Mg Dose Of Moxifloxacin Research Articles

The predictive ability of the QT response in supine-standing test for drug induced QT prolongation

Abstract Funding Acknowledgements Type of funding sources: None. Introduction A significant cause of sudden cardiac death is arrhythmias induced by QT prolongation. The acquired long QT syndrome is much more common than the congenital form. A major cause of acquired long QT prolongation is drug exposure. Drug-induced QT prolongation is common when taking cardiac drugs such as antiarrhythmics but also common with other medication groups such as antibiotics, antihistamines, and psychiatric drugs. These medications prolong QT by inhibiting the HERG channel which controls the rectifier potassium current (IKr) and prolong depolarization. As HERG inhibition is multifactorial an individual’s effect of medications on QT is difficult to predict and thus leaving many patients with significant risk once they initiate treatment with such medications. In the last decade, tests that measure the QT reaction to sudden changes in heart rate while changing position for supine to standing have shown usefulness in assessing the possibility of congenital long QT in patients with equivocal QT interval, probably by measuring the repolarization reserve which is deficient in patients with congenital long QT syndrome. Lol Purpose We sought to identify whether the same tests can be useful in prediction of acquired QT prolongation after exposure to HERG potassium channel suppressing medications. Methods Fifty four healthy volunteers undergone a supine-standing test where QT changes: QT stretching, and QT stunning were examined after brisk standing. Afterward the volunteers received one 400 mg dose of moxifloxacin, a drug known to prolong QT by affecting the HERG channel. Results of the standing test were compared to the drug effects on QTc and predictive ability was assessed. Results There was no significant correlation between the maximal drug evoked QTc prolongation and either change in QTc during the stretching or stunning phase (R=0.090, p= 0.538 and R=0.224, p=0.176 accordingly). Both stunning and stretching tests results did not differ significantly between patient with a significant (>20msecs) QT prolongation in response to drugs and no such prolongation (p> 0.361). The area under the ROC curves of the QTc prolongation during both phases stunning phase did not show usefulness in predicting substantial QTc prolongation (>20msec) during drug therapy with an AUCs of 0.593 (95% CI 0.418-0.769) and 0.617 (95%CI 0.375-0.859) accordingly. Conclusions Repolarization reserve assessment using a simple brisk standing test did not efficiently aid in predict QT drug response in patients treated with HERG inhibiting drugs.

Effects of buprenorphine on QT intervals in healthy subjects: results of 2 randomized positive- and placebo-controlled trials

ABSTRACTObjectives: To study the effect of transdermal buprenorphine on QTc prolongation at dose levels of 10, 40, and 80 mcg/h, (BTDS 10, BTDS 40, BTDS 80).Methods: Two randomized, placebo- and positive-controlled, parallel-group, dose-escalating clinical studies evaluated healthy adult subjects randomized to BTDS, placebo, or moxifloxacin in the first study; and to BTDS only, BTDS plus naltrexone, naltrexone alone at the same dose, placebo, or moxifloxacin in the second study. QT intervals were corrected for heart rate using data from each individual subject (QTcI).Results: In the first study (n = 44), the maximum upper bounds of the 90% confidence interval (CI) for mean placebo-corrected change from baseline in QTcI across 13 time points over 24 h were: 10.0 msec for BTDS 10 (Day 6) and 13.3 msec for BTDS 40 (Day 13); and 17.0 msec (Day 6) and 15.5 msec (Day 13) for moxifloxacin, respectively. Similarly, in the second study (n = 66), the upper bound of the 90% CI for mean placebo-corrected change from baseline for QTcI was under 10 msec at all time points for BTDS 10 (maximum upper bound, 5.63 msec), over 10 msec at 5 time points for BTDS 40 (maximum 11.81 msec) and over 10 msec at all 13 time points for BTDS 80 (maximum, 14.14 msec). Naltrexone administered with BTDS eliminated the QTcI prolongation seen with supratherapeutic BTDS doses (BTDS 40, BTDS 80) administered without naltrexone.Conclusions: At the therapeutic dose of 10 mcg/h, BTDS has no clinically significant effect on QTc. At supratherapeutic doses of 40 and 80 mcg/h, BTDS treatment produces prolongation of QTcI similar in magnitude to that produced by a 400 mg dose of moxifloxacin. Despite the modest, dose-dependent increase in QTcI noted in these studies, transdermal buprenorphine has not been associated with proarrhythmic effects.

