd ] is very large at 2815 liters, The metabolism mainly takes place via CYP3A4.
Telithromycin has a mean oral bioavailability [ F ] of 57%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The protein binding [ Pb ] is rather weak at 70% and the volume of distribution [ Vd ] is very large at 218 liters. The metabolism mainly takes place via CYP3A4 and the active transport takes place partly via MRP2 and PGP.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither abiraterone nor telithromycin increase serotonergic activity.
|Kiesel & Durán b||0||Ø||Ø|
Rating: According to our findings, neither abiraterone nor telithromycin increase anticholinergic activity.
QT time prolongation
Rating: In combination, abiraterone and telithromycin can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||abi||tel|
|Peripheral edema||20.0 %||20.0||n.a.|
|Elevated ALT||13.0 %||13.0||n.a.|
|Elevated AST||13.0 %||13.0||n.a.|
|Urinary tract infection||10.0 %||10.0||n.a.|
Headache (4%): telithromycin
Atrial fibrillation (2.6%): abiraterone
Angina pectoris (1.6%): abiraterone
Ventricular arrhythmia: telithromycin
Ventricular tachycardia: telithromycin
Vomiting (2.4%): telithromycin
Blurred vision (1.1%): telithromycin
Myasthenia gravis: telithromycin
Respiratory failure: telithromycin
Based on your
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: 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.
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.