Dose Of Moxifloxacin Research Articles

Cagrilintide is not associated with clinically relevant QTc prolongation: A thorough QT study in healthy participants.

The combination of cagrilintide and semaglutide (CagriSema) is being developed for the treatment of obesity and type 2 diabetes. The objective of this thorough QT study was to confirm that cagrilintide does not result in a clinically relevant prolongation in cardiac repolarization compared with placebo. This was a double-blind study (NCT05804162) in which healthy participants were randomized to cagrilintide, administered as a once-weekly subcutaneous injection dose escalated to 4.5 mg, or a placebo. The primary end point was the time-matched change from baseline in Fridericia heart rate-corrected QT interval (QTcF) at 12-, 24-, 48- and 72 h after the last cagrilintide 4.5-mg dose. To conclude that cagrilintide does not induce a clinically relevant prolongation, the upper limit of the two-sided 90% confidence interval (CI) for the treatment difference at each of the four time points must fall below 10 ms. To establish QT assay sensitivity, participants in the placebo arms received a single 400-mg oral moxifloxacin dose as a positive control and moxifloxacin placebo in a nested cross-over fashion. A total of 105 participants received cagrilintide (n = 53) or placebo (n = 52). No clinically relevant QTcF prolongation occurred after the last cagrilintide 4.5-mg dose; the upper limits of the two-sided 90% CIs of the placebo-adjusted QTcF changes from baseline were below 10 ms at all time points. QT assay sensitivity was demonstrated with moxifloxacin as a positive control. Cagrilintide did not result in clinically relevant QTcF prolongation, indicating no increased risk of ventricular tachyarrhythmias.

Continuous evaluation of single-dose moxifloxacin concentrations in brain extracellular fluid, cerebrospinal fluid, and plasma: a novel porcine model.

Knowledge regarding CNS pharmacokinetics of moxifloxacin is limited, with unknown consequences for patients with meningitis caused by bacteria resistant to beta-lactams or caused by TB. (i) To develop a novel porcine model for continuous investigation of moxifloxacin concentrations within brain extracellular fluid (ECF), CSF and plasma using microdialysis, and (ii) to compare these findings to the pharmacokinetic/pharmacodynamic (PK/PD) target against TB. Six female pigs received an intravenous single dose of moxifloxacin (6 mg/kg) similar to the current oral treatment against TB. Subsequently, moxifloxacin concentrations were determined by microdialysis within five compartments: brain ECF (cortical and subcortical) and CSF (ventricular, cisternal and lumbar) for the following 8 hours. Data were compared to simultaneously obtained plasma samples. Chemical analysis was performed by high pressure liquid chromatography with mass spectrometry. The applied PK/PD target was defined as a maximum drug concentration (Cmax):MIC ratio >8. We present a novel porcine model for continuous in vivo CNS pharmacokinetics for moxifloxacin. Cmax and AUC0-8h within brain ECF were significantly lower compared to plasma and lumbar CSF, but insignificantly different compared to ventricular and cisternal CSF. Unbound Cmax:MIC ratio across all investigated compartments ranged from 1.9 to 4.3. A single dose of weight-adjusted moxifloxacin administered intravenously did not achieve adequate target site concentrations within the uninflamed porcine brain ECF and CSF to reach the applied TB CNS target.

ASCRS clinical advisory on intracameral moxifloxacin injection for infection prophylaxis.

Moxifloxacin solution is frequently injected at the conclusion of cataract surgery for endophthalmitis prophylaxis. 2 different concentrations are most commonly available in the United States for intracameral (IC) use: 0.5% (5 mg/mL) and 0.1% (1 mg/mL). The recommended volume to be injected is different for the 2 concentrations, and incorrect dosing can increase the risk of toxic anterior segment syndrome or endophthalmitis. In addition, the U.S. Food and Drug Administration recently published an alert regarding potential adverse events associated with intraocular compounded moxifloxacin. This clinical advisory reviews the optimal dosing of IC moxifloxacin based on current evidence.

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.

