Verlängerung der QT-Zeit
|Infektion der oberen Atemwege|
Varianten ✨Für die rechenintensive Bewertung der Varianten bitte das kostenpflichtige Standard Abonnement wählen.
Eklärungen für Patienten zu den Wirkstoffen
Die Gabe von Ketoconazol und Alfuzosin sollte vermieden werden.
Erhöhte Alfuzosinkonzentrationen - HypotonierisikoMechanismus: Alfuzosin wird über CYP3A4 metabolisiert. Hemmer von CYP3A4 können darüber den Abbau von Alfuzosin inhibieren.
Effekt: Ketoconazol, ein starker Hemmer von CYP3A4, bewirkte in Studien des Herstellers einen 2-3-fachen Anstieg der Alfuzosin-Plasmakonzentrationen. Folgen können u.a. sein: Hypotension, Schwindel, Synkope. Die Kombination mit anderen Azol-Antimykotika wurde in Studien noch nicht untersucht. Aufgrund des vergleichbaren Hemmpotentials von CYP3A4 ist jedoch ein ähnlicher Effekt zu erwarten.
Massnahmen: Die Kombination ist zu vermeiden. Falls die Kombination zwingend erforderlich ist, Blutdruck und klinische Symptome (Schwindel, Kopfschmerzen) sorgfältig monitorisieren.
Die genannten Expositionsveränderungen beziehen sich jeweils auf Veränderungen der Plasmakonzentrations-Zeit-Kurve [ AUC ]. Die Exposition von Alfuzosin erhöht sich auf 230%, wenn eine Kombination mit Ketoconazol (230%) erfolgt. Dadurch können vermehrt Nebenwirkungen auftreten. Für Ketoconazol erwarten wir keine Veränderung der Exposition, wenn eine Kombination mit Alfuzosin (100%) erfolgt.
Für die Berechnung der individuellen Expositionsveränderungen durch die Wechselwirkungen werden als Ausgangsbasis die pharmakokinetischen Parameter der durchschnittlichen Population verwendet.
Alfuzosin hat eine mittlere orale Bioverfügbarkeit [ F ] von 49%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell verändern. Die terminale Halbwertszeit [ t12 ] beträgt 9.55 Stunden und konstante Plasmaspiegel [ Css ] werden ungefähr nach 38.2 Stunden erreicht. Die Proteinbindung [ Pb ] ist mit 86% mässig stark und das Verteilungsvolumen [ Vd ] ist mit 224 Liter sehr gross, da die Substanz eine tiefe hepatische Extraktionsrate von 0.23 besitzt, kann eine Verdrängung aus der Proteinbindung [Pb] im Rahmen einer Interaktion die Exposition erhöhen. Die Metabolisierung findet vor allem über CYP3A4 statt.
Ketoconazol hat eine mittlere orale Bioverfügbarkeit [ F ] von 67%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell verändern. Die terminale Halbwertszeit [ t12 ] ist mit 5 Stunden eher kurz und konstante Plasmaspiegel [ Css ] werden schnell erreicht. Die Proteinbindung [ Pb ] ist mit 91.5% mässig stark und das Verteilungsvolumen [ Vd ] ist mit 84 Liter sehr gross, da die Substanz eine tiefe hepatische Extraktionsrate von 0.09 besitzt, kann eine Verdrängung aus der Proteinbindung [Pb] im Rahmen einer Interaktion die Exposition erhöhen. Die Metabolisierung findet vor allem über CYP3A4 statt und der aktive Transport erfolgt insbesondere über PGP. Unter anderem ist Ketoconazol ein Hemmer von CYP3A4.
|Serotonerge Effekte a||0||Ø||Ø|
Bewertung: Gemäss unseren Erkenntnissen erhöhen weder Alfuzosin noch Ketoconazol die serotonerge Aktivität.
|Kiesel & Durán b||0||Ø||Ø|
Bewertung: Gemäss unseren Erkenntnissen erhöhen weder Alfuzosin noch Ketoconazol die anticholinerge Aktivität.
Verlängerung der QT-Zeit
Bewertung: In Kombination können Alfuzosin und Ketoconazol potentiell ventrikuläre Arrhythmien vom Typ Torsades de pointes auslösen.
