Verlängerung der QT-Zeit
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Eklärungen für Patienten zu den Wirkstoffen
Monitorisierung von Etravirin und Sildenafil empfohlen.
Erniedrigte SildenafilkonzentrationenMechanismus: Etravirin ist ein schwacher Induktor von CYP3A4 sowie ein schwacher Inhibitor von CYP2C9, CYP2C19 und P-Glykoprotein. Sildenafil wird primär über CYP3A4 und zu einem geringeren Teil über CYP2C9 metabolisiert.
Effekt: In Kombination mit Etravirin sank die AUC von Sildenafil um 57% (Fachinformation). Dies geht möglicherweise mit einer reduzierten Sildenafilwirkung einher.
Massnahmen: Zunächst klinisches Monitorisieren der Sildenafilwirkung. Bei ungenügender Wirksamkeit unter Ko-Medikation mit Etravirin, Dosis von Sildenafil anpassen.
|Etravirin||1.28 [1.28,2.8] 1||1.11||1.22|
Die genannten Expositionsveränderungen beziehen sich jeweils auf Veränderungen der Plasmakonzentrations-Zeit-Kurve [ AUC ]. Eine Veränderung der Exposition von Ciprofloxacin haben wir nicht erkannt. Den Einfluss von Etravirin und Sildenafil können wir aktuell nicht abschätzen. Die Exposition von Etravirin erhöht sich auf 128%, wenn eine Kombination mit Ciprofloxacin (111%) und Sildenafil (122%) erfolgt. Die AUC liegt dabei je nach CYP2C9
Für die Berechnung der individuellen Expositionsveränderungen durch die Wechselwirkungen werden als Ausgangsbasis die pharmakokinetischen Parameter der durchschnittlichen Population verwendet.
Ciprofloxacin hat eine mittlere orale Bioverfügbarkeit [ F ] von 70%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell verändern. Die terminale Halbwertszeit [ t12 ] ist mit 3.5 Stunden eher kurz und konstante Plasmaspiegel [ Css ] werden schnell erreicht. Die Proteinbindung [ Pb ] ist mit 30% sehr schwach. Ungefähr 55.0% einer verabreichten Dosis werden unverändert über die Niere ausgeschieden und dieser Anteil wird selten durch Interaktionen verändert. Die Metabolisierung findet vor allem über CYP1A2 statt und der aktive Transport erfolgt zum Teil über BCRP, OATP1A2 und PGP. Unter anderem ist Ciprofloxacin ein Hemmer von CYP3A4.
Etravirin hat eine tiefe orale Bioverfügbarkeit [ F ] von 7%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell stark verändern. Die terminale Halbwertszeit [ t12 ] ist mit 35 Stunden eher lang und konstante Plasmaspiegel [ Css ] werden erst nach mehr als 140 Stunden erreicht. Die Proteinbindung [ Pb ] ist mit 99.9% sehr stark und das Verteilungsvolumen [ Vd ] ist mit 53 Liter gross. Die Metabolisierung findet unter anderem über CYP2C19, CYP2C9 und CYP3A4 statt. Unter anderem ist Etravirin nicht nur ein Hemmer von BCRP, PGP und CYP2C9 sondern auch Induktor von CYP3A4.
Sildenafil hat eine tiefe orale Bioverfügbarkeit [ F ] von 36%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell stark verändern. Die terminale Halbwertszeit [ t12 ] ist mit 3.9 Stunden eher kurz und konstante Plasmaspiegel [ Css ] werden schnell erreicht. Die Proteinbindung [ Pb ] ist mit 96% stark und das Verteilungsvolumen [ Vd ] ist mit 105 Liter sehr gross, Die Metabolisierung findet unter anderem über CYP2C9 und CYP3A4 statt und der aktive Transport erfolgt zum Teil über BCRP und PGP. Unter anderem ist Sildenafil ein Hemmer von CYP1A2, CYP2C19, CYP2C9 und CYP3A4.
|Serotonerge Effekte a||0||Ø||Ø||Ø|
Bewertung: Gemäss unseren Erkenntnissen erhöhen weder Ciprofloxacin, Etravirin noch Sildenafil die serotonerge Aktivität.
|Kiesel & Durán b||0||Ø||Ø||Ø|
Bewertung: Gemäss unseren Erkenntnissen erhöhen weder Ciprofloxacin, Etravirin noch Sildenafil die anticholinerge Aktivität.
Verlängerung der QT-Zeit
Bewertung: Ciprofloxacin kann potentiell ventrikuläre Arrhythmien vom Typ Torsades de pointes auslösen. Für Etravirin und Sildenafil ist uns kein QT-Zeit verlängerndes Potential bekannt.
