Thorough QT/QTc Evaluation of the Cardiac Safety of Enarodustat (JTZ-951), an Oral Erythropoiesis-Stimulating Agent, in Healthy Adults.

This study evaluated the effect of enarodustat on cardiac repolarization in healthy subjects. Enarodustat (20 and 150 mg [supratherapeutic dose]), placebo, and moxifloxacin (positive control, 400 mg) were administered orally to males and females (N = 54) in a crossover fashion. Continuous 12-lead Holter electrocardiogram (ECG) data were obtained before and after dosing, and blood samples were obtained for pharmacokinetic assessments of enarodustat, its circulating metabolite (R)-M2, and moxifloxacin. Central tendency analysis was performed for relevant ECG parameters, the relationship between individual-corrected interval from beginning of the QRS complex to end of the T wave in the frontal plane (QTcI, the primary end point) and plasma concentrations of enarodustat and (R)-M2 were assessed, and ECG waveforms were evaluated for morphological changes. The supratherapeutic dose resulted in 7- and 9-fold higher geometric mean maximum concentrations for enarodustat and (R)-M2, respectively, than the 20 mg dose. Based on time point analysis, the upper bound of the 2-sided 90% confidence interval (CI) for QTcI did not exceed 10 milliseconds at any of the time points for either dose. Based on QTcI-concentration analysis, the slopes for enarodustat and (R)-M2 were not statistically different than 0, and the upper bounds of the 2-sided 90% CI for QTcI at the geometric mean maximum concentrations for the supratherapeutic dose were 1.97 and 1.68 milliseconds for enarodustat and (R)-M2, respectively. The lower bound of the 2-sided 90% CI for moxifloxacin was ≥5 milliseconds, demonstrating assay sensitivity. The study demonstrated no clinically relevant effect of enarodustat and (R)-M2 on cardiac repolarization. There was no evidence of any clinically significant effect on the PR interval and QRS duration, and ECG waveforms showed no new clinically relevant morphological changes.

Simultaneous determination of moxifloxacin with NSAIDs in API, dosage and serum by reverse phase high-performance liquid chromatography: Application to in vitro drug interactions.

Experimental design is a significant tool for optimization and validation for the development of HPLC methods to determine API in both human serum and pharmaceutical formulations. In this study, RP-HPLC method is developed and validated for the simultaneous determination of moxifloxacin and NSAIDs. In this experiment, Purospher STAR C18 column with optimum assay conditions (10:90, v/v, water: methanol, pH 2.75) used as mobile phase having flow rate of 1.5mL min-1 and screened at 240 nm. The experimental results exhibit reliability through accuracy (98-102%), precision (0.011-1.85%) and linearity (R2>0.999) in range of 0.15-40µgmL-1. The LOD and LOQ limits for moxifloxacin and NSAIDs are found to be 0.015 and 0.046 µgmL-1 respectively. The significant outcomes conclude that the developed method for assay is effectively suitable to human serum and pharmaceutical formulations and there is no interference from excipients of tablets and serum. The proposed method is useful for drug-interaction and investigation of moxifloxacin with NSAIDs.

Development and validation of a UPLC-MS/MS method for simultaneous quantification of levofloxacin, ciprofloxacin, moxifloxacin and rifampicin in human plasma: Application to the therapeutic drug monitoring in osteoarticular infections.

BACKGROUND: Fluoroquinolones and rifampicin are antibiotics frequently used for the treatment of osteoarticular infections, and their therapeutic drug monitoring is recommended. The aim of this study was to develop and validate a rapid and selective method of simultaneous quantification of levofloxacin, ciprofloxacin, moxifloxacin and rifampicin with short pretreatment and run times in order to be easily used in clinical practice. METHODS: After a simple protein precipitation of plasma samples, the chromatographic separation was performed using an ultra-performance liquid chromatography system coupled with mass tandem spectrometry in a positive ionization mode. The mobile phase consisted of a gradient elution of water-formic acid (100:0.1, v/v)-ammonium acetate 2 mM (A) and methanol-formic acid (100:0.1, v/v)-ammonium acetate 2 mM (B) at a flow rate at 0.3 mL/min. RESULTS: Analysis time was 5 min per run, and all analytes and internal standards eluted within 0.85-1.69 minutes. The calibration curves were linear over the range from 0.5-30 µg/mL for levofloxacin, ciprofloxacin, moxifloxacin and rifampicin with linear regression coefficients above 0.995 for all analytes. The intra-day and inter-day coefficients of variation were below 10 % for lower and higher concentration. This method was successfully applied to drug monitoring in patients with an osteoarticular infection. CONCLUSION: A simple, rapid, and selective liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of levofloxacin, ciprofloxacin, moxifloxacin and rifampicin in human plasma.

Effects of the Fluoroquinolones Moxifloxacin and Levofloxacin on the QT Subintervals: Sex Differences in Ventricular Repolarization.

Women are associated with longer electrocardiographic QT intervals and increased proarrhythmic risks of QT-prolonging drugs. The purpose of this study was to characterize the differences in cardiac electrophysiology between moxifloxacin and levofloxacin in men and women and to assess the balance of inward and outward currents through the analysis of QT subintervals. Data from 2 TQT studies were used to investigate the impact of moxifloxacin (400 mg) and levofloxacin (1000 and 1500 mg) on QT subintervals using algorithms for measurement of J-Tpeak and Tpeak -Tend intervals. Concentration-effect analyses were performed to establish potential relationships between the ECG effects and the concentrations of the 2 fluoroquinolones. Moxifloxacin was shown to be a more potent prolonger of QT interval corrected by Fredericia (QTcF) and had a pronounced effect on J-Tpeak c. Levofloxacin had little effect on J-Tpeak c. For moxifloxacin, the concentration-effect modeling showed a greater effect for women on QTcF and J-Tpeak c, whereas for levofloxacin the inverse was true: women had smaller QTcF and J-Tpeak c effects. The different patterns in repolarization after administration of both drugs suggested a sex difference, which may be related to the combined IKs and IKr inhibitory properties of moxifloxacin versus IKr suppression only of levofloxacin. The equipotent inhibition of IKs and IKr appears to affect women more than men. Sex hormones are known to influence cardiac ion channel expression and differences in QT duration. Differences in IKr and IKs balances, influenced by sex hormones, may explain the results. These results support the impact of sex differences on the cardiac safety assessment of drugs.

Effects of Celecoxib on the QTc Interval: A Thorough QT/QTc Study.

PURPOSE: Celecoxib is a selective cyclooxygenase-2 inhibitor widely used in patients with osteoarthritis and rheumatoid arthritis. Recently, nonclinical data on the inhibition of human ether-à-go-go-related gene potassium channels by celecoxib were reported, but there is no compelling evidence for this finding in humans. The aim of this study was to assess the potential effects of celecoxib on cardiac repolarization by conducting a thorough QT study, which was designed in compliance with the related guidelines. METHODS: This randomized, open-label, positive- and negative-controlled, crossover clinical study was conducted in healthy male and female subjects. Each subject received, in 1 of 4 randomly assigned sequences, all of the following 3 interventions: celecoxib 400 mg once daily for 6 days; a single dose of moxifloxacin 400 mg, which served as a positive control to assess the assay sensitivity; and water without any drug, which served as a negative control. Serial 12-lead ECG and blood samples for pharmacokinetic analysis were collected periodically over 24 h. Individually RR-corrected QT intervals (QTcI) and Fridericia method-corrected QT intervals (QTcF) were calculated and evaluated. FINDINGS: Twenty-eight subjects were allocated to 1 of the 4 intervention sequences. The largest time-matched mean effects of celecoxib on the QTcI and QTcF were <5 ms, and the upper bounds of the 1-sided 95% CIs of those values did not exceed 10 ms. Moreover, none of the subjects had an absolute QTcI value of >450 ms or a change from baseline in QTcI of >60 ms after multiple administrations of celecoxib. The QTcI did not show a positive correlation with celecoxib concentrations in the range up to ~2700 µg/L. The overall effects of moxifloxacin on the QTcI and QTcF were enough to establish assay sensitivity. No serious adverse events were reported, with a total of 11 AEs reported in 8 subjects. IMPLICATIONS: Celecoxib caused no clinically relevant increase in the QT/QTc interval at the maximum dose level used in current practice settings. ClinicalTrials.gov identifier: NCT03822520.

Long-Term Effects on QT Prolongation of Pretomanid Alone and in Combinations in Patients with Tuberculosis.

Concentration-QTc modeling was applied to pretomanid, a new nitroimidazooxazine antituberculosis drug. Data came from eight phase 2 and phase 3 studies. Besides pretomanid alone, various combinations with bedaquiline, linezolid, moxifloxacin, and pyrazinamide were considered; special attention was given to the bedaquiline-pretomanid-linezolid (BPaL) regimen that has demonstrated efficacy in the Nix-TB study in subjects with extensively drug-resistant or treatment-intolerant or nonresponsive multidrug-resistant tuberculosis. Three heart rate corrections to QT were considered: Fridericia's QTcF, Bazett's QTcB, and a population-specific correction, QTcN. QTc increased with the plasma concentrations of pretomanid, bedaquiline's M2 metabolite, and moxifloxacin in a manner described by a linear model in which the three slope coefficients were constant across studies, visits within study, and times postdose within visit but where the intercept varied across those dimensions. The intercepts tended to increase on treatment to a plateau after several weeks, a pattern termed the secular trend. The slope terms were similar for the three QTc corrections, but the secular trends differed, suggesting that at least some of the secular trend was due to the elevated heart rates of tuberculosis patients decreasing to normal levels on treatment. For pretomanid 200 mg once a day (QD) alone, a typical steady-state maximum concentration of drug in plasma (Cmax) resulted in a mean change from baseline of QTcN of 9.1 ms, with an upper 90% confidence interval (CI) limit of 10.2 ms. For the BPaL regimen, due to the additional impact of the bedaquiline M2 metabolite, the corresponding values were 13.6 ms and 15.0 ms. The contribution to these values from the secular trend was 4.0 ms.

A simple and sensitive HPLC-fluorescence method for the determination of moxifloxacin in human plasma and its application in a pharmacokinetic study.

A simple sample preparation technique coupled with the specific and sensitive fluorescence detection for the determination of moxifloxacin in human plasma was developed and fully validated. Levofloxacin was chosen as an internal standard. Chromatographic separation was achieved using a Shiseido C18 MGII (250×4.6mm i.d.; 5 µm) column under an isocratic mobile phase comprising of 50 mM potassium dihydrogen phosphate (pH 2.4) - acetonitrile (77:23, v/v) at a flow rate of 1.5 mL/min. Fluorescence detection was optimized for the determination of moxifloxacin in human plasma at an excitation wavelength of 296 nm and an emission wavelength of 504 nm. The total chromatographic run time was 8 min with the retention times of moxifloxacin and internal standard at 6.5 and 3.0 min, respectively. Calibration curves were established over the dynamic range of 20-3000 ng/mL. The analytical method was validated as per US-FDA and EMA guidelines for specificity, sensitivity, linearity, accuracy, precision, recovery, hemolytic effect, lipemic effect, dilution integrity and stability. The validated analytical method was successfully applied in a pharmacokinetic study of a single-dose oral administration of a moxifloxacin 400 mg tablet in Thai healthy volunteers.

A Randomized Study of the Single-Dose Safety, Pharmacokinetics, and Food Effect of Chinfloxacin and Its Effect on Thorough QT/QTc Interval in Healthy Chinese Volunteers.

Chinfloxacin hydrochloride is a novel tricyclic fluorinated quinolone in development for treatment of conventional and biothreat infections. This first-in-human randomized study in Chinese healthy subjects was divided into 5 parts. Part A was a single-ascending-dose study to assess safety and tolerability of chinfloxacin. The single-dose pharmacokinetic study, a food effect study, and a multiple-dose pharmacokinetics study were conducted in parts B, C, and D, respectively. Part E was a randomized, placebo-controlled and positive-control single-dose, crossover study to evaluate the effect of chinfloxacin on thorough electrocardiographic QT/corrected QT (QTc) interval. The results suggest that single and multiple oral administrations of chinfloxacin were well tolerated. The observed adverse events (AEs) were dizziness, nausea, weakness, photosensitive dermatitis, and increased frequency of defecation. All AEs were mild and were resolved spontaneously without any treatment. The time to peak plasma concentration (Tmax and Cmax, respectively) was about 2 h, and the half-life was 14 to 16 h. Food slightly affected the drug's rate and extent of absorption, increasing the Tmax from 1.60 to 2.59 h and reducing the Cmax by 13.6% and area under the concentration-time curve by 8.95%. Chinfloxacin at 400 mg had no effect on prolongation of QT/QTc intervals. Although 600 mg chinfloxacin had a mild effect on the prolongation of the QT/QTc interval, the effect was less pronounced than that of the positive control, 400 mg moxifloxacin. The pharmacokinetics and safety profiles of chinfloxacin in healthy Chinese volunteers support its once-daily dosing in future clinical investigations. (This study has been registered at www.ChiCTR.org.cn under identifiers ChiCTR-TRC-10001619 for parts A to D and ChiCTR1800015906 for part E.).

Elevated Plasma Moxifloxacin Concentrations and SLCO1B1 g.-11187G>A Polymorphism in Adults with Pulmonary Tuberculosis.

Moxifloxacin exhibits concentration-dependent prolongation of human QTc intervals and bactericidal activity against Mycobacterium tuberculosis However, moxifloxacin plasma concentrations are variable between patients. We evaluated whether human gene polymorphisms affect moxifloxacin plasma concentrations in tuberculosis patients from two geographic regions. We enrolled a convenience sample of 49 adults with drug-sensitive pulmonary tuberculosis from Africa and the United States enrolled in two treatment trials of moxifloxacin as part of multidrug therapy. Pharmacokinetic parameters were evaluated by noncompartmental techniques. Human single-nucleotide polymorphisms of transporter genes were evaluated by analysis of covariance (ANCOVA) on moxifloxacin exposure and the peak (maximum) concentration (Cmax). The moxifloxacin area under the concentration-time curve from 0 to 24 h (AUC0-24) and Cmax were significantly increased by the drug milligram-per-kilogram dosage and the genotype of variant g.-11187G>A in the SLCO1B1 gene (rs4149015) but not by geographic region. The median moxifloxacin AUC0-24 was 46% higher and the median Cmax was 30% higher in 4 (8%) participants who had the SLCO1B1 g.-11187 AG genotype than in 45 participants who had the wild-type GG genotype (median AUC0-24 from the model, 34.4 versus 23.6 µg · h/ml [P = 0.005, ANCOVA]; median Cmax from the model, 3.5 versus 2.7 µg/ml [P = 0.009, ANCOVA]). Because moxifloxacin exhibits concentration-dependent prolongation of human QTc intervals and prolonged QTc intervals are associated with cardiac arrhythmia, further study is needed to evaluate the risk associated with the SLCO1B1 g.-11187G>A variant. (This study has been registered at ClinicalTrials.gov under identifier NCT00164463.).