Abstract #1403093: Absence of QT Prolongation Associated with Relacorilant, a Selective Glucocorticoid Receptor Modulator in Development for the Treatment of Cushing Syndrome

QT prolongation is a significant concern for patients with Cushing syndrome (CS). Approximately 26% of men with CS present with QT prolongation, and the risk of cardiac arrhythmic events correlates with the extent of QT prolongation. All currently approved CS medications are associated with QT prolongation, posing a significant risk for the management of CS. Here, we evaluate the impact relacorilant, an investigational selective glucocorticoid receptor modulator, on QT prolongation in healthy volunteers and patients with CS. In a 3-part, single-center, first-in-human study (NCT03508635, “phase 1 study”), 103 healthy volunteers received single or multiple ascending doses of relacorilant (up to 500 mg QD) for up to 14 days; 24 received placebo. In a randomized, partial double-blind, crossover thorough QT study (NCT04795479, “TQT study”), the effect of multiple therapeutic (400 mg QD, n=25) and supra-therapeutic (800 mg QD, n=28) doses of relacorilant on cardiac repolarization was studied in healthy volunteers. A single dose of moxifloxacin (400 mg, n=28) was used as a positive control; 29 participants received placebo. In a single-arm, open-label phase 2 study (NCT02804750, “CS study”), 17 patients with CS received low-dose relacorilant (100–200 mg QD) for 12 weeks and 18 patients received high-dose relacorilant (250–400 mg QD) for 16 weeks. In all studies, ECG data were collected, and the heart rate-corrected QT interval using Fridericia’s formula (QTcF) was assessed. In the phase 1 study, relacorilant up to 500 mg daily did not adversely affect ECG parameters. An effect on placebo-corrected change from baseline QTcF (ΔΔQTcF) above 10 msec was excluded. In the TQT study, moxifloxacin control showed the expected QT prolongation, confirming assay sensitivity. Relacorilant had no adverse effects on ECG parameters and showed effects similar to placebo. Based on concentration-QTc analysis, an effect on ΔΔQTcF exceeding 10 msec was excluded within the full observed range of relacorilant plasma concentrations. These results constitute a negative TQT study. The CS study confirmed that these favorable findings also apply to patients with CS: Throughout the CS study, no significant changes in median QTcF were observed in either dose group. There is an unmet need for medications to treat CS that do not cause QT prolongation and possibly fatal arrhythmias. Based on the TQT study and supported by additional data in healthy volunteers and patients with CS, relacorilant did not show an association with QT prolongation.

Optimizing Moxifloxacin Dose in MDR-TB Participants with or without Efavirenz Coadministration Using Population Pharmacokinetic Modeling.

Moxifloxacin is included in some treatment regimens for drug-sensitive tuberculosis (TB) and multidrug-resistant TB (MDR-TB). Aiming to optimize dosing, we described moxifloxacin pharmacokinetic and MIC distribution in participants with MDR-TB. Participants enrolled at two TB hospitals in South Africa underwent intensive pharmacokinetic sampling approximately 1 to 6 weeks after treatment initiation. Plasma drug concentrations and clinical data were analyzed using nonlinear mixed-effects modeling with simulations to evaluate doses for different scenarios. We enrolled 131 participants (54 females), with median age of 35.7 (interquartile range, 28.5 to 43.5) years, median weight of 47 (42.0 to 54.0) kg, and median fat-free mass of 40.1 (32.3 to 44.7) kg; 79 were HIV positive, 29 of whom were on efavirenz-based antiretroviral therapy. Moxifloxacin pharmacokinetics were described with a 2-compartment model, transit absorption, and elimination via a liver compartment. We included allometry based on fat-free mass to estimate disposition parameters. We estimated an oral clearance for a typical patient to be 17.6 L/h. Participants treated with efavirenz had increased clearance, resulting in a 44% reduction in moxifloxacin exposure. Simulations predicted that, even at a median MIC of 0.25 (0.06 to 16) mg/L, the standard daily dose of 400 mg has a low probability of attaining the ratio of the area under the unbound concentration-time curve from 0 to 24 h to the MIC (fAUC0-24)/MIC target of >53, particularly in heavier participants. The high-dose WHO regimen (600 to 800 mg) yielded higher, more balanced exposures across the weight ranges, with better target attainment. When coadministered with efavirenz, moxifloxacin doses of up to 1,000 mg are needed to match these exposures. The safety of higher moxifloxacin doses in clinical settings should be confirmed.