|Periphere Neuropathie||4.0 %||0.0||4.0||n.a.|
Verschwommenes Sehen (2%): Sildenafil, Etravirin
Nierenversagen (2%): Ciprofloxacin, Etravirin
Hämorrhagische Blasenentzündung: Ciprofloxacin
Tubulointerstitielle Nephritis: Ciprofloxacin
Erhöhtes Serumkreatinin: Etravirin
Immunrekonstitutionssyndrom (1.9%): Etravirin
DRESS- Syndrom: Etravirin
Erbrechen (1.5%): Ciprofloxacin
Clostridium difficile Durchfall: Ciprofloxacin
Pankreatitis: Ciprofloxacin, Etravirin
Synkope: Sildenafil, Ciprofloxacin
Ventrikuläre Arrhythmie: Sildenafil
Pseudotumor cerebri: Ciprofloxacin
Erhöhter Hirndruck: Ciprofloxacin
Verstopfte Nase: Sildenafil
Toxische epidermale Nekrolyse: Ciprofloxacin, Etravirin
Stevens Johnson-Syndrom: Ciprofloxacin, Etravirin
Erythema multiforme: Etravirin
Thrombozytopenie: Ciprofloxacin, Etravirin
Aplastische Anämie: Ciprofloxacin
Hämolytische Anämie: Ciprofloxacin
Steatose der Leber: Etravirin
Diabetes mellitus: Etravirin
Myasthenia gravis: Ciprofloxacin
Basierend auf Ihren
Abstract: The pharmacokinetics of intravenous ciprofloxacin and its metabolites were characterized in 42 subjects with various degrees of renal function (group 1, Clcr (mL/min/1.73 m2) > 90, n = 10; group 2, Clcr 61-90, n = 11; group 3, Clcr 31-60, n = 11; group 4, Clcr < or = 30, n = 10). The dosage regimens were-groups 1 and 2: 400 mg i.v. at 8 hourly intervals; group 3: 400 mg i.v. at 12 hourly intervals and group 4: 300 mg i.v. at 12 hourly intervals. Subjects received a single dose on days 1 and 5 and multiple doses on days 2-4. Multiple plasma and urine samples were collected on days 1 and 5 for the analysis of ciprofloxacin and its metabolites (M1, M2 and M3). Plasma concentrations (Cmax and AUC) of ciprofloxacin and its M1 and M2 metabolites were significantly increased in subjects with reduced Clcr values (Clcr < 60 mL/min/1.73 m2) compared with normal subjects (Clcr > 90 mL/min/1.73 m2). A positive correlation was observed between ciprofloxacin clearance (Cl) and Clcr with a slope of 0.29 (r2 = 0.78) and between renal clearance (Clr) and Clcr with a slope of 0.19 (r2 = 0.84). For patients with severe infections a dosage regimen of 400 mg iv 8 hourly is appropriate in patients with Clcr > 60 mL/min/1.73 m2. In patients with Clcr values of 31-60 mL/min/1.73 m2 a dosage regimen of 400 mg 12 hourly provides similar plasma concentrations to those observed for subjects with Clcr 61-90 mL/min/1.73 m2 receiving 400 mg 8 hourly. Based on modeling of the plasma concentrations in subjects with Clcr < or = 30 ml/min/1.73 m2, a dosage regimen of 400 mg every 24 h will provide plasma concentrations similar to those observed in subjects with Clcr between 61-90 mL/min/1.73 m2 given 400 mg every 8 h.
Abstract: AIMS: To investigate the effect of the antiretroviral protease inhibitors saquinavir (soft gelatin capsule) and ritonavir on the pharmacokinetic properties and tolerability of sildenafil and to investigate the effect of sildenafil on the steady-state pharmacokinetics of saquinavir and ritonavir. METHODS: Two independent, 8 day, open, randomized, placebo-controlled, parallel-group studies (containing a double-blind crossover phase) were conducted at Pfizer Clinical research units (Canterbury, UK. and Brussels, Belgium). Twenty-eight healthy male volunteers entered each study. In each study, volunteers were randomized (n = 14 per group) to receive sildenafil on day 1 followed by a 7-day treatment period (days 2-8) with saquinavir or placebo (Study I) or ritonavir or placebo (Study II). Sildenafil or placebo (Study I and Study II) was administered alternately on day 7 or day 8, depending on initial randomization. The effect of saquinavir and ritonavir on the pharmacokinetics of sildenafil and its primary circulating metabolite (UK-103, 320) and the effect of single-dose sildenafil on the steady-state pharmacokinetics of saquinavir (1200 mg three times daily) and ritonavir (500 mg twice daily) were determined. The safety and tolerability of sildenafil coadministered with saquinavir or ritonavir were also assessed. RESULTS: Both protease inhibitors significantly increased Cmax, AUC, tmax and t(1/2) values for both sildenafil and UK-103, 320. Ritonavir showed a significantly greater effect than saquinavir with increases in sildenafil AUC and Cmax of 11-fold (95% CI: 9.0, 12.0) and 3.9-fold (95% CI: 3.2, 4.9), respectively. This compared with increases of 3.1-fold (95% CI: 2.5, 4.0) and 2.4-fold (95% CI: 1.8, 3.3) for coadministration with saquinavir. In contrast, the steady-state pharmacokinetics of saquinavir and ritonavir were unaffected by sildenafil. The increases in systemic exposure to sildenafil and UK-103, 320 were not associated with an increased incidence of adverse events or clinically significant changes in blood pressure, heart rate or ECG parameters. CONCLUSIONS: These results indicate that both saquinavir and ritonavir modify the pharmacokinetics of sildenafil presumably through inhibition of CYP3A4. The more pronounced effect of ritonavir may be attributed to its additional potent inhibition of CYP2C9. No change in safety or tolerability was observed when sildenafil was coadministered with either protease inhibitor. However, given the extent of the interactions, a lower sildenafil starting dose (25 mg) should be considered for patients receiving saquinavir and it is recommended not to exceed a maximum single dose of 25 mg in a 48 h period for patients receiving ritonavir.
