BACKGROUND:Padsevonil is an antiseizure medication candidate intended to benefit patients with drug-resistant epilepsy. Our investigations aimed at characterizing pharmacokinetics and drug-drug interaction (DDI) profile of padsevonil. RESEARCH DESIGN AND METHODS:An overview of preclinical and clinical pharmacology studies conducted during padsevonil development is provided. RESULTS:In preclinical studies, cytochrome (CYP) 3A4 was identified as the main P450 isoform involved in padsevonil metabolism, with potential minor contribution from CYP2C19. Padsevonil was shown to be a time-dependent CYP2C19-inhibitor, weak CYP3A4-inducer, weak inhibitor of P-gp/OCT1/MATE2-K, and potent OCT2-inhibitor. Initial clinical pharmacology studies in healthy participants showed that padsevonil had (i) good absorption, (ii) clearance mediated mainly by metabolism, and (iii) time-dependent kinetics. A study in genotyped participants confirmed the role of CYP2C19 in clearance and time-dependent kinetics; the major contribution of CYP3A4 was confirmed in DDI studies with CYP3A4-inducers (carbamazepine, oxcarbazepine) and -inhibitor (erythromycin). Padsevonil did not affect pharmacokinetics of valproate/lamotrigine/levetiracetam/oxcarbazepine or oral contraceptives. In a cocktail clinical study, padsevonil showed moderate CYP2C19 inhibition (omeprazole) and weak CYP3A4 induction (oral midazolam). No specific effects on CYP1A2 (caffeine), CYP2C9 (S-warfarin), and CYP2D6 (dextromethorphan) were observed. CONCLUSIONS:The studies presented helped in understanding padsevonil disposition and risks of DDIs, which would inform dosing and prescribing. CLINICAL TRIAL REGISTRATION:https://www.clinicaltrials.gov identifiers are NCT04131517, NCT03480243, NCT03695094, NCT04075409.

Direct targeting of alpha-synuclein (ASYN) has emerged as a disease-modifying strategy for Parkinson’s disease and other synucleinopathies which is being approached using both small molecule compounds and ASYN-targeted biologics. Minzasolmin (UCB0599) is an orally bioavailable and brain-penetrant small molecule ASYN misfolding inhibitor in clinical development as a disease-modifying therapeutic for Parkinson’s disease. Herein the results of preclinical evaluations of minzasolmin that formed the basis for subsequent clinical development are described. Pharmacokinetic evaluations of intraperitoneal 1 and 5 mg/kg minzasolmin in wildtype mice revealed parallel and dose-proportional exposures in brain and plasma. Three-month administration studies in the Line 61 transgenic mouse model of PD were conducted to measure ASYN pathology and other PD-relevant endpoints including markers of CNS inflammation, striatal DAT labeling and gait. Reductions in ASYN pathology were correlated with improved aspects of gait and balance, reductions in CNS inflammation marker abundance, and normalized striatal DAT levels. These findings provide support for human dose determinations and have informed the translational strategy for clinical trial design and biomarker selection for the ongoing clinical studies of minzasolmin in patients living with early-stage Parkinson’s disease (ClinicalTrials.gov ID: NCT04658186; EudraCT Number 2020–003265).

Volumetric absorptive microsampling (VAMS) techniques have gained popularity these last years as innovative tool for collection of blood pharmacokinetic (PK) samples in clinical trials as they offer many advantages over dried blood spot and conventional venous blood sampling. The use of Mitra ® , a blood collection device based on volumetric absorptive microsampling (VAMS) technology, was implemented during clinical development of padsevonil (PSL), an anti-seizure medication (ASM) candidate. The present study describes the approach used to bridge plasma (obtained from conventional venous blood sampling) and blood exposures (obtained with Mitra ® ) to support the use of Mitra as sole blood PK sampling method in clinical trials. Paired blood (using Mitra ® ) and plasma samples (using conventional venous blood sampling) were collected in healthy volunteers as well as in patients with epilepsy. PSL concentration in plasma and blood were analyzed using different approaches which included evaluation of blood-to-plasma ratios (B/P) over time, linear regression, Bland-Altman analysis as well as development of a linear-mixed effect model based on clinical pharmacology studies. Results showed that the observed in vivo B/P and the measured bias between the 2 collection methods were consistent with the measured in vitro B/P. Graphical analysis demonstrated a clear time effect on the B/P which was confirmed in the linear mixed effect model with sampling time identified as significant covariate. Finally, the built-in model was validated using independent datasets and was shown to adequately predict plasma concentration based on blood concentration with a mean bias of less than 9% (predicted versus observed plasma concentration). Graphical Abstract