Effect of Retosiban on Cardiac Repolarization in a Randomized, Placebo- and Positive-controlled, Crossover Thorough QT/QTc Study in Healthy Men and Women

PurposeRetosiban is a small molecule oxytocin receptor antagonist that is under evaluation in clinical studies for treatment of spontaneous preterm labor. A Thorough QT/QTc study was conducted to evaluate the effect of retosiban on cardiac repolarization according to International Conference on Harmonization E14 guidance. This was a randomized, placebo- and positive-controlled, single-dose, crossover study of healthy men and women. MethodsAll study participants received a 100 mg dose of retosiban (therapeutic target exposure), a 800 mg dose of retosiban (supratherapeutic target exposure), a 400 mg dose of moxifloxacin (positive control), and placebo with an appropriate washout. Holter monitoring data at baseline (predose) and at 13 subsequent time points during the next 24 hours were extracted and manually read by a central ECG reader who was blinded to the treatment assignment and corrected for heart rate by using the Fridericia formula (QTcF). A linear exposure-QTc response model was developed: ΔΔQTcF=RI+Cp,R⋅RS+MI+Cp,M⋅MS, where RI and MI are intercept terms for retosiban and moxifloxacin, respectively, RS and MS are slope terms for retosiban and moxifloxacin, respectively, and Cp,R and Cp,M are plasma concentrations for retosiban and moxifloxacin, respectively. FindingsA total of 52 healthy men (n = 27) and women (n = 25), with a mean age of 32 years, were enrolled in the study, and 43 (83%) completed all treatment periods and assessments. Mean placebo-corrected change from baseline QT (ΔΔQTcF) for the 2 retosiban dose groups revealed statistically significant decreases in ΔΔQTcF between 2 and 3 hours after administration, reaching a value of −2.5 msec for both retosiban dose groups. The 400 mg moxifloxacin group had a statistically significant increase in the ΔΔQTcF value at 0.75 hours after administration, reaching a maximal increase of 11.10 msec at 4 hours after administration. Results of the exposure-QTc response modeling revealed that there was no significant effect of retosiban on the ΔΔQTcF at therapeutic exposures. For the supratherapeutic exposure of retosiban, there was a slight negative effect, with a mean decrease of −3.05 msec. The moxifloxacin arm had a mean increase in ΔΔQTcF of 10.7 msec. ImplicationsAt therapeutic and supratherapeutic exposures, retosiban had no significant effect on cardiac repolarization, as estimated by the ΔΔQTcF. However, both doses of retosiban had a minor shortening effect. This is not considered to be clinically significant. ClinicalTrials.gov identifierNCT01702376.

Pharmacokinetic-pharmacodynamic analysis to evaluate the effect of moxifloxacin on QT interval prolongation in healthy Korean male subjects.

A single 400 mg dose of moxifloxacin has been the standard positive control for thorough QT (TQT) studies. However, it is not clearly known whether a 400 mg dose is also applicable to TQT studies in Asian subjects, including Koreans. Thus, we aimed to develop a pharmacokinetic (PK)-pharmacodynamic (PD) model for moxifloxacin, to evaluate the time course of its effect on QT intervals in Koreans. Data from three TQT studies of 33 healthy male Korean subjects who received 400 and 800 mg of moxifloxacin and placebo (water) were used. Twelve-lead electrocardiograms were taken for 2 consecutive days: 1 day to record diurnal changes and the next day to record moxifloxacin or placebo effects. Peripheral blood samples were also obtained for PK analysis. The PK-PD data obtained were analyzed using a nonlinear mixed-effects method (NONMEM ver. 7.2). A two-compartment linear model with first-order absorption provided the best description of moxifloxacin PK. Individualized QT interval correction, by heart rate, was performed by a power model, and the circadian variation of QT intervals was described by two mixed-effect cosine functions. The effect of moxifloxacin on QT interval prolongation was well explained by the nonlinear dose-response (Emax) model, and the effect by 800 mg was only slightly greater than that of 400 mg. Although Koreans appeared to be more sensitive to moxifloxacin-induced QT prolongation than were Caucasians, the PK-PD model developed suggests that a 400 mg dose of moxifloxacin is also applicable to QT studies in Korean subjects.