Abstract: STUDY OBJECTIVE: To compare the rates of torsades de pointes associated with ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin administration. DESIGN: Retrospective database analysis. INTERVENTION: Evaluation of reported rates of torsades de pointes in patients who received these quinolones between January 1, 1996, and May 2, 2001. MEASUREMENTS AND MAIN RESULTS: In the United States, 25 cases of torsades de pointes associated with these quinolones (ciprofloxacin 2, ofloxacin 2, levofloxacin 13, gatifloxacin 8, moxifloxacin 0) were identified. Ciprofloxacin was associated with a significantly lower rate of torsades de pointes (0.3 cases/10 million prescriptions, 95% confidence interval [CI] 0.0-1.1) than levofloxacin (5.4/10 million, 95% CI 2.9-9.3, p<0.001) or gatifloxacin (27/10 million, 95% CI 12-53, p<0.001 for comparison with ciprofloxacin or levofloxacin). When the analysis was limited to the first 16 months after initial U.S. approval of the agent, the rates for levofloxacin (16/10 million) and gatifloxacin (27/10 million) were similar (p>0.5). CONCLUSION: Levofloxacin should be administered with caution in patients with risk factors for QT prolongation. Gatifloxacin should be avoided in the same patient population, and the recommended dosage of 400 mg/day should not be exceeded.
Abstract: BACKGROUND AND OBJECTIVES: Because of extensive first-pass metabolism, oral bioavailability of sildenafil reaches only 40%. Formation of the primary metabolite, N -desmethylsildenafil, is mainly mediated by the cytochrome P450 enzyme CYP3A4. In this study we investigated the influence of grapefruit juice, containing inhibitors of intestinal CYP3A4, on the pharmacokinetics of sildenafil and N -desmethylsildenafil. METHODS: In a randomized crossover study, 24 healthy white male volunteers received single 50-mg doses of sildenafil. Two doses each of 250 ml grapefruit juice or water, respectively, were administered 1 hour before and together with the drug. Plasma concentrations of sildenafil and N -desmethylsildenafil were determined up to 24 hours post dose by use of liquid chromatography-tandem mass spectrometry (limit of quantification, 1 ng/ml). RESULTS: Grapefruit juice changed the area under the sildenafil plasma concentration-time curve from time zero to infinity [AUC(0-infinity) from 620 [1.53] ng/ml x h to 761 [1.58] ng/ml x h (geometric mean with geometric standard deviation), corresponding to a 23% increase (90% confidence interval, 13%-33%). N-Desmethyl sildenafil AUC(0-infinity) increased by 24% (90% confidence interval, 17%-32%). Maximum plasma concentrations (C(max)) of sildenafil and N -desmethylsildenafil were essentially unchanged. There was a trend toward a prolonged time to reach C(max) during the grapefruit juice period (from a median of 0.75 hour to a median of 1.13 hours), corresponding to an increase by 0.25 hour (90% confidence interval, 0-0.63 hour). Interindividual variability was pronounced in both periods. CONCLUSIONS: Grapefruit juice increases sildenafil bioavailability and tends to delay sildenafil absorption. Sildenafil pharmacokinetics may become less predictable with grapefruit juice. Although patients usually will not be endangered by concomitant use of grapefruit juice, it seems advisable to avoid this combination.
Abstract: AIMS: To determine the absolute bioavailability, dose proportionality and the effects of food on the pharmacokinetics of single oral doses of sildenafil citrate. METHODS: Three open-label, randomized crossover studies were conducted in healthy male subjects. Absolute bioavailability was determined by comparing pharmacokinetic data after administration of single oral and intravenous 50-mg doses of sildenafil (n=12 subjects). Food effects were examined by comparing pharmacokinetic data for sildenafil and its primary circulating metabolite, UK-103,320, after administration of a single oral 100-mg dose in the fasted and fed states (n=34 subjects). Dose proportionality was assessed from pharmacokinetic data obtained after administration of four single oral doses of sildenafil (25, 50, 100 and 200 mg) to 32 subjects. The safety and tolerability of sildenafil were also assessed in all of these studies. RESULTS: The calculated absolute oral bioavailability of sildenafil was 41% (90% CI: 36--47). Food slowed the rate of absorption, delaying mean tmax by approximately 1 h and reducing Cmax by 29% (90% CI: 19--38). Systemic exposure, as assessed by the mean area under the plasma concentration--time curve (AUC), was reduced by 11% (90% CI: 6--16). These food effects were not considered to be of clinical significance. There was statistical evidence of nonproportionality in Cmax and AUC over the dose range 25--200 mg. However the degree of nonproportionality was small, with predicted increases in Cmax and AUC of 2.2- and 2.1-fold, respectively, for a doubling in dose, and was thought to be clinically nonsignificant. Sildenafil was well tolerated in the three studies; the majority of adverse events were mild and transient. CONCLUSIONS: Sildenafil had a mean absolute bioavailability of 41%. Food caused small reductions in the rate and extent of systemic exposure; these reductions are unlikely to be of clinical significance. Across the dose range of 25--200 mg, systemic exposure increased in a slightly greater than dose-proportional manner.
