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Aims: AP30663 is a novel compound under development for pharmacological conversion of atrial fibrillation by targeting the small conductance Ca2+ activated K+ (KCa2) channel. The aim of this extension phase 1 study was to test AP30663 at higher single doses compared to the first‐in‐human trial. Methods: Sixteen healthy male volunteers were randomized into 2 cohorts: 6‐ and 8‐mg/kg intravenous single‐dose administration of AP30663 vs. placebo. Safety, pharmacokinetic and pharmacodynamic data were collected. Results: AP30663 was associated with mild and transient infusion site reactions with no clustering of other adverse events but with an estimated maximum mean QTcF interval prolongation of 45.2 ms (95% confidence interval 31.5–58.9) in the 6 mg/kg dose level and 50.4 ms (95% confidence interval 36.7–64.0) with 8 mg/kg. Pharmacokinetics was dose proportional with terminal half‐life of around 3 h. Conclusion: AP30663 in doses up to 8 mg/kg was associated with mild and transient infusion site reactions and an increase of the QTcF interval. Supporting Information support that the QTc effect may be explained by an off‐target inhibition of the IKr channel. [ABSTRACT FROM AUTHOR]

Aims: Hydroxychloroquine has been suggested as possible treatment for severe acute respiratory syndrome‐coronavirus‐2. Studies reported an increased risk of QTcF‐prolongation after treatment with hydroxychloroquine. The aim of this study was to analyse the concentration‐dependent effects of hydroxychloroquine on the ventricular repolarization, including QTcF‐duration and T‐wave morphology. Methods: Twenty young (≤30 y) and 20 elderly (65–75 y) healthy male subjects were included. Subjects were randomized to receive either a total dose of 2400 mg hydroxychloroquine over 5 days, or placebo (ratio 1:1). Follow‐up duration was 28 days. Electrocardiograms (ECGs) were recorded as triplicate at baseline and 4 postdose single recordings, followed by hydroxychloroquine concentration measurements. ECG intervals (RR, QRS, PR, QTcF, J‐Tpc, Tp‐Te) and T‐wave morphology, measured with the morphology combination score, were analysed with a prespecified linear mixed effects concentration–effect model. Results: There were no significant associations between hydroxychloroquine concentrations and ECG characteristics, including RR‐, QRS‐ and QTcF‐interval (P =.09,.34,.25). Mean ΔΔQTcF‐interval prolongation did not exceed 5 ms and the upper limit of the 90% confidence interval did not exceed 10 ms at the highest measured concentrations (200 ng/mL). There were no associations between hydroxychloroquine concentration and the T‐wave morphology (P =.34 for morphology combination score). There was no significant effect of age group on ECG characteristics. Conclusion: In this study, hydroxychloroquine did not affect ventricular repolarization, including the QTcF‐interval and T‐wave morphology, at plasma concentrations up to 200 ng/mL. Based on this analysis, hydroxychloroquine does not appear to increase the risk of QTcF‐induced arrhythmias. [ABSTRACT FROM AUTHOR]

Selective M1 muscarinic acetylcholine receptor (mAChR) agonists are being developed as symptomatic treatment for neurodegenerative and neuropsychiatric disorders that lead to cognitive dysfunction. Demonstrating cognition‐enhancing effects in early‐phase clinical development in healthy subjects is difficult. A challenge with the M1 mAChR antagonist biperiden could be used to demonstrate procognitive and pharmacological effects of selective M1 mAChR agonists. The aim of this study was to develop such a model. To this end, 12 healthy elderly subjects participated in a randomized, placebo‐controlled, 3‐way crossover study investigating tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) effects of 2 and 4 mg biperiden. Repeated PD assessments were performed using neurocognitive tasks and electrophysiological measurements. A population PK‐PD model was developed. Four milligrams of biperiden showed significant impairment of sustained attention (−2.1 percentage point in adaptive tracking [95%CI, −3.043 to −1.148], verbal memory (2‐3 fewer words recalled [95%CI, −5.9 to −0.2]) and working memory (up to a 50‐millisecond increase in the n‐back task reaction time [95%CI, 21.854‐77.882]) compared with placebo. The PK data were best fitted by a 2‐compartment model and showed high interoccasion and intersubject variability. Population PK‐PD analysis quantified significant concentration‐effect relationships for the n‐back reaction time, n‐back accuracy, and adaptive tracking. In conclusion, biperiden caused M1 mAChR‐related dose‐ and concentration‐dependent temporary declines in cognitive functioning. Therefore a biperiden pharmacological challenge model can be used for proof‐of‐pharmacology studies and to demonstrate cognition‐enhancing effects of new cholinergic compounds that are being developed. [ABSTRACT FROM AUTHOR]