Verlängerung der QT-Zeit
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Für die Kombination von Telithromycin und Asenapin liegen uns keine zusätzlichen Warnhinweise vor. Bitte konsultieren Sie zusätzlich die jeweiligen Fachinformationen.
Die genannten Expositionsveränderungen beziehen sich jeweils auf Veränderungen der Plasmakonzentrations-Zeit-Kurve [ AUC ]. Für Telithromycin erwarten wir keine Veränderung der Exposition, wenn eine Kombination mit Asenapin (100%) erfolgt. Für Asenapin erwarten wir keine Veränderung der Exposition, wenn eine Kombination mit Telithromycin (100%) erfolgt.
Für die Berechnung der individuellen Expositionsveränderungen durch die Wechselwirkungen werden als Ausgangsbasis die pharmakokinetischen Parameter der durchschnittlichen Population verwendet.
Telithromycin hat eine mittlere orale Bioverfügbarkeit [ F ] von 55%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell verändern. Die Proteinbindung [ Pb ] ist mit 70% eher schwach und das Verteilungsvolumen [ Vd ] ist mit 218 Liter sehr gross, weshalb bei einer mittleren hepatische Extraktionsrate von 0.44 sowohl der Leberblutfluss [ Q ] als auch eine Veränderung der Proteinbindung [ Pb ] relevant sind. Die Metabolisierung findet vor allem über CYP3A4 statt und der aktive Transport erfolgt zum Teil über MRP2 und PGP.
Asenapin hat eine tiefe orale Bioverfügbarkeit [ F ] von 2%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell stark verändern. Die terminale Halbwertszeit [ t12 ] beträgt 24 Stunden und konstante Plasmaspiegel [ Css ] werden ungefähr nach 96 Stunden erreicht. Die Proteinbindung [ Pb ] ist mit 95% mässig stark und das Verteilungsvolumen [ Vd ] ist mit 1700 Liter sehr gross. Die Metabolisierung findet vor allem über CYP1A2 statt und der aktive Transport erfolgt insbesondere über UGT1A4.
|Serotonerge Effekte a||0||Ø||Ø|
Bewertung: Gemäss unseren Erkenntnissen erhöhen weder Telithromycin noch Asenapin die serotonerge Aktivität.
|Kiesel & Durán b||1||Ø||+|
Empfehlung: Insbesondere nach einer Dosiserhöhung und bei Dosierungen im oberen therapeutischen Bereich sollte vorsichtshalber auf anticholinerge Symptome geachtet werden.
Bewertung: Asenapin beeinflusst das anticholinerge System nur mild. Das Risiko für ein anticholinerge Syndrom ist bei dieser Medikation eher als gering einzustufen, wenn die Dosierung sich im üblichen Bereich befindet. Gemäss unseren Erkenntnisse erhöht Telithromycin nicht die anticholinerge Aktivität.
Verlängerung der QT-Zeit
Bewertung: In Kombination können Telithromycin und Asenapin potentiell ventrikuläre Arrhythmien vom Typ Torsades de pointes auslösen.
Orthostatische Hypotonie (1.5%): Asenapin
Ventrikuläre Arrhythmie: Telithromycin
Ventrikuläre Tachykardie: Telithromycin
Verschwommenes Sehen (1.1%): Telithromycin
Myasthenia gravis: Telithromycin
Malignes neuroleptisches Syndrom: Asenapin
Basierend auf Ihren
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: An assessment of the effects of asenapine on QTc interval in patients with schizophrenia revealed a discrepancy between the results obtained by two different methods: an intersection-union test (IUT) (as recommended in the International Conference on Harmonisation E14 guidance) and an exposure-response (E-R) analysis. Simulations were performed in order to understand and reconcile this discrepancy. Although estimates of the time-matched, placebo-corrected mean change in QTc from baseline (ddQTc) at peak plasma concentrations from the E-R analysis ranged from 2 to 5 ms per dose level, the IUT applied to simulated data from the E-R model yielded maximum ddQTc estimates of 7-10 ms for the various doses of asenapine. These results indicate that the IUT can produce biased estimates that may induce a high false-positive rate in individual thorough QTc trials. In such cases, simulations from an E-R model can aid in reconciling the results from the two methods and may support the use of E-R results as a basis for labeling.