Abstract: AIMS: To examine the effect of concomitant cimetidine or antacid administration on the pharmacokinetic profile of sildenafil citrate in healthy male volunteers in two open-label, randomized studies. METHODS: The first study was a parallel-group design in which 22 healthy male volunteers received sildenafil (50 mg) on days 1 and 5 and cimetidine (800 mg) or placebo on days 3, 4, 5, and 6. Blood samples were collected predose and at specified times up to 48 h postdose on days 1 and 5 to determine plasma levels of sildenafil and its metabolite, UK-103,320. The second study was a two-way crossover design in which 12 volunteers received sildenafil with or without a 30-ml dose of a magnesium hydroxide/aluminium hydroxide antacid. Blood samples were collected and analysed as in the first study. The two study periods were separated by at least 14 days. RESULTS: Coadministration of cimetidine had no statistically significant effect on the tmax or kel of sildenafil but caused a statistically significant increase in sildenafil AUCt and Cmax of 56% and 54%, respectively (P<0.01). Differences between the two treatment groups were smaller for the metabolite than for sildenafil, although cimetidine treatment did significantly (P<0.05) increase the AUCt for UK-103,320 by 30%. Antacid coadministration had no statistically significant effect on any pharmacokinetic parameter of sildenafil or UK-103,320. Whether taken alone, with cimetidine, or with an antacid, sildenafil was well tolerated. Most adverse events were mild in nature, and no subject withdrew from either study for any reason related to the drug. CONCLUSIONS: Cimetidine co-administration produced an increase in sildenafil plasma levels; however, this increase is not sufficient to warrant dosage adjustment of either drug. Antacid coadministration had no effect on the pharmacokinetic profile of sildenafil.
Abstract: AIMS: Sildenafil, an effective oral treatment for erectile dysfunction, is predominantly metabolized by the cytochrome P450 isozyme 3A4, which is inhibited by a number of the macrolide antibiotics. Therefore, two placebo-controlled, parallel-group studies were conducted to evaluate the effects of multiple doses of erythromycin and azithromycin on the pharmacokinetics, safety and tolerability of a single oral 100-mg dose of sildenafil. METHODS: In the erythromycin interaction study, 26 male volunteers (18--45 years of age) received open-label sildenafil 100 mg on day 1. Half received blinded erythromycin (500 mg) twice daily on days 2--6, and the other half received placebo. On day 6, all subjects received a second 100-mg dose of sildenafil. In the azithromycin interaction study, 24 male volunteers (19--33 years of age) received open-label 100 mg sildenafil on day 1. Half then received blinded azithromycin (500 mg) once daily on days 2--4, and the other half received placebo. On day 4, all subjects received another 100-mg dose of sildenafil. In both studies, blood samples were collected on the first and last study day for the analysis of plasma concentrations of sildenafil and its primary metabolite, UK-103,320. RESULTS: Repeated dosing with erythromycin caused statistically significant increases in the AUC and Cmax of sildenafil (2.8-fold and 2.6-fold, respectively) but had no effect on Tmax, kel or t1/2. A statistically significant 1.4-fold increase in the AUC of UK-103,320 was also observed, as well as a significant decrease in kel, resulting in an increase of about 1 h in t1/2. In contrast, repeated dosing with azithromycin caused no significant change in any pharmacokinetic parameter of either sildenafil or UK-103,320. Erythromycin, azithromycin and sildenafil were well tolerated; adverse events were mild and transient. No subject withdrew from either trial for any reason related to study drug. CONCLUSIONS: These results indicate that erythromycin modifies the pharmacokinetics of sildenafil by inhibiting its CYP3A4-mediated first-pass metabolism. Given these data, a lower starting dose of sildenafil (25 mg) may be considered for patients receiving erythromycin or other potent CYP3A4 inhibitors. Azithromycin did not affect the pharmacokinetics of sildenafil; therefore, no adjustment in dosage is necessary for patients receiving these drugs concomitantly.
Abstract: Ciprofloxacin has been widely used for treating infections and has been found to have very low cardiovascular side effects. QTc prolongation with the use of ciprofloxacin is yet to be reported in literature. A case report highlighting QTc prolongation by use of ciprofloxacin is being presented.