Cycloserine Induced Psychosis, Insomnia and Suicidal Attempts in a Young Female Patient with Pre-Extensively Drug Resistant Tuberculosis

The World Health Organization classifies cycloserine as a group four second line anti tubercular drug for the treatment of drug resistant tuberculosis. Neuropsychiatric adverse drug reactions associated with cycloserine need more attention as they may compromise treatment success. Here, we report a case of cycloserine induced psychosis, insomnia and suicidal attempts in a young female patient with pre-extensively drug resistant tuberculosis (pre-XDR-TB). A 20-year-old female patient was prescribed longer oral XDR-TB regimen (high dose of moxifloxacin, cycloserine, linezolid, clofazimine, bedaquiline and pyridoxine). After fifteen days of treatment, patient developed changes in behaviour with frequent episodes of spontaneous and excessive laughing or crying. She also developed insomnia, started to hear voices and made two attempts of suicide. Following this, cycloserine was discontinued. Clonazepam and clomipramine were prescribed to her. Patient gradually recovered over a period of one month. Extreme caution with regular and close monitoring should be exercised while administering cycloserine because psychiatric adverse drug reactions could be associated with increased risk of poor drug adherence in drug resistant tuberculosis.

Evaluation of levocetirizine in beagle dog and cynomolgus monkey telemetry assays: Defining the no QTc effect profile by timepoint and concentration-QTc analysis.

In prior clinical studies, levocetirizine (LEVO) has demonstrated no effect on ventricular repolarization (QTc intervals), therefore it is a relevant negative control to assess in nonclinical assays to define low proarrhythmic risk. LEVO was tested in beagle dog and cynomolgus monkey (nonhuman primate [NHP]) telemetry models to understand the nonclinical-clinical translation of this negative control. One oral dose of vehicle, LEVO (10mg/kg/species) or moxifloxacin (MOXI; 30 mg/kg/dog; 80 mg/kg/NHP) was administered to instrumented animals (N=8/species) using a cross-over dosing design; MOXI was the in-study positive control. Corrected QT interval values (QTcI) were calculated using an individual animal correction factor. Blood samples were taken for drug exposure during telemetry and for pharmacokinetic (PK) analysis (same animals; different day) for exposure-response (C-QTc) modeling. Statistical analysis of QTc-by-timepoint data showed that LEVO treatment was consistent with vehicle, thus no effect on ventricular repolarization was observed over 24 h in both species. PK analysis indicated that LEVO-maximum concentration levels in dogs (range: 12,300-20,100 ng/ml) and NHPs (range: 4090-12,700 ng/ml) were ≥4-fold higher than supratherapeutic drug levels in clinical QTc studies. Slope analysis values in dogs (0.00019 ms/ng/ml) and NHPs (0.00016 ms/ng/ml) were similar to the human C-QTc relationship and indicated no relationship between QTc intervals and plasma levels of LEVO. MOXI treatment caused QTc interval prolongation (dog: 18 ms; NHP: 29 ms). The characterization of LEVO in these non-rodent telemetry studies further demonstrates the value and impact of the in vivo QTc assay to define a "no QTc effect" profile and support clinical safety assessment.

Population Pharmacokinetics of Levofloxacin and Moxifloxacin, and the Probability of Target Attainment in Ethiopian Patients with Multidrug-Resistant Tuberculosis.

This study aimed to explore the population pharmacokinetic modeling (PopPK) of levofloxacin (LFX) and moxifloxacin (MXF), as well as the percent probability of target attainment (PTA) as defined by the ratio of the area under the plasma concentration-time curve over 24 h and the in vitro minimum inhibitory concentration (AUC0-24/MIC) in Ethiopian multidrug resistant tuberculosis (MDR-TB) patients. Steady state-plasma concentration of the drugs in MDR-TB patients were determined using optimized liquid chromatography-tandem mass spectrometry. PopPK and simulations were run at various doses, and pharmacokinetic parameters were estimated. The effect of covariates on the PK parameters and PTA for maximum mycobacterial kill and resistance prevention was also investigated. LFX and MXF both fit in a one-compartment model with adjustments. Serum-creatinine (Cr) influenced (p = 0.01) the clearance of LFX, whereas body mass index (BMI) influenced (p = 0.01) the apparent volume of distribution (V) of MXF. The PTA for LFX maximal mycobacterial kill at the critical MIC of 0.5 mg/L with the simulated 750 mg, 1000 mg, and 1500 mg doses were 29%, 62%, and 95%, respectively, whereas the PTA for resistance prevention at 1500 mg was only 4.8%, with none of the lower doses achieving this target. At the critical MIC of 0.25 mg/L, there was no change in the PTA for maximum bacterial kill when the MXF dose was increased (600 mg, 800 mg, and 1000 mg), but the PTA for resistance prevention was improved. The standard doses of LFX and MXF may not provide adequate drug exposure. PopPK of LFX is more predictable for maximum mycobacterial kill, whereas MXF's resistance prevention target increases with dose. Cr and BMI are likely important covariates for dose optimization in Ethiopian patients.