A thorough QT study in the context of an uptitration regimen with selexipag, a selective oral prostacyclin receptor agonist.

The effects of selexipag and its active metabolite ACT-333679 on cardiac repolarization were assessed in a thorough QT study as per International Conference on Harmonisation E14 guidance. In this randomized, double-blind, placebo/positive-controlled, parallel-group study, healthy male and female subjects were randomized to receive escalating doses of selexipag (n=91) or placebo/moxifloxacin (n=68). Ascending multiple doses of selexipag in the range of 400–1,600 μg or placebo were administered twice daily for 21 days. Following a nested crossover design, subjects in the moxifloxacin/placebo treatment group received a single oral 400 mg dose of moxifloxacin on day 2 or 24. The primary endpoint (QT interval correction using individualized formula [QTcI]) was chosen based on a prospectively defined test applied to on-treatment data. The mean baseline-adjusted placebo-corrected ΔQTcI (ΔΔQTcI) for selexipag was small at all time points and never exceeded 1.4 msec (upper bound of 90% confidence interval [CI], 3.9 msec) on 800 μg or –0.7 msec (upper bound of 90% CI, 2.1 msec) on 1,600 μg. The mean ΔΔQTcI peak effect for moxifloxacin was 7.5 msec (lower bound of 90% CI, 4.8 msec). The exposure-response analysis did not demonstrate a relevant relationship between plasma concentrations of selexipag or ACT-333679 and ΔΔQTcI but, in contrast, a positive slope within the expected range for moxifloxacin. In conclusion, selexipag does not have an effect on cardiac repolarization.

Thorough QT Studies

The International Conference on Harmonisation E14 Guidance was successful in largely standardizing the conduct of the so-called thorough QT/QTc studies (TQTS). Nevertheless, there is still a spectrum of frequently encountered problems with details of design, conduct and interpretation of TQTS. Several of these challenges are reviewed here, starting with explaining that the TQTS goal is only to identify drugs for which the proarrhythmic risk might be considered excluded for the purposes of regulatory benefit-risk assessment. Suggestions are made on how to categorize and quantify or exclude proarrhythmic risk if the TQTS is positive. There is a conceptual need for TQTS, and this is discussed, together with reasons why restricted clinical registries cannot prove the absence of proarrhythmic liability of any drug. Appropriate drug doses investigated in TQTS should be derived from the maximum clinically tolerable dose rather than from the known or expected therapeutic dose. With the help of concentration-QTc modelling, the standard therapeutic dose can be omitted from TQTS, especially if the study is expected to be negative. Conditions for single-dose TQTS acceptability are reviewed. The role of the so-called positive control is assessed, contrasting the role of a same-class comparator for the investigated drug. A single 400 mg dose of moxifloxacin is advocated as the present 'gold standard' assay sensitivity test. The necessity of careful placebo control is explained and the frequency of ECG assessments is considered. The central tendency and outlier analyses are discussed, together with the correct approaches to baseline adjustment. The review concludes that the design and interpretation of TQTS must not be approached with mechanistic stereotypes, and highlights the importance of relating the QTc changes to drug plasma levels.

