Safety, Pharmacokinetics, and Pharmacodynamics of a First-in-Class ClC-1 Inhibitor to Enhance Muscle Excitability: Phase I Randomized Controlled Trial.

NMD670 is a first-in-class inhibitor of skeletal muscle-specific chloride channel ClC-1, developed to improve muscle weakness and fatigue in neuromuscular diseases. Preclinical studies show that ClC-1 inhibition enhances muscle excitability, improving muscle contractility and strength. We describe the first-in-human, randomized, double-blind, placebo-controlled study, which evaluated the safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of NMD670 in healthy male and female subjects.

A phase 1 trial of AP30663, a K2 channel inhibitor in development for conversion of atrial fibrillation.

Aims: AP30663 is a novel compound under development for pharmacological conversion of atrial fibrillation by targeting the small conductance Ca activated K (K2) 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.

Item response theory in early phase clinical trials: Utilization of a reference model to analyze the Montgomery-Åsberg Depression Rating Scale.

In clinical trials, Montgomery-Åsberg Depression Rating Scale (MADRS) questionnaire data are added up to total scores before analysis, assuming equal contribution of each separate question. Item Response Theory (IRT)-based analysis avoids this by using individual question responses to determine the latent variable (ψ), which represents a measure of depression severity. However, utilization of IRT in early phase trials remains difficult, because large datasets are needed to develop IRT models.

Correction: Wind et al. Topical Bimiralisib Shows Meaningful Cutaneous Drug Levels in Healthy Volunteers and Mycosis Fungoides Patients but No Clinical Activity in a First-in-Human, Randomized Controlled Trial. 2022, , 1510.

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Dose escalations in phase I studies: Feasibility of interpreting blinded pharmacodynamic data.

Aims: During phase I study conduct, blinded data are reviewed to predict the safety of increasing the dose level. The aim of the present study was to describe the probability that effects are observed in blinded evaluations of data in a simulated phase I study design.

Methods: An application was created to simulate blinded pharmacological response curves over time for 6 common safety/efficacy measurements in phase I studies for 1 or 2 cohorts (6 active, 2 placebo per cohort).

Effects of Mexiletine and Lacosamide on Nerve Excitability in Healthy Subjects: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study.

Selective voltage-gated sodium channel blockers are of growing interest as treatment for pain. For drug development of such compounds, it would be critical to have a biomarker that can be used for proof-of-mechanism. We aimed to evaluate whether drug-induced changes in sodium conductance can be detected in the peripheral nerve excitability profile in 18 healthy subjects.

Topical Bimiralisib Shows Meaningful Cutaneous Drug Levels in Healthy Volunteers and Mycosis Fungoides Patients but No Clinical Activity in a First-in-Human, Randomized Controlled Trial.

Mycosis fungoides (MF) is a subtype of CTCL with a low incidence and high medical need for novel treatments. The objective of this randomized, placebo-controlled, double-blinded, first-in-human study was to evaluate safety, efficacy, cutaneous and systemic pharmacokinetics (PK) of topical bimiralisib in healthy volunteers (HVs) and MF patients. In this trial, a total of 6 HVs and 19 early-stage MF patients were treated with 2.

Population pharmacokinetics of clonazepam in saliva and plasma: Steps towards noninvasive pharmacokinetic studies in vulnerable populations.

Aim: Traditional studies focusing on the relationship between pharmacokinetics (PK) and pharmacodynamics necessitate blood draws, which are too invasive for children or other vulnerable populations. A potential solution is to use noninvasive sampling matrices, such as saliva. The aim of this study was to develop a population PK model describing the relationship between plasma and saliva clonazepam kinetics and assess whether the model can be used to determine trough plasma concentrations based on saliva samples.

An exploratory first-in-man study to investigate the pharmacokinetics and safety of liposomal dexamethasone at a 2- and 1-week interval in patients with metastatic castration resistant prostate cancer.

Dexamethasone has antitumor activity in metastatic castration resistant prostate cancer (mCRPC). We aimed to investigate intravenous liposome-encapsulated dexamethasone disodium phosphate (liposomal dexamethasone) administration in mCRPC patients. In this exploratory first-in-man study, patients in part A received a starting dose of 10 mg followed by five doses of 20 mg liposomal dexamethasone at 2-week intervals.

Effect of hydroxychloroquine on the cardiac ventricular repolarization: A randomized clinical trial.

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.

Accelerating vaccine trial conduct in a pandemic with a hot spot-based inclusion strategy using trial and epidemic simulation.

Clinical development of vaccines in a pandemic situation should be rigorous but expedited to tackle the pandemic threat as fast as possible. We explored the effects of a novel vaccine trial strategy that actively identifies and enrolls subjects in local areas with high infection rates. In addition, we assessed the practical requirements needed for such a strategy.

Theoretical Performance of Nonlinear Mixed-Effect Models Incorporating Saliva as an Alternative Sampling Matrix for Therapeutic Drug Monitoring in Pediatrics: A Simulation Study.

Background: Historically, pharmacokinetic (PK) studies and therapeutic drug monitoring (TDM) have relied on plasma as a sampling matrix. Noninvasive sampling matrices, such as saliva, can reduce the burden on pediatric patients. The variable plasma-saliva relationship can be quantified using population PK models (nonlinear mixed-effect models).

Biperiden Challenge Model in Healthy Elderly as Proof-of-Pharmacology Tool: A Randomized, Placebo-Controlled Trial.

Selective M 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 M mAChR antagonist biperiden could be used to demonstrate procognitive and pharmacological effects of selective M mAChR agonists.