Population Pharmacokinetics of Moxifloxacin in Children.

Moxifloxacin is a fluoroquinolone that is commonly used in adults, but not children. Certain clinical situations compel pediatric clinicians to use moxifloxacin, despite its potential for toxicity and limited pharmacokinetics (PK) data. Our objective was to further characterize the pharmacokinetics of moxifloxacin in children. We performed an opportunistic, open-label population PK study of moxifloxacin in children <18 years of age who received moxifloxacin as part of standard care. A set of structural PK models and residual error models were explored using nonlinear mixed-effects modeling. Covariates with known biological relationships were investigated for their influence on PK parameters. We obtained 43 moxifloxacin concentrations from 14 participants who received moxifloxacin intravenously (n=8) or orally (n=6). The dose of moxifloxacin was 10mg/kg daily in participants ≤40kg and 400mg daily in participants >40kg. The population mean clearance and mean volume of distribution were 18.2L/h and 167L, respectively. The oral absorption was described by a first-order process. The estimated extent of oral bioavailability was highly variable (range 20-91%). Total body weight was identified as a covariate on clearance and volume of distribution, and substantially reduced the random unexplained inter-individual variability for both parameters. No participants experienced suspected serious adverse reactions related to moxifloxacin. These data add to the existing literature to support use of moxifloxacin in children in certain situations; however, further prospective studies on the safety and efficacy of moxifloxacin are needed.

Increased Moxifloxacin Dosing Among Patients With Multidrug-Resistant Tuberculosis With Low-Level Resistance to Moxifloxacin Did Not Improve Treatment Outcomes in a Tertiary Care Center in Mumbai, India.

Background Mycobacterium tuberculosis (Mtb) strains resistant to isoniazid and rifampin (multidrug-resistant tuberculosis [MDR-TB]) are increasingly reported worldwide, requiring renewed focus on the nuances of drug resistance. Patients with low-level moxifloxacin resistance may benefit from higher doses, but limited clinical data on this strategy are available.MethodsWe conducted a 5-year observational cohort study of MDR-TB patients at a tertiary care center in India. Participants with Mtb isolates resistant to isoniazid, rifampin, and moxifloxacin (at the 0.5 µg/mL threshold) were analyzed according to receipt of high-dose moxifloxacin (600 mg daily) as part of a susceptibility-guided treatment regimen. Univariable and multivariable Cox proportional hazard models assessed the relationship between high-dose moxifloxacin and unfavorable treatment outcomes.ResultsOf 354 participants with MDR-TB resistant to moxifloxacin, 291 (82.2%) received high-dose moxifloxacin. The majority experienced good treatment outcomes (200 [56.5%]), which was similar between groups (56.7% vs 54.0%, P = .74). Unfavorable outcomes were associated with greater extent of radiographic disease, lower initial body mass index, and concurrent treatment with fewer drugs with confirmed phenotypic susceptibility. Treatment with high-dose moxifloxacin was not associated with improved outcomes in either unadjusted (hazard ratio [HR], 1.2 [95% confidence interval {CI}, .6–2.4]) or adjusted (HR, 0.8 [95% CI, .5–1.4]) models but was associated with joint pain (HR, 3.2 [95% CI, 1.2–8.8]).ConclusionsIn a large observational cohort, adding high-dose (600 mg) moxifloxacin to a drug susceptibility test–based treatment regimen for MDR-TB was associated with increased treatment-associated side effects without improving overall outcomes and should be avoided for empiric treatment of moxifloxacin-resistant MDR-TB.