Rapid killing of M. leprae by moxifloxacin in two patients with lepromatous leprosy

Previously we reported a 2-month clinical trial of moxifloxacin therapy in eight patients with MB leprosy (7 LL and 1 BL), finding both rapid killing of M. leprae and clinical improvement, without serious side effects or toxicities. Here we report the outcomes in two patients treated with moxifloxacin. Two previously untreated LL patients were treated with a single 400 mg dose of moxifloxacin, no therapy for 7 days and then daily 400 mg moxifloxacin for 48 days. Clinical response, viability of M. leprae in the skin, and side effects/toxicities were carefully monitored. In both patients a single dose of moxifloxacin resulted in significant killing of M. leprae (P < 0.001%). In both patients no viable M. leprae were found after 15 doses of moxifloxacin. Improvement in skin lesions occurred again remarkably rapidly and no untoward effects were noted. Loss of viable M. leprae was quite rapid, similar to that found previously only for rifampicin, patients improved rapidly, and moxifloxacin was well tolerated.

Emergence of resistant Streptococcus pneumoniae in an in vitro dynamic model that simulates moxifloxacin concentrations inside and outside the mutant selection window: related changes in susceptibility, resistance frequency and bacterial killing.

According to the mutant selection window (MSW) hypothesis, resistant mutants are selected or enriched at antibiotic concentrations above the MIC but below the mutant prevention concentration (MPC). To test this hypothesis, Streptococcus pneumoniae ATCC 49619 (MIC 0.1 mg/L; MPC 0.5 mg/L) was exposed to moxifloxacin concentrations below the MIC, above the MPC and between the MIC and MPC, i.e. within the MSW. Daily administration of moxifloxacin for 3 consecutive days was mimicked using a two-compartment dynamic model with peripheral units containing a starting inoculum of 10(8) cfu/mL S. pneumoniae. Changes in susceptibility were examined by repeated MIC determinations and by plating the specimens on agar containing zero, 2 x MIC, 4 x MIC and 8 x MIC of moxifloxacin. Both in terms of the MIC and resistance frequency, S. pneumoniae resistance developed at concentrations that fell inside the MSW [ratios of 24 h area under the curve (AUC24) to MIC between 24 and 47 h]. A Gaussian-like function fitted the AUC24/MIC-dependent increases in MIC and resistance frequency with central points at AUC24/MICs of 38 and 42 h, respectively, where resistant mutants are enriched selectively. Selective enrichment of resistant mutants was not seen at AUC24/MICs <10 h or >100 h. These data suggest that AUC24/MICs >100 h may protect against the selection of resistant S. pneumoniae mutants. Since the usual 400 mg dose of moxifloxacin provides much higher AUC24/MIC (270 h), it is expected to prevent mutant selection at clinically achievable concentrations. Also, these data provide further support for the MSW hypothesis.

Human aqueous humor levels of oral ciprofloxacin, levofloxacin, and moxifloxacin

Purpose: To evaluate the penetration of ciprofloxacin, levofloxacin, and moxifloxacin into the aqueous humor after oral administration. Setting: Alcorcon Hospital, Madrid, Spain. Methods: Forty-two patients having cataract surgery were randomly divided into 3 groups the day before surgery. The first group received 2 oral 500 mg doses of ciprofloxacin at 12-hour intervals. The second group received a single oral 500 mg dose of levofloxacin. The third group received a single oral 400 mg dose of moxifloxacin. At the time of surgery, 0.1 mL aqueous fluid was aspirated from the anterior chamber just before the operation and immediately stored at −80°C. Drug concentrations were measured using a biological assay. Results: The mean aqueous level of ciprofloxacin was 0.50 μg/mL ± 0.25 (SD); of levofloxacin, 1.50 ± 0.50 μg/mL; and of moxifloxacin, 2.33 ± 0.85 μg/mL. The mean aqueous levels of levofloxacin and moxifloxacin were above the 90% minimum inhibitory concentration for most of the common microorganisms that cause endophthalmitis. Conclusions: Therapeutic concentrations of fluoroquinolones, mainly levofloxacin and moxifloxacin, were reached with oral administration. These antibiotics may be effective for prophylaxis and adjuvant therapy of bacterial endophthalmitis.