Abstract: AIMS: To determine whether bosentan decreases the plasma concentration of sildenafil in patients with pulmonary arterial hypertension. METHODS: Ten patients (aged 39-77 years) with pulmonary arterial hypertension in WHO functional class III received bosentan 62.5 mg twice daily for 1 month, then 125 mg twice daily for a second month. Sildenafil 100 mg was given as a single dose before starting bosentan (visit 1) and at the end of each month of bosentan treatment (visits 2 and 3). Sildenafil and its primary metabolite, desmethylsildenafil, were measured in plasma at 0 h and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18 and 24 h using liquid chromatography-tandem mass spectrometry. Statistical analysis was by repeated measures anova, using log transformed data where appropriate. RESULTS: Treatment with bosentan 62.5 mg twice daily for 4 weeks was associated with a two-fold increase in sildenafil clearance/F and a 50% decrease in the AUC (P < 0.001). Increasing the dose of bosentan to 125 mg twice daily led to a further increase in sildenafil oral clearance and decrease in the AUC (P < 0.001 vs. 62.5 mg bosentan). The ratio of AUC on bosentan treatment relative to that of visit 1 was 0.47 [95% confidence interval (CI) 0.36, 0.61] for visit 2 and 0.31 (95% CI 0.23, 0.41) for visit 3 (P < 0.001). Sildenafil C(max) fell from 759 ng ml(-1) on visit 1 to 333 ng ml(-1) on visit 3 (P < 0.01) and there was a significant decrease in the plasma half-life of sildenafil on the higher bosentan dose (P < 0.05). The AUC and plasma half-life of desmethylsildenafil was also decreased by bosentan in a dose-dependent manner (P < 0.01). CONCLUSIONS: Bosentan significantly decreases the plasma concentration of sildenafil when coadministered to patients with pulmonary hypertension.
Abstract: Sildenafil used as oral drug treatment for erectile dysfunction is predominantly metabolized by the cytochrome P450 isozyme 3A4. The antidepressant fluvoxamine is an inhibitor of cytochrome P450 3A4. In a randomized, double-blind, placebo-controlled, crossover study, we evaluated the effects of fluvoxamine dosed to steady state on the pharmacokinetics and pharmacodynamics of sildenafil. Twelve healthy men received oral fluvoxamine or placebo for 10 days (50 mg every day on days 1-3; 100 mg every day on days 4-10). On day 11, all participants received a single, oral, open-label dose of 50 mg sildenafil, and blood samples were collected for analysis of sildenafil plasma concentrations by liquid chromatography/mass spectrometry. Concurrently, the effect of sildenafil on venodilation induced by a constant dose of sodium nitroprusside was assessed using the dorsal hand vein compliance technique. Sildenafil was well tolerated in the presence of fluvoxamine. During fluvoxamine, sildenafil exposure (area under the curve) significantly increased by 40% (P < 0.001), and its half-life increased by 19% (P = 0.034). Concurrently, sodium nitroprusside-induced venodilation was significantly augmented by 59% during fluvoxamine compared to placebo (P = 0.012). In conclusion, sildenafil kinetics are mildly affected by fluvoxamine which translates into an increase in vascular sildenafil effects. Whereas the pharmacokinetic changes do not suggest a large clinically relevant interaction, it may be prudent to consider a starting dose of 25 mg in patients concurrently treated with fluvoxamine.
Abstract: Sildenafil is the first oral therapeutic agent for the management of male erectile dysfunction. Its oral bioavailability is only 40% due to extensive presystemic elimination, mainly by CYP3A4. This study examined the effect of coadministration of ciprofloxacin or clarithromycin, which inhibit CYP3A4, on the bioavailability and pharmacokinetics of sildenafil. Twelve healthy male volunteers received sildenafil alone or after pretreatment with the inhibitors in a balanced three-way crossover design. The pharmacokinetic analysis showed that ciprofloxacin coadministration with sildenafil significantly increased the AUC from 1407 +/- 380 to 2986 +/- 917 microg h/l (90% confidence interval 119%-159%) and the Cmax from 287 +/- 67 to 623 +/- 192 microg/l (90% confidence interval 127%-152%). Similarly, clarithromycin coadministration increased sildenafil AUC from 1407 +/- 380 to 3209 +/- 762 microg h/l (90% confidence interval 127%-161%) and Cmax from 287 +/- 67 to 694 +/- 259 microg/l (90% confidence interval 132%-157%). Ciprofloxacin coadministration and clarithromycin coadministration with sildenafil did not affect the rate of sildenafil absorption significantly. These results indicate that coadministration of ciprofloxacin and clarithromycin significantly increased sildenafil bioavailability which can be attributed to the inhibitory effect of ciprofloxacin and clarithromycin on CYP3A4. Dose adjustment of sildenafil is thus necessary when administered with such drugs.
Abstract: The new respiratory fluoroquinolones (gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, and on the horizon, garenoxacin) offer many improved qualities over older agents such as ciprofloxacin. These include retaining excellent activity against Gram-negative bacilli, with improved Gram-positive activity (including Streptococcus pneumoniae and Staphylococcus aureus). In addition, gatifloxacin, moxifloxacin and garenoxacin all demonstrate increased anaerobic activity (including activity against Bacteroides fragilis). The new fluoroquinolones possess greater bioavailability and longer serum half-lives compared with ciprofloxacin. The new fluoroquinolones allow for once-daily administration, which may improve patient adherence. The high bioavailability allows for rapid step down from intravenous administration to oral therapy, minimizing unnecessary hospitalization, which may decrease costs and improve quality of life of patients. Clinical trials involving the treatment of community-acquired respiratory infections (acute exacerbations of chronic bronchitis, acute sinusitis, and community-acquired pneumonia) demonstrate high bacterial eradication rates and clinical cure rates. In the treatment of community-acquired respiratory tract infections, the various new fluoroquinolones appear to be comparable to each other, but may be more effective than macrolide or cephalosporin-based regimens. However, additional data are required before it can be emphatically stated that the new fluoroquinolones as a class are responsible for better outcomes than comparators in community-acquired respiratory infections. Gemifloxacin (except for higher rates of hypersensitivity), levofloxacin, and moxifloxacin have relatively mild adverse effects that are more or less comparable to ciprofloxacin. In our opinion, gatifloxacin should not be used, due to glucose alterations which may be serious. Although all new fluoroquinolones react with metal ion-containing drugs (antacids), other drug interactions are relatively mild compared with ciprofloxacin. The new fluoroquinolones gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin have much to offer in terms of bacterial eradication, including activity against resistant respiratory pathogens such as penicillin-resistant, macrolide-resistant, and multidrug-resistant S. pneumoniae. However, ciprofloxacin-resistant organisms, including ciprofloxacin-resistant S. pneumoniae, are becoming more prevalent, thus prudent use must be exercised when prescribing these valuable agents.
Abstract: AIMS: Etravirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild-type and NNRTI-resistant HIV. Proton pump inhibitors and H(2)-antagonists are frequently used in the HIV-negative-infected population, and drug-drug interactions have been described with other antiretrovirals. This study evaluated the effect of steady-state omeprazole and ranitidine on the pharmacokinetics of a single dose of etravirine. METHODS: In an open-label, randomized, one-way, three-period crossover trial, HIV-negative volunteers randomly received a single dose of 100 mg etravirine alone (treatment A); 11 days of 150 mg ranitidine b.i.d. (treatment B); and 11 days of 40 mg omeprazole q.d. (treatment C). A single dose of 100 mg etravirine was co-administered on day 8 of sessions 2 and 3. Each session was separated by a 14-day wash-out. RESULTS: Nineteen volunteers (seven female) participated. When a single dose of etravirine was administered in the presence of steady-state ranitidine, etravirine least squares means ratios (90% confidence interval) for AUC(last) and C(max) were 0.86 (0.76, 0.97) and 0.94 (0.75, 1.17), respectively, compared with administration of etravirine alone. When administered with steady-state omeprazole, these values were 1.41 (1.22, 1.62) and 1.17 (0.96, 1.43), respectively. Co-administration of a single dose of etravirine and ranitidine or omeprazole was generally safe and well tolerated. CONCLUSIONS: Ranitidine slightly decreased etravirine exposure, whereas omeprazole increased it by approximately 41%. The increased exposure of etravirine when co-administered with omeprazole is attributed to CYP2C19 inhibition. Considering the favourable safety profile of etravirine, these changes are not clinically relevant. Etravirine can be co-administered with proton pump inhibitors and H(2) antagonists without dose adjustments.
Abstract: Etravirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) developed for the treatment of HIV-1 infection. It has a high genetic barrier to the emergence of viral resistance, and maintains its antiviral activity in the presence of common NNRTI mutations. The pharmacokinetics of etravirine in HIV-infected patients at the recommended dosage of 200 mg twice daily demonstrates moderate intersubject variability and no time dependency. Due to substantially lower exposures when taken on an empty stomach, etravirine should be administered following a meal. The drug is highly protein bound (99.9%) to albumin and alpha(1)-acid glycoprotein and shows a relatively long elimination half-life of 30-40 hours. Etravirine is metabolized by cytochrome P450 (CYP) 3A, 2C9 and 2C19; the metabolites are subsequently glucuronidated by uridine diphosphate glucuronosyltransferase. Renal elimination of etravirine is negligible. Etravirine has the potential for interactions by inducing CYP3A and inhibiting CYP2C9 and 2C19; it is a mild inhibitor of P-glycoprotein but not a substrate. The drug interaction profile of etravirine has been well characterized and is manageable. No dosage adjustments are needed in patients with renal impairment or mild to moderate hepatic impairment. Race, sex, bodyweight and age do not affect the pharmacokinetics of etravirine. In the two phase III trials DUET-1 and DUET-2, no relationship was demonstrated between the pharmacokinetics of etravirine and the primary efficacy endpoint of viral load below 50 copies/mL or the safety profile of etravirine.
Abstract: Drug-drug interactions are frequently encountered in the therapy of HIV-infected patients, since the highly active antiretroviral therapy always contains several drugs. Drugs against opportunistic infections and concomitant diseases are added frequently. All protease inhibitors are inhibitors of CYP3A, which is important in the metabolism of approximately 50% of all drugs, e.g. simvastatin, atorvastatin, sildenafil, and clarithromycin. Among the protease inhibitors, ritonavir is the strongest inhibitor of CYP3A activity. This inhibition is also used to enhance ("boost") the bioavailability of other protease inhibitors. The nonnucleoside reverse transcriptase inhibitors (NNRTI) efavirenz and nevirapine lead to an increase in CYP3A activity during long-term treatment. To prevent interactions, doses of CYP3A substrates have to be adapted in the beginning and at the end of CYP3A activity-modifying treatments. Interactions can also be a result of modifications in the activities of glucuronosyltransferases and of transport proteins. Ritonavir is an inhibitor of P-glycoprotein, which leads to increased expositions towards many antineoplastic drugs.
Abstract: Etravirine (ETR) belongs to the family of non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs), with antiviral activity in patients with resistance to first-generation NNRTIs. The drug interactions caused by ETR are due to its dual effect on the CYP450 system. ETR acts as an inducer of CYP3A4 and inhibitor of CYP2C9 and CYP2C19. This drug shows few clinically significant drug interactions, the most important of which involve the unboosted protease inhibitors, the NNRTIs efavirenz and nevirapine, full-dose ritonavir and tipranavir/ritonavir. Interaction with fosamprenavir/ritonavir is not clinically significant, although their plasma levels vary slightly when used in combination with ETR. ETR shows no interactions with darunavir/ritonavir.
Abstract: Etravirine (formerly TMC125) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild-type and NNRTI-resistant strains of HIV-1. Etravirine has been approved in several countries for use as part of highly active antiretroviral therapy in treatment-experienced patients. In vivo, etravirine is a substrate for, and weak inducer of, the hepatic cytochrome P450 (CYP) isoenzyme 3A4 and a substrate and weak inhibitor of CYP2C9 and CYP2C19. Etravirine is also a weak inhibitor of P-glycoprotein. An extensive drug-drug interaction programme in HIV-negative subjects has been carried out to assess the potential for pharmacokinetic interactions between etravirine and a variety of non-antiretroviral drugs. Effects of atorvastatin, clarithromycin, methadone, omeprazole, oral contraceptives, paroxetine, ranitidine and sildenafil on the pharmacokinetic disposition of etravirine were of no clinical relevance. Likewise, etravirine had no clinically significant effect on the pharmacokinetics of fluconazole, methadone, oral contraceptives, paroxetine or voriconazole. No clinically relevant interactions are expected between etravirine and azithromycin or ribavirin, therefore, etravirine can be combined with these agents without dose adjustment. Fluconazole and voriconazole increased etravirine exposure 1.9- and 1.4-fold, respectively, in healthy subjects, however, no increase in the incidence of adverse effects was observed in patients receiving etravirine and fluconazole during clinical trials, therefore, etravirine can be combined with these antifungals although caution is advised. Digoxin plasma exposure was slightly increased when co-administered with etravirine. No dose adjustments of digoxin are needed when used in combination with etravirine, however, it is recommended that digoxin levels should be monitored. Caution should be exercised in combining rifabutin with etravirine in the presence of certain boosted HIV protease inhibitors due to the risk of decreased exposure to etravirine. Although adjustments to the dose of clarithromycin are unnecessary for the treatment of most infections, the use of an alternative macrolide (e.g. azithromycin) is recommended for the treatment of Mycobacterium avium complex infection since the overall activity of clarithromycin against this pathogen may be altered when co-administered with etravirine. Dosage adjustments based on clinical response are recommended for clopidogrel, HMG-CoA reductase inhibitors (e.g. atorvastatin) and for phosphodiesterase type-5 inhibitors (e.g. sildenafil) because changes in the exposure of these medications in the presence of co-administered etravirine may occur. When co-administered with etravirine, a dose reduction or alternative to diazepam is recommended. When combining etravirine with warfarin, the international normalized ratio (INR) should be monitored. Systemic dexamethasone should be co-administered with caution, or an alternative to dexamethasone be found as dexamethasone induces CYP3A4. Caution is also warranted when co-administering etravirine with some antiarrhythmics, calcineurin inhibitors (e.g. ciclosporin) and antidepressants (e.g. citalopram). Co-administration of etravirine with some antiepileptics (e.g. carbamazepine and phenytoin), rifampicin (rifampin), rifapentine or preparations containing St John's wort (Hypericum perforatum) is currently not recommended as these are potent inducers of CYP3A and/or CYP2C and may potentially decrease etravirine exposure. Antiepileptics that are less likely to interact based on their known pharmacological properties include gabapentin, lamotrigine, levetiracetam and pregabalin. Overall, pharmacokinetic and clinical data show etravirine to be well tolerated and generally safe when given in combination with non-antiretroviral agents, with minimal clinically significant drug interactions and no need for dosage adjustments of etravirine in any of the cases, or of the non-antiretroviral agent in the majority of cases studied.
Abstract: OBJECTIVES: This study was conducted to compare the effect of CYP3A5*3 genotype on the disposition of three phosphodiesterase type 5 inhibitors (PDE5Is), vardenafil, sildenafil, and udenafil, because our previous in-vitro microsomal incubation study showed that the relative contribution of CYP3A5 enzyme to their metabolism was different among these PDE5Is. METHODS: An open-label three-way crossover study was performed with a single oral dose of PDE5Is (20 mg vardenafil, 100 mg sildenafil, or 200 mg udenafil) in 21 healthy men carrying CYP3A5*1/*1, *1/*3, or *3/*3. After each dose, plasma concentrations of the parents and their major metabolites were measured up to 24 or 48 h. RESULTS: The AUC(∞) and C(max) of vardenafil were 2.9-fold and 3.1-fold higher in CYP3A5*3/*3 carriers than in individuals with CYP3A5*1/*1 (P=0.003 and 0.002, respectively). The AUC(∞) and C(max) of sildenafil were 1.5-fold and 1.7-fold higher in CYP3A5*3/*3 carriers compared with individuals with CYP3A5*1/*1, but the statistical difference of both parameters among genotype groups was not observed. The disposition of udenafil differed little among groups in relation to the CYP3A5*3 allelic variant. CONCLUSION: These results suggest that the disposition of these PDE5Is are differently influenced by the CYP3A5*3 genotype of individual participants. The CYP3A5*3 genotype affects the oral disposition of vardenafil significantly. The pharmacokinetic diversity of PDE5Is in relation to CYP3A5 genotype may lead to the clinical response variation and remains to be evaluated.