|Infektion der oberen Atemwege||3.0 %||3.0↑||n.a.|
|Brennendes Gefühl||1.0 %||n.a.||+|
Orthostatische Hypotonie: Alfuzosin
Ventrikuläre Arrhythmie: Ketoconazol
Intraoperatives Floppy-Iris-Syndrom: Alfuzosin
Basierend auf Ihren
Abstract: The aim of this study was to assess the linearity of pharmacokinetic of alfuzosin, administered by oral route, at the doses of 1, 2.5, and 5 mg to 12 young healthy volunteers. The pharmacokinetic parameters (tmax, Cmax, AUC, t1/2 beta) obtained from plasma alfuzosin concentrations after administration of the three doses show that pharmacokinetics of alfuzosin is linear in the range of doses 1-5 mg. Mean pharmacokinetic parameters of alfuzosin observed after 1, 2.5, and 5 mg were, respectively: tmax (h) 1.5 +/- 0.3, 1.1 +/- 0.2, 1.3 +/- 0.1; Cmax (ng ml-1) 2.6 +/- 0.3, 9.4 +/- 1.2, 13.5 +/- 1.0; AUC (ng ml-1 h) 17.7 +/- 2.9, 51.7 +/- 7.1, 99.0 +/- 14.1; t1/2 (h) 3.7 +/- 0.4, 3.9 +/- 0.2, 3.8 +/- 0.3. Cmax (corrected by the dose) obtained after 2.5 mg was significantly higher than those obtained after 1 and 5 mg. This difference seems to be due principally to the intraindividual variability. The absence of statistically significant difference on individual values of AUC corrected by the administered dose, supports the linearity of the pharmacokinetics of alfuzosin in the range of doses between 1 and 5 mg. Some postural hypotension, clinical criterion, was observed with a frequency increasing with the dose in these healthy subjects: 0 volunteers of 12 after 1 mg, 3 volunteers of 12 after 2.5 mg and 4 volunteers of 12 after 5 mg.
Abstract: The effect of renal impairment on the safety and pharmacokinetics of a once-daily formulation of alfuzosin, 10 mg, was evaluated. In an open, single-dose study, 26 volunteers, ages 18 to 65 years, were classified as having normal renal function (n = 8) or mild (n = 6), moderate (n = 6), or severe (n = 6) renal impairment. Mean Cmax values increased by a factor of 1.20, 1.52, and 1.20 in subjects with mild, moderate, or severe renal impairment, respectively, compared with controls. Values for AUC(0-infinity) were 1.46, 1.47, and 1.44, respectively. The t(1/2z) was increased only in the group with severe renal impairment. Emergent vasodilatory adverse events were reported by 4 of 26 subjects. No discontinuations due to adverse events occurred. Laboratory parameters were satisfactory in all groups. In conclusion, once-daily alfuzosin, 10 mg, could be safely administered to patients with impaired renal function, and dosage adjustment does not seem necessary.
Abstract: BACKGROUND: Extended-release (ER) alfuzosin hydrochloride is the most recently approved alpha-adrenergic receptor antagonist (AARA) for the management of symptomatic benign prostatic hyperplasia (BPH). Although new to the United States, alfuzosin has been available in immediate-release (IR) and sustained-release (SR) formulations in other countries for many years. OBJECTIVE: This article reviews data on the pharmacodynamics, pharmacokinetics, efficacy, tolerability, drug-interaction potential, and dosing of alfuzosin ER. METHODS: Relevant articles were identified through MEDLINE, EMBASE, and International Pharmaceutical Abstracts searches of the English-language literature published between 1986 and September 2003 using the terms alfuzosin, alpha-adrenergic receptor antagonists, and quinazolines. The reference lists of identified articles were also searched, as were abstracts from annual meetings of the American Urological Association for the past 5 years. Data regarding the ER formulation were emphasized, and data involving the IR/SR formulations were included only when data for the ER formulation were not available or as needed for clarification. RESULTS: In comparative trials with its IR counterpart (alfuzosin ER 10 mg QD vs alfuzosin IR 2.5 mg TID), alfuzosin ER was an equieffective once-daily AARA. No comparative trials of alfuzosin ER with the SR (BID) formulation or with other AARAs were identified. Food has been found to exert a clinically important effect by enhancing the bioavailability of the ER formulation; thus, the drug should be taken on a full stomach. Hepatic impairment has been found to significantly delay the elimination of alfuzosin IF, which constitutes a contraindication to use of the ER formulation. Renal impairment does not appear to exert clinically important effects on the pharmacokinetics of alfuzosin ER. Adverse events with alfuzosin ER include dizziness, upper respiratory tract infection, headache, and fatigue, with hypotension and syncope reported rarely. Concurrent use of inhibitors of the cytochrome P450 3A4 isozyme (eg, ketoconazole, diltiazem, cimetidine, atenolol) can significantly elevate serum concentrations of alfuzosin and enhance its pharmacodynamic effects. CONCLUSIONS: In the absence of direct head-to-head comparative trials, the role of alfuzosin ER in the management of symptomatic BPH relative to that of other AARAs is unclear. Because the effect size (drug response minus placebo response) of alfuzosin ER is comparable to that of other AARAs, marked differences in efficacy are unlikely. Extrapolating from direct comparative trials between these agents and alfuzosin IR/SR, alfuzosin ER would be expected to have better cardiovascular tolerability (eg, in terms of dizziness and orthostasis) than prazosin, terazosin, or doxazosin, and to have similar tolerability to tamsulosin. However, the existing data do not suggest that alfuzosin ER is likely to represent a significant advance over tamsulosin.