A concentration-QTc analysis of vericiguat

Abstract Introduction Vericiguat is a soluble guanylate cyclase stimulator developed for the treatment of symptomatic chronic heart failure (HF) in patients with ejection fraction less than 45% who had a previous decompensation event. A dedicated, randomised, Phase Ib, QT study of vericiguat (NCT03504982) in 74 adult patients with stable coronary artery disease demonstrated no clinically significant prolongation of the time-matched, placebo-adjusted change from baseline in the Fridericia-corrected QT interval (QTcF) after vericiguat 10 mg once daily at steady state. Purpose We conducted a concentration–QTc (C-QTc) modelling analysis, on data from the QT study, to investigate the potential effect of vericiguat on QTcF and define the vericiguat plasma concentration window within which a relevant prolongation in QTcF can be excluded. Methods In the QT study, the effect of vericiguat once daily (2.5 mg titrated to 5 mg and then to 10 mg [treatments A, B, C] over 42±9 days) on the QT interval was investigated. The positive control was a single dose of moxifloxacin 400 mg (treatment D) on Day 8 or Day 50 (7 days before the first vericiguat dose or 7 days after the last vericiguat dose), depending on the treatment sequence (Figure 1). Baseline electrocardiogram assessments were performed 24 h before the start of treatment (“baseline”) and at follow-up (“back-up baseline”; Figure 1). Time-matched, baseline- and placebo-adjusted QTcF (ΔΔQTc) mean values and 90% confidence intervals (CIs) were calculated. Two analytical approaches were used to calculate ΔΔQTc. The first one (“single baseline ΔΔQTc” approach) was data-driven, where ΔΔQTc was adjusted with placebo- and either “baseline” or “back-up baseline”. The second one (“modelled baseline ΔΔQTc”) accounted for individual baseline and placebo effects, such as diurnal time course, used linear mixed effects and integrated all individual baseline and placebo data. Calculated ΔΔQTc values were then related to observed vericiguat concentrations in the C-QTc modelling step, performed with linear mixed effects implemented in R (R, the R Foundation for Statistical Computing, version 3.2.5). Results The C-QTc modelling of ΔΔQTc calculated with the “single baseline ΔΔQTc” approach indicated a positive, but non-significant, slope (Figure 2A). The “modelled baseline ΔΔQTc” approach indicated a positive and statistically significant slope (Figure 2B). In both cases, the upper limits of the 90% CI were below the threshold of clinical relevance of 10 ms within the investigated exposure range (up to 745 μg/l). Conclusion Based on the presented analysis, a clinically meaningful QT prolongation was robustly excluded within the plasma concentration range associated with the recommended target dose of vericiguat 10 mg. The C-QTc analysis supports the conclusion of the primary study statistical analysis that administration of vericiguat between 2.5 and 10 mg is not associated with a clinically meaningful QTc prolongation. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Funding was provided by Bayer AG, Berlin, Germany and Merck Sharp &amp; Dohme Corp., a subsidiary of Merck &amp; Co., Inc., Kenilworth, NJ, USA Figure 1Figure 2

Impact of Daridorexant, a Dual Orexin Receptor Antagonist, on Cardiac Repolarization Following Bedtime Dosing: Results from a Thorough QT Study Using Concentration-QT Analysis.

Daridorexant is a new dual orexin receptor antagonist currently in late-stage clinical development for the treatment of insomnia. This randomized, double-blind, placebo-controlled, four-period crossover study investigated the effect of daridorexant at a therapeutic and supratherapeutic dose on QT interval duration. Thirty-six healthy subjects received single oral doses of daridorexant (50mg; 200mg), moxifloxacin (400mg; open label), and placebo. All treatments were administered at bedtime to mimic therapeutic practice. The primary analysis was based on linear mixed-effects concentration-QT modelling. Triplicate ECG data were extracted from Holter recordings at baseline and until 24h post dosing at time points matching those for pharmacokinetic sampling. Plasma concentrations of daridorexant were determined over 24h. Assay sensitivity was demonstrated based on mean baseline- and placebo-corrected QT interval using Fridericia's formula (ΔΔQTcF) >5ms following moxifloxacin administration (p<0.01). Following daridorexant administration, mean (90% confidence interval, CI) ΔΔQTcF was 1.40ms (0.48; 2.32ms) and 1.84ms (-0.12; 3.79ms) at the Cmax of 747ng/mL (50mg dose) and 1809ng/mL (200mg dose), respectively, i.e., the upper bounds of the CIs were<10ms defined as threshold of regulatory concern. Lack of relevant QT prolongation was confirmed by secondary by-time point analysis and absence of relevant findings in the categorical outlier analysis. Daridorexant was safe and well tolerated and its pharmacokinetics were consistent with previous data. Daridorexant does not impair cardiac repolarization evidenced by absence of relevant QT prolongation at therapeutic and supratherapeutic doses. Clinical Trials Registration ID: NCT04250506.

Absence of QTc Prolongation with Sodium N-(8-[2-Hydroxybenzoyl] Amino) Caprylate (SNAC), an Absorption Enhancer Co-Formulated with the GLP-1 Analogue Semaglutide for Oral Administration.

IntroductionOral delivery of proteins, including glucagon-like peptide 1 (GLP-1) receptor agonists, is impeded by low gastrointestinal permeation. Oral semaglutide has been developed for once-daily oral administration by co-formulation of the GLP-1 analogue semaglutide with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC, 300 mg). A randomised, partially double-blind, placebo-controlled thorough QT/corrected QT (QTc) trial was conducted to confirm the absence of unacceptable QTc interval prolongation with SNAC. QT is defined as interval on the electrocardiogram, measured from the start of the QRS complex to the end of the T wave.MethodsPart A of the study sought to identify an appropriate dose of SNAC (which was substantially higher than that used in the oral semaglutide co-formulation) for QTc assessment. Three sequential healthy volunteer cohorts were randomised to escalating single oral doses of SNAC (1.2, 2.4 or 3.6 g) or placebo. Following identification of an appropriate dose, a cross-over trial was conducted (Part B). Healthy volunteers received one of four treatment sequences, including single oral doses of SNAC, moxifloxacin (positive control) and placebo. Primary objectives were to (1) assess adverse events (AEs) with escalating SNAC doses and (2) confirm that SNAC does not cause unacceptable QTc interval prolongation versus placebo, using the Fridericia heart rate-corrected QT interval (QTcF).ResultsAll subjects completed Part A (N = 36) and 46 subjects completed Part B. In Part A, all AEs were mild to moderate in severity; no relationship was identified between AE incidence and SNAC dose. SNAC 3.6 g, the maximum investigated SNAC dose, was selected for Part B. There was no unacceptable prolongation of the QTcF interval with SNAC 3.6 g, and assay sensitivity was demonstrated with moxifloxacin as the positive control. There was no significant exposure–response relationship between SNAC concentration and QTcF interval, and no instances of QTc interval > 450 ms or increases > 30 ms.ConclusionThis QT/QTc trial demonstrates that SNAC doses 12-fold higher than the 300 mg dose used in the oral formulation of semaglutide do not cause unacceptable prolongation of the QTcF interval.Trial RegistrationClinicaltrials.gov identifier: NCT02911870.

Moxifloxacin Pharmacokinetics, Cardiac Safety, and Dosing for the Treatment of Rifampicin-Resistant Tuberculosis in Children.

Moxifloxacin is a recommended drug for rifampin-resistant tuberculosis (RR-TB) treatment, but there is limited pediatric pharmacokinetic and safety data, especially in young children. We characterize moxifloxacin population pharmacokinetics and QT interval prolongation and evaluate optimal dosing in children with RR-TB. Pharmacokinetic data were pooled from 2 observational studies in South African children with RR-TB routinely treated with oral moxifloxacin once daily. The population pharmacokinetics and Fridericia-corrected QT (QTcF)-interval prolongation were characterized in NONMEM. Pharmacokinetic simulations were performed to predict expected exposure and optimal weight-banded dosing. Eighty-five children contributed pharmacokinetic data (median [range] age of 4.6 [0.8-15] years); 16 (19%) were aged <2 years, and 8 (9%) were living with human immunodeficiency virus (HIV). The median (range) moxifloxacin dose on pharmacokinetic sampling days was 11 mg/kg (6.1 to 17). Apparent clearance was 6.95 L/h for a typical 16-kg child. Stunting and HIV increased apparent clearance. Crushed or suspended tablets had faster absorption. The median (range) maximum change in QTcF after moxifloxacin administration was 16.3 (-27.7 to 61.3) ms. No child had QTcF ≥500 ms. The concentration-QTcF relationship was nonlinear, with a maximum drug effect (Emax) of 8.80 ms (interindividual variability = 9.75 ms). Clofazimine use increased Emax by 3.3-fold. Model-based simulations of moxifloxacin pharmacokinetics predicted that current dosing recommendations are too low in children. Moxifloxacin doses above 10-15 mg/kg are likely required in young children to match adult exposures but require further safety assessment, especially when coadministered with other QT-prolonging agents.