Comparative pharmacodynamics of moxifloxacin and levofloxacin in an in vitro dynamic model: prediction of the equivalent AUC/MIC breakpoints and equiefficient doses

To demonstrate the impact of the different pharmacokinetics of moxifloxacin and levofloxacin on their antimicrobial effects (AMEs), killing and regrowth kinetics of two clinical isolates of Staphylococcus aureus and one each of Escherichia coli and Klebsiella pneumoniae were studied. With each organism, a series of monoexponential pharmacokinetic profiles of single doses of moxifloxacin (T:1/2 = 12.1 h) and levofloxacin (T:(1/2) = 6.8 h) were simulated. The respective eight-fold ranges of the ratios of area under the concentration-time curve (AUC) to the MIC were 58-475 and 114-934. Species- and strain-independent linear relationships observed between the intensity of AME (I:(E)) and log AUC/MIC were not superimposed for moxifloxacin and levofloxacin (r(2) = 0.99 in both cases). The predicted AUC/MIC ratios for moxifloxacin and levofloxacin that might be equivalent to Schentag's AUC/MIC breakpoint for ciprofloxacin (125) were estimated at 80 and 130, respectively. The respective equivalent MIC breakpoints were 0.41 mg/L (for a 400 mg dose of moxifloxacin) and 0.35 mg/L (for a 500 mg dose of levofloxacin). Based on the I:(E)-log AUC/MIC relationships, equiefficient 24 h doses (D:(24)s) of moxifloxacin and levofloxacin were calculated for hypothetical strains of S. aureus, E. coli and K. pneumoniae with MICs equal to the respective MIC50s (weighted geometric means of reported values). To provide an 'acceptable' I:(E) = 200 (log cfu/mL)*h, the D:(24)s of moxifloxacin for all three organisms were much lower (150, 30 and 60 mg, respectively) than the clinically proposed 400 mg dose. Although the usual dose of levofloxacin (500 mg) would be in excess for E. coli and K. pneumoniae (D:(24) = 36 and 220 mg, respectively), it might be insufficient for S. aureus (the estimated D:(24) = 850 mg). Moreover, to provide the same effect as a 400 mg D:(24) of moxifloxacin against staphylococci, levofloxacin would have to be given in a 5000 mg D:(24), which is 10-fold higher than its clinically accepted dose. The described method of generalization of data obtained with specific organisms to other representatives of the same species might be useful to predict the AMEs of new quinolones.

A comparison of the safety and efficacy of moxifloxacin (BAY 12-8039) and cefuroxime axetil in the treatment of acute bacterial sinusitis in adults

The aim of this multicentre, randomized study was to compare the efficacy and safety of moxifloxacin (BAY 12-8039), a new 8-methoxy fluoroquinolone, with that of cefuroxime axetil for the treatment of acute bacterial sinusitis in adults. Diagnosis was made on a range of clinical signs and symptoms combined with radiology and microbiology.A 400 mg dose of moxifloxacin was administered once daily for 7 days to 242 patients and 250 mg twice daily of cefuroxime axetil was administered to 251 patients for 10 days. The clinical success rate at the end of treatment in the evaluable population was significantly higher (96·7%) in the moxifloxacin group (204/211) than in the cefuroxime axetil group (204/225, 90·7%; 95% confidence intervals 1·5%; 10·6%). At follow-up the success rate in the moxifloxacin group was 90·7% and that for the cefuroxime axetil group was 89·2% (95% confidence intervals −4·3%; 5·4%). The predominant pathogens isolated were Streptococcus pneumoniae and Haemophilus influenzae, followed by Moraxella catarrhalis and Staphylococcus aureus. The bacteriological eradication rates were higher for moxifloxacin (94·5%, 103/109) than for cefuroxime axetil (83·5%, 96/115; 95% CI 3·6%; 19·7%). Only one S. pneumoniae infection persisted following moxifloxacin therapy in contrast with three in individuals on cefuroxime axetil. There were slightly more adverse events in the moxifloxacin group than in the cefuroxime axetil group, but there were fewer serious adverse events following moxifloxacin treatment (three vs. eight). The drug was discontinued because of adverse events in 14 moxifloxacin patients and in 11 cefuroxime axetil patients.Overall, in all assessments, moxifloxacin was at least as effective clinically and bacteriologically, and as well tolerated, as cefuroxime axetil in the treatment of acute sinusitis.