Abstract: OBJECTIVES: We aimed to characterize the efflux transport properties of vardenafil and sildenafil, and to compare the kinetics of these compounds via efflux transporters such as P-gp, BCRP and MRP2. METHODS: We measured the basal-to-apical and apical-to-basal transport of vardenafil and sildenafil within the concentration range of 1-100 µm using MDCKII cells overexpressing P-gp, BCRP and MRP2, and Caco-2 cells. KEY FINDINGS: Vardenafil had a much greater basal-to-apical than apical-to-basal transport rate in MDCKII cells overexpressing P-gp, BCRP and MRP2. Sildenafil showed P-gp- and BCRP-mediated efflux transport, but did not seem to be pumped out via MRP2 transporters. Consequently, the absorptive transport of vardenafil and sildenafil in Caco-2 cells increased linearly over the concentration range of 1-100 µm, whereas the secretory transport of these drugs was saturable and inhibited by the presence of specific inhibitors of P-gp and BCRP. MK571, a representative MRP2 inhibitor, inhibited the basal-to-apical transport of vardenafil, but not of sildenafil. CONCLUSION: The involvement of P-gp, BCRP and MRP2 for vardenafil and the involvement of P-gp and BCRP for sildenafil in the secretory transport with linear absorptive transport may contribute to the limited intestinal absorption of these drugs.
Abstract: Fluoroquinolone antimicrobial drugs are absorbed efficiently after oral administration despite of their hydrophilic nature, implying an involvement of carrier-mediated transport in their membrane transport process. It has been that several fluoroquinolones are substrates of organic anion transporter polypeptides OATP1A2 expressed in human intestine derived Caco-2 cells. In the present study, to clarify the involvement of OATP in intestinal absorption of ciprofloxacin, the contribution of Oatp1a5, which is expressed at the apical membranes of rat enterocytes, to intestinal absorption of ciprofloxacin was investigated in rats. The intestinal membrane permeability of ciprofloxacin was measured by in situ and the vascular perfused closed loop methods. The disappeared and absorbed amount of ciprofloxacin from the intestinal lumen were increased markedly in the presence of 7,8-benzoflavone, a breast cancer resistance protein inhibitor, and ivermectin, a P-glycoprotein inhibitor, while it was decreased significantly in the presence of these inhibitors in combination with naringin, an Oatp1a5 inhibitor. Furthermore, the Oatp1a5-mediated uptake of ciprofloxacin was saturable with a K(m) value of 140 µm, and naringin inhibited the uptake with an IC(50) value of 18 µm by Xenopus oocytes expressing Oatp1a5. Naringin reduced the permeation of ciprofloxacin from the mucosal-to-serosal side, with an IC(50) value of 7.5 µm by the Ussing-type chamber method. The estimated IC(50) values were comparable to that of Oatp1a5. These data suggest that Oatp1a5 is partially responsible for the intestinal absorption of ciprofloxacin. In conclusion, the intestinal absorption of ciprofloxacin could be affected by influx transporters such as Oatp1a5 as well as the efflux transporters such as P-gp and Bcrp.
Abstract: BACKGROUND: Etravirine is a non-nucleoside reverse transcriptase inhibitor indicated in combination with other antiretrovirals for treatment-experienced HIV patients ≥6 years of age. Etravirine is primarily metabolized by cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A. This analysis determined the impact of concomitant antiretrovirals and CYP2C9/CYP2C19 phenotype on the pharmacokinetics of etravirine. METHODS: We used 4728 plasma concentrations from 817 adult subjects collected from four clinical studies to develop the population pharmacokinetic model. The presence of atazanavir/ritonavir, lopinavir/ritonavir, darunavir/ritonavir, tenofovir disoproxil fumarate, or enfuvirtide together with the CYP2C9 and CYP2C19 phenotype and other demographics were evaluated. RESULTS: A one-compartment model with first-order input and a lag-time best described the data. Estimates of apparent total clearance (CL/F), apparent central volume of distribution (V,/F), first-order absorption rate constant (k,), and absorption lag-time were 41.7 L/h, 972 L, 1.16 h, and 1.32 h, respectively. Estimates of between-subject variability on CL/F, V,/F, and relative bioavailability (F) were 39.4 %CV (percentage coefficient of variation), 35.9 %CV and 35.5 %CV, respectively. Between-occasion variability on F was estimated to be 30.0 %CV. CL/F increased non-linearly with body weight and creatinine clearance (CL,), and also varied based on CYP2C9/CYP2C19 phenotype. CONCLUSIONS: In this analysis, body weight, CL,, and CYP2C9/CYP2C19 phenotype were found to describe some of the variability in CL/F. It was not possible to show an impact of concomitant antiretrovirals on the pharmacokinetics of etravirine for adults predominantly taking coadministered boosted protease inhibitors as a background antiretroviral regimen.
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.