Abstract: The metabolism and excretion of asenapine [(3aRS,12bRS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]-oxepino [4,5-c]pyrrole (2Z)-2-butenedioate (1:1)] were studied after sublingual administration of [(14)C]-asenapine to healthy male volunteers. Mean total excretion on the basis of the percent recovery of the total radioactive dose was ∼90%, with ∼50% appearing in urine and ∼40% excreted in feces; asenapine itself was detected only in feces. Metabolic profiles were determined in plasma, urine, and feces using high-performance liquid chromatography with radioactivity detection. Approximately 50% of drug-related material in human plasma was identified or quantified. The remaining circulating radioactivity corresponded to at least 15 very polar, minor peaks (mostly phase II products). Overall, >70% of circulating radioactivity was associated with conjugated metabolites. Major metabolic routes were direct glucuronidation and N-demethylation. The principal circulating metabolite was asenapine N(+)-glucuronide; other circulating metabolites were N-desmethylasenapine-N-carbamoyl-glucuronide, N-desmethylasenapine, and asenapine 11-O-sulfate. In addition to the parent compound, asenapine, the principal excretory metabolite was asenapine N(+)-glucuronide. Other excretory metabolites were N-desmethylasenapine-N-carbamoylglucuronide, 11-hydroxyasenapine followed by conjugation, 10,11-dihydroxy-N-desmethylasenapine, 10,11-dihydroxyasenapine followed by conjugation (several combinations of these routes were found) and N-formylasenapine in combination with several hydroxylations, and most probably asenapine N-oxide in combination with 10,11-hydroxylations followed by conjugations. In conclusion, asenapine was extensively and rapidly metabolized, resulting in several regio-isomeric hydroxylated and conjugated metabolites.
Abstract: BACKGROUND AND OBJECTIVE: The effects of hepatic or renal impairment on the pharmacokinetics of atypical antipsychotics are not well understood. Drug exposure may increase in patients with hepatic disease, owing to a reduction of certain metabolic enzymes. The objective of the present study was to study the effects of hepatic or renal impairment on the pharmacokinetics of asenapine and its N-desmethyl and N⁺-glucuronide metabolites. METHODS: Two clinical studies were performed to assess exposure to asenapine, desmethylasenapine and asenapine N⁺-glucuronide in subjects with hepatic or renal impairment. Pharmacokinetic parameters were determined from plasma concentration-time data, using standard noncompartmental methods. The pharmacokinetic variables that were studied included the maximum plasma concentration (C(max)) and the time to reach the maximum plasma concentration (t(max)). Eligible subjects, from inpatient and outpatient clinics, were aged ≥18 years with a body mass index of ≥18 kg/m² and ≤32 kg/m². Sublingual asenapine (Saphris®) was administered as a single 5 mg dose. RESULTS: Thirty subjects participated in the hepatic impairment study (normal hepatic function, n = 8; mild hepatic impairment [Child-Pugh class A], n = 8; moderate hepatic impairment [Child-Pugh class B], n = 8; severe hepatic impairment [Child-Pugh class C], n = 6). Thirty-three subjects were enrolled in the renal impairment study (normal renal function, n = 9; mild renal impairment, n = 8; moderate renal impairment, n = 8; severe renal impairment, n = 8). Asenapine and N-desmethylasenapine exposures were unaltered in subjects with mild or moderate hepatic impairment, compared with healthy controls. Severe hepatic impairment was associated with increased area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) values for total asenapine, N-desmethylasenapine and asenapine N⁺-glucuronide (5-, 3-, and 2-fold, respectively), with slight increases in the C(max) of asenapine but 3- and 2-fold decreases in the C(max) values for N-desmethylasenapine and asenapine N⁺-glucuronide, respectively, compared with healthy controls. The mean AUC(∞) of unbound asenapine was more than 7-fold higher in subjects with severe hepatic impairment than in healthy controls. Mild renal impairment was associated with slight elevations in the AUC(∞) of asenapine compared with healthy controls; alterations observed with moderate and severe renal impairment were marginal. N-desmethylasenapine exposure was only slightly altered by renal impairment. No correlations were observed between exposure and creatinine clearance. CONCLUSION: Severe hepatic impairment (Child-Pugh class C) was associated with pronounced increases in asenapine exposure, but significant increases were not seen with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, or with any degree of renal impairment. Asenapine is not recommended in patients with severe hepatic impairment; no dose adjustment is needed in patients with mild or moderate hepatic impairment, or in patients with renal impairment.