Pharmacodynamics of fluoroquinolones.

Fluctuating concentrations of three fluoroquinolones (moxifloxacin, sparfloxacin and ofloxacin) and a beta-lactam (amoxycillin) were used in vitro to simulate antibiotic concentrations in human serum after oral doses of antibiotics. The antibiotics were tested against Staphylococcus aureus 12241 and Streptococcus pneumoniae 4241. Moxifloxacin and sparfloxacin were also tested against Escherichia coli Neumann. Human serum concentrations of moxifloxacin and ciprofloxacin were also simulated in an in-vivo murine thigh muscle model against S. aureus, S. pneumoniae and E. coli. Ciprofloxacin, sparfloxacin and ofloxacin had a dose-independent effect on gram-positive organisms beyond their optimal dose that gave a maximum effect, as did amoxycillin. In contrast, moxifloxacin had a dose-dependent and therefore concentration-dependent effect on both gram-positive and beta-lactam-susceptible and-resistant gram-negative organisms. The marked activity of moxifloxacin against both gram-positive and gram-negative organisms was confirmed in an in-vivo model. A human dose equivalent of 200 mg moxifloxacin reduced viable counts of S. pneumoniae below the limit of detection and regrowth did not occur. S. aureus was eliminated almost as effectively as S. pneumoniae. A 200 mg dose of moxifloxacin completely eliminated the original inoculum of E. coli within 6 h. Treatment of S. aureus with ciprofloxacin (250 or 500 mg) resulted in a dose-independent decrease in viable counts by approximately 3.5 log10 cfu/mL. A 125 mg dose of ciprofloxacin almost completely eliminated the original inoculum of E. coli within 8 h, whereas both the 250 mg and 500 mg doses reduced viable counts below the limit of detection. Thus, the in-vitro and in-vivo pharmacodynamic models used in this study established that moxifloxacin was highly effective against both gram-negative and gram-positive bacteria.

Pharmacokinetics of Moxifloxacin in A 5/6th Nephrectomized Rat Model

Moxifloxacin (MFLX) is a new 8-methoxyfluoroquinolone derivative with a broad spectrum of antibacterial activity. MFLX at doses of 200 and 400 mg was selected to conduct the pharmacokinetic study and the drug was given orally to control and nephrectomized rats. A 5/6th nephrectomized rat model was used in this study. The drug levels in the plasma were determined using a spectrofluorimetric assay. The pharmacokinetic parameters viz. peak plasma concentration (Cmax) and area under the curve (AUC0-8) of the nephrectomized and control rats were compared. The Cmax for both 200 and 400 mg dose of MFLX in nephrectomized rats showed significant difference(P&lt;0.001) from the control group, which reveals the changes in the Cmax of MFLX in renal failure. The AUC0-8 for both 200 and 400 mg dose of MFLX in nephrectomized rats differ significantly (P&lt;0.001) from sham operated control group, which implies the variation in MFLX availability in altered renal function. The AUC0-8 for 400 mg dose of MFLX in nephrectomized rats differ significantly from 200 mg dose of MFLX in nephrectomized group, which reveals that in higher dose, MFLX shows an abrupt increase in the drug availability in renal failure. It is conclude that preclinical drug monitoring of moxifloxacin in laboratory animals can be performed by using 5/6th nephrectomized rat models for determining the dose of MFLX for kidney failured patients. Various pharmacokinetic parameters determined differed in nephrectomised rats when compared to the control.