Evaluation of moxifloxacin in canine and non-human primate telemetry assays: Comparison of QTc interval prolongation by timepoint and concentration-QTc analysis.

The in vivo correct QT (QTc) assay is used by the pharmaceutical industry to characterize the potential for delayed ventricular repolarization and is a core safety assay mentioned in International Conference on Harmonization (ICH) S7B guideline. The typical telemetry study involves a dose‐response analysis of QTc intervals over time using a crossover (CO) design. This method has proven utility but does not include direct integration of pharmacokinetic (PK) data. An alternative approach has been validated and is used routinely in the clinical setting that pairs pharmacodynamic (PD) responses with PK exposure (e.g., concentration‐QTc (C‐QTc) analysis. The goal of our paper was to compare the QTc sensitivity of two experimental approaches in the conscious dog and non‐human primate (NHP) QTc assays. For timepoint analysis, a conventional design using eight animals (8 × 4 CO) to detect moxifloxacin‐induced QTc prolongation was compared to a PK/PD design in a subset (N = 4) of the same animals. The findings demonstrate that both approaches are equally sensitive in detecting threshold QTc prolongation on the order of 10 ms. Both QTc models demonstrated linearity in the QTc prolongation response to moxifloxacin dose escalation (6 to 46 ms). Further, comparison with human QTc findings with moxifloxacin showed agreement and consistent translation across the three species: C‐QTc slope values were 0.7‐ (dog) and 1.2‐ (NHP) fold of the composite human value. In conclusion, our data show that dog and NHP QTc telemetry with an integrated PK arm (C‐QTc) has the potential to supplement clinical evaluation and improve integrated QTc risk assessment.

A randomized, double-blind, placebo- and positive-controlled crossover study of the effects of durlobactam on cardiac repolarization in healthy subjects.

Durlobactam (formerly ETX2514) is a diazabicyclooctane β‐lactamase inhibitor that inhibits class A, C, and D β‐lactamases. Sulbactam combined with durlobactam has in vitro and in vivo activity against Acinetobacter baumannii including carbapenem‐ and colistin‐resistant isolates and is being developed for treating serious infections due to A. baumannii. The effect of a single supratherapeutic dose of durlobactam on the heart rate corrected QT interval (QTc) was evaluated in healthy subjects in a placebo‐ and active‐controlled, single‐infusion, three‐way crossover study. Subjects were randomized to 1 of 6 sequences that included a single 3‐h i.v. infusion of durlobactam 4 g (supratherapeutic dose), a single 3‐h i.v. infusion of placebo, and a single 3‐h i.v. infusion of placebo plus a single oral dose of moxifloxacin 400 mg given open‐label at the end of the i.v. infusion. In each treatment period, Holter electrocardiogram (ECG) measurements were obtained from predose through 24 h post‐start of infusion. For the primary ECG end point, placebo‐corrected change‐from‐baseline corrected QT Fridericia’s formula (ΔΔQTcF), no significant change was observed with durlobactam. A concentration‐QT analysis demonstrated no significant effect of durlobactam on ECG parameters, including QT interval prolongation. Thus, durlobactam has a low risk for prolonging the QT interval and is unlikely to produce any proarrhythmic effects.

