Effect of Cefiderocol, a Siderophore Cephalosporin, on QT/QTc Interval in Healthy Adult Subjects.

PURPOSE: Cefiderocol is a novel siderophore cephalosporin with potent activity against gram-negative bacteria, including multidrug-resistant strains. This Phase I study was conducted to assess the tolerability of single-ascending doses of cefiderocol (part 1) and the effect of cefiderocol on cardiac repolarization, assessed using the electrocardiographic corrected QT interval (QTcF) and other ECG parameters (part 2), in healthy adult subjects. METHODS: Part 1 was a randomized, double-blind, placebo-controlled, single-ascending dose study in healthy adult male and female subjects. Part 2 was a 4-period crossover study in which subjects received a single 2-g dose of cefiderocol (therapeutic dose), a single 4-g dose of cefiderocol (supratherapeutic dose), or saline (placebo), each infused over 3 hours, and a single oral 400-mg dose of moxifloxacin. In each treatment period, continuous cardiac monitoring was used to assess the effects of cefiderocol on ECG parameters. The QT interval corrected using the Fridericia formula (QTcF) was the primary ECG parameter; the time-matched placebo- and baseline-adjusted (dd)-QTcF interval was the primary end point. The plasma pharmacokinetic properties of cefiderocol were calculated on the basis of concentration-time profiles in all evaluable subjects. FINDINGS: All point estimates for the ddQTcF interval were <5 ms and the upper bound of the 90% CIs were <10 ms at each timepoint after the initiation of the cefiderocol 3-hour infusion. Concentration-effect modeling showed a slightly negative slope and predicted modestly negative values of the ddQTcF interval at the Cmax of cefiderocol. Both doses of cefiderocol were well tolerated. All adverse events were mild in severity, with no deaths or serious adverse events reported. IMPLICATIONS: Overall, therapeutic and supratherapeutic doses of cefiderocol had no apparent clinically significant effect on the QTcF.

NYX-2925, A Novel N-methyl-D-aspartate Receptor Modulator: A First-in-Human, Randomized, Double-blind Study of Safety and Pharmacokinetics in Adults.

NYX-2925, a new chemical entity, acts as a co-agonist to glutamate at the N-methyl-D-aspartate receptor (NMDAR). At low concentrations of endogenous agonists (glycine/D-serine), NYX-2925 partially activates NMDARs, modulating neural pathways relevant for chronic pain. NYX-2925 is being developed for the treatment of chronic pain conditions, including painful diabetic peripheral neuropathy and fibromyalgia. In this first-in-human, phase I, single-ascending dose (50-1,200 mg) and multiple-ascending dose (150-900 mg) study, the safety, tolerability, and pharmacokinetics (PKs) of NYX-2925 were evaluated in 84 healthy adult volunteers. No safety concerns emerged, including no dissociative side effects. NYX-2925 exhibited dose-proportional PKs and minimal accumulation following once-daily dosing for 7 days. Cerebrospinal fluid (CSF) measurements confirmed that NYX-2925 crosses the blood brain barrier, with maximum CSF concentrations approximating 6-9% of maximum plasma concentrations at the same dose level. NYX-2925 was safe and well-tolerated in healthy volunteers, and the study results support the continued clinical development for chronic pain conditions.

Evaluation of the Cardiac Safety of Long-Acting Endectocide Moxidectin in a Randomized Concentration-QT Study.

Potential effects on cardiac repolarization of single doses of moxidectin, a potent long-acting macrocyclic lactone endectocide, were assessed in a concentration-QT (c-QT; exposure-response) study. This double-blind, placebo-controlled, parallel-group study in healthy male volunteers (n = 60) randomized subjects to a single oral dose of moxidectin (4 mg, 8 mg, 16 mg, 24 mg, or 36 mg) or matching placebo. Serial plasma samples for pharmacokinetic (PK) analysis and concurrent triplicate electrocardiogram measurements were taken at baseline and 14 prespecified time points over 72 hours, yielding 900 QT interval-plasma concentration time-matched pairs. Moxidectin had no statistically significant or clinically relevant impact on QT interval at any dose level. The primary mixed effects model analysis revealed no treatment-related impact on the Fridericia-corrected QT interval-plasma concentration gradient (-0.0077, 90% confidence interval (CI) -0.0255 to +0.0101).

ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials.