Purpose Minzasolmin (UCB0599) is an orally administered, small molecule inhibitor of ASYN misfolding in development as a potential disease-modifying therapy for Parkinson’s disease. Here we describe the preclinical development of a radiolabeled tracer and results from a phase 1 study using the tracer to investigate the brain distribution of minzasolmin. Procedures In the preclinical study, two radiolabeling positions were investigated on the S -enantiomer of minzasolmin (UCB2713): [ 11 C]methylamine UCB2713 ([ 11 C- N -CH 3 ]UCB2713) and [ 11 C]carbonyl UCB2713 ([ 11 C-CO]UCB2713). Male C57 black 6 mice ( N = 10) received intravenous [ 11 C- N -CH 3 ]UCB2713; brain homogenates were assessed for radioactivity and plasma samples analyzed by high-performance liquid chromatography. Positron emission tomography-computed tomography (PET-CT) was used to image brains in a subset of mice ( n = 3). In the open-label, phase 1 study, healthy volunteers were scanned twice with PET-CT following injection with [ 11 C]minzasolmin radiotracer (≤ 10 µg), first without, then with oral dosing with non-radiolabeled minzasolmin 360 mg. Primary objective: to determine biodistribution of minzasolmin in the human brain; secondary objectives included minzasolmin safety/tolerability. Results Preclinical data supported the use of [ 11 C]minzasolmin in clinical studies. In the phase 1 study, PET data showed substantial drug signal in the brain of healthy volunteers ( N = 4 ). The mean estimated whole brain total distribution volume (V T ) at equilibrium across all regions of interest was 0.512 mL/cm 3 , no difference in V T was observed following administration of minzasolmin 360 mg. Treatment-emergent adverse events (TEAEs) were reported by 75% ( n = 3) of participants. No drug-related TEAEs, deaths, serious adverse events, or discontinuations were reported. Conclusion Following positive preclinical results with the N-methyl labeled PET tracer, [ 11 C]minzasolmin was used in the phase 1 study, which demonstrated that minzasolmin readily crossed the blood–brain barrier and was well distributed throughout the brain. Safety and pharmacokinetic findings were consistent with previous early-phase studies (such as UP0077, NCT04875962).