Abstract: BACKGROUND: The formulas for heart rate (HR) correction of QT interval have been shown to overcorrect or undercorrect this interval with changes in HR. A Holter-monitoring method avoiding the need for any correction formulas is proposed as a means to assess drug-induced QT interval changes. METHODS: A thorough QT study included 2 single doses of the alpha1-adrenergic receptor blocker alfuzosin, placebo, and a QT-positive control arm (moxifloxacin) in 48 healthy subjects. Bazett, Fridericia, population-specific (QTcN), and subject-specific (QTcNi) correction formulas were applied to 12-lead electrocardio-graphic recording data. QT1000 (QT at RR = 1000 ms), QT largest bin (at the largest sample size bin), and QT average (average QT of all RR bins) were obtained from Holter recordings by use of custom software to perform rate-independent QT analysis. RESULTS: The 3 Holter end points provided similar results, as follows: Moxifloxacin-induced QT prolongation was 7.0 ms (95% confidence interval [CI], 4.4-9.6 ms) for QT1000, 6.9 ms (95% CI, 4.8-9.1 ms) for QT largest bin, and 6.6 ms (95% CI, 4.6-8.6 ms) for QT average. At the therapeutic dose (10 mg), alfuzosin did not induce significant change in the QT. The 40-mg dose of alfuzosin increased HR by 3.7 beats/min and induced a small QT1000 increase of 2.9 ms (95% CI, 0.3-5.5 ms) (QTcN, +4.6 ms [95% CI, 2.1-7.0 ms]; QTcNi, +4.7 ms [95% CI, 2.2-7.1 ms]). Data corrected by "universal" correction formulas still showed rate dependency and yielded larger QTc change estimations. The Holter method was able to show the drug-induced changes in QT rate dependence. CONCLUSIONS: The direct Holter-based QT interval measurement method provides an alternative approach to measure rate-independent estimates of QT interval changes during treatment.
Abstract: Ketoconazole is not known to be proarrhythmic without concomitant use of QT interval-prolonging drugs. We report a woman with coronary artery disease who developed a markedly prolonged QT interval and torsades de pointes (TdP) after taking ketoconazole for treatment of fungal infection. Her QT interval returned to normal upon withdrawal of ketoconazole. Genetic study did not find any mutation in her genes that encode cardiac IKr channel proteins. We postulate that by virtue of its direct blocking action on IKr, ketoconazole alone may prolong QT interval and induce TdP. This calls for attention when ketoconazole is administered to patients with risk factors for acquired long QT syndrome.
Abstract: OBJECTIVE: To investigate the effect of efavirenz on the ketoconazole pharmacokinetics in HIV-infected patients. METHODS: Twelve HIV-infected patients were assigned into a one-sequence, two-period pharmacokinetic interaction study. In phase one, the patients received 400 mg of ketoconazole as a single oral dose on day 1; in phase two, they received 600 mg of efavirenz once daily in combination with 150 mg of lamivudine and 30 or 40 mg of stavudine twice daily on days 2 to 16. On day 16, 400 mg of ketoconazole was added to the regimen as a single oral dose. Ketoconazole pharmacokinetics were studied on days 1 and 16. RESULTS: Pretreatment with efavirenz significantly increased the clearance of ketoconazole by 201%. C(max) and AUC(0-24) were significantly decreased by 44 and 72%, respectively. The T ((1/2)) was significantly shorter by 58%. CONCLUSION: Efavirenz has a strong inducing effect on the metabolism of ketoconazole.
Abstract: AIMS: To investigate the interaction between ketoconazole and darunavir (alone and in combination with low-dose ritonavir), in HIV-healthy volunteers. METHODS: Volunteers received darunavir 400 mg bid and darunavir 400 mg bid plus ketoconazole 200 mg bid, in two sessions (Panel 1), or darunavir/ritonavir 400/100 mg bid, ketoconazole 200 mg bid and darunavir/ritonavir 400/100 mg bid plus ketoconazole 200 mg bid, over three sessions (Panel 2). Treatments were administered with food for 6 days. Steady-state pharmacokinetics following the morning dose on day 7 were compared between treatments. Short-term safety and tolerability were assessed. RESULTS: Based on least square means ratios (90% confidence intervals), during darunavir and ketoconazole co-administration, darunavir area under the curve (AUC(12h)), maximum plasma concentration (C(max)) and minimum plasma concentration (C(min)) increased by 155% (80, 261), 78% (28, 147) and 179% (58, 393), respectively, compared with treatment with darunavir alone. Darunavir AUC(12h), C(max) and C(min) increased by 42% (23, 65), 21% (4, 40) and 73% (39, 114), respectively, during darunavir/ritonavir and ketoconazole co-administration, relative to darunavir/ritonavir treatment. Ketoconazole pharmacokinetics was unchanged by co-administration with darunavir alone. Ketoconazole AUC(12h), C(max) and C(min) increased by 212% (165, 268), 111% (81, 144) and 868% (544, 1355), respectively, during co-administration with darunavir/ritonavir compared with ketoconazole alone. CONCLUSIONS: The increase in darunavir exposure by ketoconazole was lower than that observed previously with ritonavir. A maximum ketoconazole dose of 200 mg day(-1) is recommended if used concomitantly with darunavir/ritonavir, with no dose adjustments for darunavir/ritonavir.
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.
Abstract: All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit), located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level). A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK) model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s) including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies.