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 ciprofloxacin and etravirine. Please also consult the relevant specialist information.
|Etravirine||1.11 [1.11,2.24] 1||1.11|
The changes in exposure mentioned relate to changes in the plasma concentration-time curve [AUC]. We did not detect any change in exposure to ciprofloxacin. We cannot currently estimate the influence of etravirine. Etravirine exposure increases to 111%, when combined with ciprofloxacin (111%). The AUC is between 111% and 224% depending on the CYP2C9
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Ciprofloxacin has a mean oral bioavailability [ F ] of 70%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather short at 3.5 hours and constant plasma levels [ Css ] are reached quickly. The protein binding [ Pb ] is very weak at 30%. About 55.0% of an administered dose is excreted unchanged via the kidneys and this proportion is seldom changed by interactions. The metabolism mainly takes place via CYP1A2 and the active transport takes place partly via BCRP, OATP1A2 and PGP.
Etravirine has a low oral bioavailability [ F ] of 7%, which is why the maximum plasma level [Cmax] tends to change strongly with an interaction. The terminal half-life [ t12 ] is rather long at 35 hours and constant plasma levels [ Css ] are only reached after more than 140 hours. The protein binding [ Pb ] is very strong at 99.9% and the volume of distribution [ Vd ] is 53 liters. The metabolism takes place via CYP2C19, CYP2C9 and CYP3A4, among others.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither ciprofloxacin nor etravirine increase serotonergic activity.
|Kiesel & Durán b||0||Ø||Ø|
Rating: According to our findings, neither ciprofloxacin nor etravirine increase anticholinergic activity.
QT time prolongation
Rating: Ciprofloxacin can trigger potentially torsades de pointes ventricular arrhythmias. We do not know of any QT-prolonging potential for etravirine.
General adverse effects
|Side effects||∑ frequency||cip||etr|
|Peripheral neuropathy||4.0 %||0.0||4.0|
|Nasal discharge||3.0 %||3.0||n.a.|
|Myocardial infarction||2.9 %||+||1.9|
|Renal failure||2.0 %||+||+|
Immune reconstitution syndrome (1.9%): etravirine
Hypersensitivity reaction: ciprofloxacin
DRESS syndrome: etravirine
Vomiting (1.5%): ciprofloxacin
Clostridium difficile diarrhea: ciprofloxacin
Gastrointestinal hemorrhage: ciprofloxacin
Pancreatitis: ciprofloxacin, etravirine
Atrial fibrillation: etravirine
Toxic epidermal necrolysis: ciprofloxacin, etravirine
Stevens johnson syndrome: ciprofloxacin, etravirine
Erythema multiforme: etravirine
Thrombocytopenia: ciprofloxacin, etravirine
Aplastic anemia: ciprofloxacin
Hemolytic anemia: ciprofloxacin
Liver failure: ciprofloxacin
Steatosis of liver: etravirine
Diabetes mellitus: etravirine
Hemorrhagic cystitis: ciprofloxacin
Tubulointerstitial nephritis: ciprofloxacin
Elevated serum creatinine: etravirine
Disturbance of attention: ciprofloxacin
Memory impairment: ciprofloxacin
Pseudotumor cerebri: ciprofloxacin
Raised intracranial pressure: ciprofloxacin
Blurred vision: etravirine
Myasthenia gravis: ciprofloxacin
Rupture of tendon: ciprofloxacin
Aortic aneurysm: ciprofloxacin
Based on your
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: 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: 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: 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: 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.