Background: Parkinson's disease (PD) and its progression are thought to be caused and driven by misfolding of alpha-synuclein (ASYN). UCB0599 is an oral, small-molecule inhibitor of ASYN misfolding, aimed at slowing disease progression. Objective: The aim was to investigate safety/tolerability and pharmacokinetics (PK) of single and multiple doses of UCB0599. Methods: Safety/tolerability and PK of single and multiple doses of UCB0599 and its metabolites were investigated in two phase 1 studies in healthy participants (HPs), where food effect and possible interaction with itraconazole (ITZ) were assessed (UP0030 [randomized, placebo-controlled, dose-escalation, crossover study, N = 65] and UP0078 [open-label study, N = 22]). Safety/tolerability and multi-dose PK of UCB0599 were subsequently investigated in a phase 1b randomized, double-blind, placebo-controlled study of participants with PD (UP0077 [NCT04875962], N = 31). Results: Across all studies, UCB0599 displayed rapid absorption with linear, time-independent PK properties; PK of multiple doses of UCB0599 were predictable from single-dose exposures. No notable food-effect was observed; co-administration with ITZ affected UCB0599 disposition (maximum plasma concentration and area under the curve increased similar to 1.3- and similar to 2 to 3-fold, respectively) however, this did not impact the safety profile. Hypersensitivity reactions were reported in UP0030 (n = 2) and UP0077 (n = 2). Treatment-related adverse events occurred in 43% (UCB0599), and 30% (placebo) of participants with PD were predominantly mild-to-moderate in intensity and were not dose related. Conclusions: Seventy-three HPs and 21 participants with PD received UCB0599 doses; an acceptable safety/tolerability profile and predictable PK support continued development of UCB0599 for the slowing of PD progression. A phase 2 study in early-stage PD is underway (NCT04658186). (C) 2022 UCB Pharma. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Leucine‐rich repeat kinase 2 (LRRK2) inhibitors are currently in clinical development as interventions to slow progression of Parkinson’s disease (PD). Understanding the rate of progression in PD as measured by both motor and nonmotor features is particularly important in assessing the potential therapeutic effect of LRRK2 inhibitors in clinical development. Using standardized data from the Critical Path for Parkinson’s Unified Clinical Database, we quantified the rate of progression of the Movement Disorder Society–sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS‐UPDRS) Part I (nonmotor aspects of experiences of daily living) in 158 participants with PD who were carriers and 598 participants with PD who were noncarriers of at least one of three different LRRK2 gene mutations (G2019S, R1441C/G, or R1628P). Age and disease duration were found to predict baseline disease severity, while presence of at least one of these three LRRK2 mutations was a predictor of the rate of MDS‐UPDRS Part I progression. The estimated progression rate in MDS‐UPDRS Part I was 0.648 (95% confidence interval: 0.544, 0.739) points per year in noncarriers of a LRRK2 mutation and 0.259 (95% confidence interval: 0.217, 0.295) points per year in carriers of a LRRK2 mutation. This analysis demonstrates that the rate of progression based on MDS‐UPDRS Part I is ~ 60% lower in carriers as compared with noncarriers of LRRK2 gene mutations.

A quantitative assessment of Parkinson's disease (PD) progression is critical for optimizing clinical trials design. Disease progression model was developed using pooled data from the Progression Marker Initiative study and the Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation in Parkinson's Disease study. Age, gender, concomitant medication, and study arms were predictors of baseline. A mutation in the leucine‐rich repeat kinase 2 (LRRK2) encoding gene was associated with the disease progression rate. The progression rate in subjects with PD who carried LRRK2 mutation was slightly slower (~0.170 points/month) than that in PD subjects without the mutation (~0.222 points/month). For a nonenriched placebo‐controlled clinical trial, approximately 70 subjects/arm would be required to detect a drug effect of 50% reduction in the progression rate with 80% probability, whereas 85, 93, and 100 subjects/arm would be required for an enriched clinical trial with 30%, 50%, and 70% subjects with LRRK2 mutations, respectively.

Developing disease modifying therapies for Parkinson’s disease (PD) calls for outcome measurement strategies focused on characterizing early stage disease progression. We explored the psychometric evidence for using the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part II (patient motor experience of daily living) and part III (clinician motor examination) in this context. MDS-UPDRS-II and -III data were collected at screening, month 12, and month 24 from 384 early stage PD patients (diagnosis ≤ 2 years; Hoehn and Yahr stage 1/2) in the Parkinson’s Progression Markers Initiative (PPMI) study. Psychometric analysis, based on Rasch measurement theory (RMT), was performed on both the original MDS UPDRS-II and -III scales and exploratory content-driven scale structures. RMT analyses showed neither scale was well targeted to early PD. A marked floor effect appeared for most items and a clear item gap was consistently observed in very mild severity of motor signs and levels of motor impact. The original MDS-UPDRS-II and -III scales also displayed disordered thresholds (9/13 and 20/33 items, respectively), indicating response scales not functioning as expected, and misfit (5/13 and 12/33 items, respectively), flagging areas for potential improvement. The MDS-UPDRS-II and -III have psychometric limitations which limits the precision of measurement of motor symptoms and impact in early PD. This can lead to insensitivity in detecting differences and clinical change. Importantly, the diagnostic psychometric evidence provided by the RMT analysis provides a clear starting point for how to improve the quantification of clinically relevant concepts to characterize the course of early PD.