Endophthalmitis Prophylaxis Failures in Patients Injected With Intracameral Antibiotic During Cataract Surgery

To estimate the association of cefuroxime and moxifloxacin in relation to the occurrence of endophthalmitis following phacoemulsification cataract surgery. Retrospective clinical cohort study. We studied patients with noncomplex phacoemulsification cataract surgery in Kaiser Permanente Northern California during 2014-2019. Data were obtained for acute, postoperative endophthalmitis within 90 days of phacoemulsification, including culture and antibiogram results, intracameral and topical antibiotic agent, and dose. In a post hoc analysis, we also examined preoperative anterior chamber depth (ACD) and postoperative anterior chamber volume (ACV). Of 216,141 surgeries, endophthalmitis occurred in 0.020% of moxifloxacin-injected eyes and 0.013% of cefuroxime eyes (relative risk 1.62 with 95% CI 0.82-3.20, P=.16). Of the 34 (0.016%) cases of endophthalmitis, cefuroxime 1 mg was injected into 13 eyes and moxifloxacin 0.1% into 21 eyes. Organisms with antibiograms were identified in 12 (35%) cases. Of these, bacteria recovered from cefuroxime-injected eyes were resistant to cefuroxime in all cases (4/4), with Enterococcus comprising half of these. In eyes injected with moxifloxacin 0.1%, 6 out of 7 organisms were sensitive to moxifloxacin injected with 0.1 mL and in 1 eye injected with 1 mL. Streptococcus was the most common organism recovered (6/9) in moxifloxacin-injected eyes. Preoperative ACD and postoperative calculated ACV were higher in eyes injected with moxifloxacin. Endophthalmitis cases with positive cultures were generally related to organism resistance in cefuroxime eyes but to sensitive organisms in moxifloxacin eyes. Moxifloxacin doses may have been insufficient in eyes with larger ACV.

Oral absorption and drug interaction kinetics of moxifloxacin in an animal model of weightlessness

To investigate the effect of simulated weightlessness on the pharmacokinetics of orally administered moxifloxacin and the antacid Maalox or the antidiarrheal Pepto-Bismol using a tail-suspended (TS) rat model of microgravity. Fasted control and TS, jugular-vein-cannulated, male Sprague-Dawley rats received either a single 5 mg/kg intravenous dose or a single 10 mg/kg oral dose of moxifloxacin alone or with a 0.625 mL/kg oral dose of Maalox or a 1.43 mL/kg oral dose of Pepto-Bismol. Plasma concentrations of moxifloxacin were measured by HPLC. Pharmacokinetic data were analyzed using WinNonlin. Simulated weightlessness had no effect on moxifloxacin disposition after intravenous administration but significantly decreased the extent of moxifloxacin oral absorption. The coadministration of moxifloxacin with Maalox to either control or TS rats caused significant reductions in the rate and extent of moxifloxacin absorption. In contrast, the coadministration of moxifloxacin with Pepto-Bismol to TS rats had no significant effect on either the rate or the extent of moxifloxacin absorption. These interactions showed dose staggering when oral administrations of Pepto-Bismol and moxifloxacin were separated by 60 min in control rats but not in TS rats. Dose staggering was more apparent after the coadministration of Maalox and moxifloxacin in TS rats.

Incremental effect of topical and oral moxifloxacin administration with surgical intracameral prophylaxis

ObjectiveTo determine how supplemental perioperative topical or oral moxifloxacin administration impacts anterior chamber (AC) antibiotic concentrations beyond those achieved by intracameral (IC) administration alone for postoperative endophthalmitis (POE) prophylaxis. DesignMathematical modeling. MethodsThe mathematical model developed by Arshinoff, Modabber, and Felfeli was adapted to calculate all reported data. A literature review of pharmacokinetic data for topical and oral moxifloxacin was used to inform the expansion of the model. ResultsOur previously constructed IC model yields a dose of moxifloxacin in the AC sufficient to confer bactericidal coverage against the most common POE pathogen, methicillin-sensitive Staphylococcus aureus (MSSA), for ∼40 hours postoperatively. Topical 0.5% moxifloxacin eye drops alone, administered every 4 or 6 hours, achieve an AC concentration just above or at the mutant prevention concentration (MPC) for MSSA, respectively, whereas 8-hour dosing produces levels generally below the MPC. Combining topical moxifloxacin with IC increases the AC concentration above IC alone only after 20 or more hours and maintains the AC concentration at, or just below, the MPC for MSSA for as long as the drops are continued. Combined perioperative oral moxifloxacin with IC increases AC levels over IC alone only after 16 hours and maintains the AC concentration above the MPC for MSSA for an additional 5 hours, owing to the systemic reservoir. ConclusionsThe addition of topical or oral moxifloxacin supplemental to IC can extend the duration of bactericidal coverage for the most common, but not the most resistant POE-causing pathogens.