Phase 1 clinical trial of losmapimod in facioscapulohumeral dystrophy: Safety, tolerability, pharmacokinetics, and target engagement.

Aims: Evaluate safety, tolerability, pharmacokinetics (PK) and target engagement (TE) of losmapimod in blood and muscle in facioscapulohumeral dystrophy (FSHD).

Methods: This study included Part A: 10 healthy volunteers randomized to single oral doses of losmapimod (7.5 mg then 15 mg; n = 8) or placebo (both periods; n = 2); Part B: 15 FSHD subjects randomized to placebo (n = 3), or losmapimod 7.

A novel sustained-release cysteamine bitartrate formulation for the treatment of cystinosis: Pharmacokinetics and safety in healthy male volunteers.

The strict intake regimen of cysteamine bitartrate formulations, associated with side effects, is a concern for the treatment compliance in cystinosis therapy. Therefore, there is a need for a cysteamine formulation with an improved pharmacokinetic profile. This study investigated the pharmacokinetics, safety and tolerability of a new sustained-release cysteamine dosage form, PO-001, in healthy volunteers.

The power of modelling pulsatile profiles.

The quantitative description of individual observations in non-linear mixed effects models over time is complicated when the studied biomarker has a pulsatile release (e.g. insulin, growth hormone, luteinizing hormone).

Predictive performance of parent-metabolite population pharmacokinetic models of (S)-ketamine in healthy volunteers.

Purpose: The recent repurposing of ketamine as treatment for pain and depression has increased the need for accurate population pharmacokinetic (PK) models to inform the design of new clinical trials. Therefore, the objectives of this study were to externally validate available PK models on (S)-(nor)ketamine concentrations with in-house data and to improve the best performing model when necessary.

Methods: Based on predefined criteria, five models were selected from literature.

Safety, pharmacokinetics, and pharmacodynamics of Gln-1062, a prodrug of galantamine.

Introduction: Gln-1062 (MEMOGAIN) is an intranasally administered lipophilic prodrug of galantamine. Based on high brain-to-blood concentrations observed in pre-clinical studies, Gln-1062 is expected to have superior cognitive efficacy compared to oral galantamine.

Methods: Forty-eight healthy elderly subjects were randomized 12:4 to Gln-1062 (5.

Impact of enantiomer-specific changes in pharmacokinetics between infants and adults on the target concentration of racemic ketorolac: A pooled analysis.

Aims: Ketorolac is a nonsteroidal anti-inflammatory racemic drug with analgesic effects only attributed to its S-enantiomer. The aim of this study is to quantify enantiomer-specific maturational pharmacokinetics (PK) of ketorolac and investigate if the contribution of both enantiomers to the total ketorolac concentration remains equal between infants and adults or if a change in target racemic concentration should be considered when applied to infants.

Methods: Data were pooled from 5 different studies in adults, children and infants, with 1020 plasma concentrations following single intravenous ketorolac administration.

First-in-Human Assessment of cRGD-ZW800-1, a Zwitterionic, Integrin-Targeted, Near-Infrared Fluorescent Peptide in Colon Carcinoma.

Purpose: Incomplete oncologic resections and damage to vital structures during colorectal cancer surgery increases morbidity and mortality. Moreover, neoadjuvant chemoradiotherapy has become the standard treatment modality for locally advanced rectal cancer, where subsequent downstaging can make identification of the primary tumor more challenging during surgery. Near-infrared (NIR) fluorescence imaging can aid surgeons by providing real-time visualization of tumors and vital structures during surgery.

Quantification of the endogenous growth hormone and prolactin lowering effects of a somatostatin-dopamine chimera using population PK/PD modeling.

A phase 1 clinical trial in healthy male volunteers was conducted with a somatostatin-dopamine chimera (BIM23B065), from which information could be obtained on the concentration-effect relationship of the inhibition of pulsatile endogenous growth hormone and prolactin secretion. Endogenous growth hormone profiles were analyzed using a two-step deconvolution-analysis-informed population pharmacodynamic modeling approach, which was developed for the analyses of pulsatile profiles. Prolactin concentrations were modelled using a population pool model with a circadian component on the prolactin release.

Model informed quantification of the feed-forward stimulation of growth hormone by growth hormone-releasing hormone.

Aims: Growth hormone (GH) secretion is pulsatile and secretion varies highly between individuals. To understand and ultimately predict GH secretion, it is important to first delineate and quantify the interaction and variability in the biological processes underlying stimulated GH secretion. This study reports on the development of a population nonlinear mixed effects model for GH stimulation, incorporating individual GH kinetics and the stimulation of GH by GH-releasing hormone (GHRH).

Pharmacokinetics of intravenous and inhaled salbutamol and tobramycin: An exploratory study to investigate the potential of exhaled breath condensate as a matrix for pharmacokinetic analysis.

Concentrations of drugs acting in the lungs are difficult to measure, resulting in relatively unknown local pharmacokinetics. The aim of this study is to assess the potential of exhaled breath condensate (EBC) as a matrix for pharmacokinetic analysis of inhaled and intravenous medication. A 4-way crossover study was conducted in 12 volunteers with tobramycin and salbutamol intravenously and via inhalation.

The Oral Pheneticillin Absorption Test: An Accurate Method to Identify Patients with Inadequate Oral Pheneticillin Absorption.

Severe streptococcal infections are commonly treated with intravenous followed by oral penicillin (pheneticillin) therapy. However, switching from iv to oral therapy is complicated by the variability in oral pheneticillin absorption. We employed an Oral Absorption Test (OAT) for pheneticillin to identify patients in whom oral pheneticillin absorption is poor.