BACKGROUND: Development of new therapies for Alzheimer's disease (AD) is increasingly focused on more mildly affected populations, and requires new assessment and outcome strategies. Patients in early stages of AD have mild cognitive decline and no, or limited, functional impairment. To respond to these assessment challenges, we developed a measurement approach based on established scale items that exhibited change in previous amnestic Mild Cognitive Impairment (aMCI) trials. METHODS: Partial least squares regression with a longitudinal clinical decline model identified items from commonly used clinical scales with the highest combined sensitivity to change over time in aMCI and weighted these items according to their relative contribution to detecting clinical progression in patients' early stages of AD. The resultant AD Composite Score (ADCOMS) was assessed for its ability to detect treatment effect in aMCI/prodromal AD (pAD) clinical trial populations. RESULTS: ADCOMS consists of 4 Alzheimer's Disease Assessment Scale-cognitive subscale items, 2 Mini-Mental State Examination items, and all 6 Clinical Dementia Rating-Sum of Boxes items. ADCOMS demonstrated improved sensitivity to clinical decline over individual scales in pAD, aMCI and in mild AD dementia. ADCOMS also detected treatment effects associated with the use of cholinesterase inhibitors in these populations. Improved sensitivity predicts smaller sample size requirements when ADCOMS is used in early AD trials. CONCLUSIONS: ADCOMS is proposed as new standard outcome for pAD and mild AD dementia trials, and is progressing in a CAMD-sponsored qualification process for use in registration trials of pAD.

Effects of application durations and heat on the pharmacokinetic properties of drug delivered by a lidocaine/tetracaine patch: a randomized, open-label, controlled study in healthy volunteers.

BACKGROUND: The lidocaine/tetracaine heated patch is typically applied to the skin for 20 to 30 minutes to provide local dermal analgesia prior to venous access or minor dermatologic procedures. The potential exists for the use of multiple heated patches for longer application times, but the pharmacokinetic properties and tolerability of these multiple and/or longer applications have not been assessed. OBJECTIVE: The aim of this study was to assess the effects of heat and application time on the pharmacokinetic properties and tolerability of the patch after the application of 4 lidocaine/tetracaine (70/70 mg) heated patches applied at the same time in healthy volunteers for up to 12 hours. METHODS: In this randomized, open-labeled, controlled study, healthy subjects underwent 4 treatment periods (2-, 4-, or 12-hour application of 4 heated patches, or 4-hour application of 4 unheated patches), each separated by a 1-week washout period. RESULTS: Twelve subjects were enrolled (8 women, 4 men; mean age, 31.8 years; mean body mass index, 24.1 kg/m(2)). No tetracaine was detected in the plasma of any subject. Plasma concentrations of lidocaine increased rapidly during the first 2 hours of application in each heated-patch group, and with mean (SD) C(max) values of 18.2 (5.1), 25.7 (5.9), and 30.3 (8.1) ng/mL in the 2-, 4-, and 12-hour groups, respectively. Estimates of application time-normalized AUC(0-t) were not significantly different between the 2- and 4-hour applications of the heated patches, but were 25% lower during the 12-hour application time, suggesting continued but diminished drug delivery between 4 and 12 hours. Compared with subjects who received the unheated patch, those who received the heated patch had plasma lidocaine concentrations 5- and 3-fold higher after 30 and 60 minutes, respectively. Fifteen mild to moderate adverse events (AEs) were reported in 7 subjects, and none of the subjects discontinued the study due to treatment-related AEs. CONCLUSION: The heated patch continuously delivered drug for up to 12 hours and was generally well tolerated in these healthy subjects. ClinicalTrials.gov identifier: NCT01602757.

Pharmacokinetics and metabolism of transdermal oxybutynin: in vitro and in vivo performance of a novel delivery system.

PURPOSE: The purpose of this work was to characterize in vitro/in vivo delivery and pharmacokinetics of oxybutynin (OXY) and its active metabolite. N-desethyloxybutynin (DEO), by a novel matrix transdermal system (TDS). METHODS: Two in vivo, randomized, three-way crossover trials examined single/multiple OXY TDS doses. Abdomen, buttock, and hip application sites were compared and dose proportionality was evaluated. Model independent pharmacokinetics, elimination rate constants, and metabolite/drug ratios were derived from both plasma OXY and DEO concentrations. RESULTS: Single/multiple applications of the OXY TDS to the abdomen yielded mean Cmax OXY concentrations of 3.4 +/- 1.1/6.6 +/- 2.4 ng/mL and median tmax of 36/10 h, with steady state achieved during the second application. Plasma OXY and DEO concentrations decreased gradually after Cmax until system removal. Buttock and hip applications resulted in bioequivalent OXY absorption. AUC ratios of DEO/OXY were 1.5 +/- 0.4 (single dose) and 1.3 +/- 0.3 (multiple dose). Mean in vitro OXY skin absorption (186 microg/h) was comparable to the estimated in vivo delivery (163 microg/h) over 96 h. CONCLUSIONS: Sustained delivery over 4 days and multiple sites allow a convenient, well-tolerated, twice-weekly OXY TDS dosing. A low incidence of anticholinergic side effects is expected during clinical use because of the avoidance of presystemic metabolism and low DEO plasma concentrations. The consistent delivery, absorption, and pharmacokinetics should result in an effective treatment of patients with overactive bladder.