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: No Abstract available
Abstract: Asenapine is one of the newer atypical antipsychotics on the market. It is a sublingually administered drug that is indicated for the treatment of both schizophrenia and bipolar disorder, and is considered to be safe and well tolerated. Herein, we report a 71-year-old female with a history of bipolar disorder who had ventricular trigemini and experienced a large increase in her QTc interval after starting treatment with asenapine. These changes ceased following withdrawal of asenapine. In this case report, we discuss the importance of cardiac monitoring when switching antipsychotics, even to those that are considered to have low cardiac risk.
Abstract: BACKGROUND: Anticholinergic drugs put elderly patients at a higher risk for falls, cognitive decline, and delirium as well as peripheral adverse reactions like dry mouth or constipation. Prescribers are often unaware of the drug-based anticholinergic burden (ACB) of their patients. This study aimed to develop an anticholinergic burden score for drugs licensed in Germany to be used by clinicians at prescribing level. METHODS: A systematic literature search in pubmed assessed previously published ACB tools. Quantitative grading scores were extracted, reduced to drugs available in Germany, and reevaluated by expert discussion. Drugs were scored as having no, weak, moderate, or strong anticholinergic effects. Further drugs were identified in clinical routine and included as well. RESULTS: The literature search identified 692 different drugs, with 548 drugs available in Germany. After exclusion of drugs due to no systemic effect or scoring of drug combinations (n = 67) and evaluation of 26 additional identified drugs in clinical routine, 504 drugs were scored. Of those, 356 drugs were categorised as having no, 104 drugs were scored as weak, 18 as moderate and 29 as having strong anticholinergic effects. CONCLUSIONS: The newly created ACB score for drugs authorized in Germany can be used in daily clinical practice to reduce potentially inappropriate medications for elderly patients. Further clinical studies investigating its effect on reducing anticholinergic side effects are necessary for validation.
Abstract: A highly selective and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay has been described for the determination of asenapine (ASE) in presence of its inactive metabolites-desmethyl asenapine (DMA) and asenapine--glucuronide (ASG). ASE, and ASE 13C-d3, used as internal standard (IS), were extracted from 300 µL human plasma by a simple and precise liquid-liquid extraction procedure using methyl-butyl ether. Baseline separation of ASE from its inactive metabolites was achieved on Chromolith Performance RP(100 mm × 4.6 mm) column using acetonitrile-5.0 mM ammonium acetate-10% formic acid (90:10:0.1, v/v/v) within 4.5 min. Quantitation of ASE was done on a triple quadrupole mass spectrometer equipped with electrospray ionization in the positive mode. The protonated precursor to product ion transitions monitored for ASE and ASE 13C-d3 were286.1 → 166.0 and290.0 → 166.1, respectively. The limit of detection (LOD) and limit of quantitation (LOQ) of the method were 0.0025 ng/mL and 0.050 ng/mL respectively in a linear concentration range of 0.050-20.0 ng/mL for ASE. The intra-batch and inter-batch precision (% CV) and mean relative recovery across quality control levels were ≤ 5.8% and 87.3%, respectively. Matrix effect, evaluated as IS-normalized matrix factor, ranged from 1.03 to 1.05. The stability of ASE under different storage conditions was ascertained in presence of the metabolites. The developed method is much simpler, matrix free, rapid and economical compared to the existing methods. The method was successfully used for a bioequivalence study of asenapine in healthy Indian subjects for the first time.