1.This phase-I study (NCT02240290) was designed to investigate the human absorption, disposition and mass balance of C-14-tozadenant, a novel A2a receptor antagonist in clinical development for Parkinson s disease.2.Six healthy male subjects received a single oral dose of tozadenant (240mg containing 81.47KBq of [C-14]-tozadenant). Blood, urine and feces were collected over 14 days. Radioactivity was determined by liquid scintillation counting or accelerator mass spectrometry (AMS). Tozadenant and metabolites were characterized using HPLC-MS/MS and HPLC-AMS with fraction collection.3.At 4h, the C-max of tozadenant was 1.74g/mL and AUC((0-t)) 35.0hg/mL, t(1/2) 15h, Vz/F 1.82L/kg and CL/F 1.40mL/min/kg. For total [C-14] radioactivity, the C-max was 2.29geq/mL at 5h post-dose and AUC((0-t)) 43.9hgeq/mL. Unchanged tozadenant amounted to 93% of the radiocarbon AUC((0-48h)). At 312h post-dose, cumulative urinary and fecal excretion of radiocarbon reached 30.5% and 55.1% of the dose, respectively. Unchanged tozadenant reached 11% in urine and 12% of the dose in feces. Tozadenant was excreted as metabolites, including di-and mono-hydroxylated metabolites, N/O dealkylated metabolites, hydrated metabolites.4.The only identified species circulating in plasma was unchanged tozadenant. Tozadenant was primarily excreted in urine and feces in the form of metabolites.

Given the recognition that disease-modifying therapies should focus on earlier Parkinson's disease stages, trial enrollment based purely on clinical criteria poses significant challenges. The goal herein was to determine the utility of dopamine transporter neuroimaging as an enrichment biomarker in early motor Parkinson's disease clinical trials. Patient-level longitudinal data of 672 subjects with early-stage Parkinson's disease in the Parkinson's Progression Markers Initiative (PPMI) observational study and the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) clinical trial were utilized in a linear mixed-effects model analysis. The rate of worsening in the motor scores between subjects with or without a scan without evidence of dopamine transporter deficit was different both statistically and clinically. The average difference in the change from baseline of motor scores at 24 months between biomarker statuses was -3.16 (90% confidence interval [CI] = -0.96 to -5.42) points. Dopamine transporter imaging could identify subjects with a steeper worsening of the motor scores, allowing trial enrichment and 24% reduction of sample size.

Social anxiety disorder (SAD) is associated with increased fear-related neural activity in the amygdala and we recently found enhanced serotonin synthesis rate in the same region. Anxiolytic agents like selective serotonin re-uptake inhibitors (SSRIs) and neurokinin-1 receptor (NK1R) antagonists reduce amygdala activity and may attenuate serotonin formation according to animal studies. Here, we examined the effects of SSRI pharmacotherapy, NK1R antagonism, and placebo on serotonin synthesis rate in relation to neural activity, measured as regional cerebral blood flow (rCBF), and symptom improvement in SAD. Eighteen SAD patients were randomized to receive daily double-blind treatment for six weeks either with the SSRI citalopram (n=6; 40mg), the NK1R antagonist GR205171 (n=6; 5mg; 4 weeks following 2 weeks of placebo), or placebo (n=6). Serotonin synthesis rate at rest and rCBF during stressful public speaking were assessed, before and after treatment, using positron emission tomography with the tracers [11C]5-hydroxytryptophan and [15O]water respectively. The Liebowitz Social Anxiety Scale (LSAS-SR) indexed symptom severity. All groups exhibited attenuated amygdala serotonin synthesis rate after treatment, which was associated with reduced amygdala rCBF during public speaking and accompanied by symptom improvement. These results are consistent with the notion that serotonin in the amygdala exerts an anxiogenic influence and, conversely, that anxiolysis is achieved through decreased serotonin formation in the amygdala.

Animal studies support the role of the dopamine D3 receptor (DRD3) in alcohol reinforcement or liking. Sustained voluntary alcohol drinking in rats has been associated with an upregulation of striatal DRD3 gene expression and selective blockade of DRD3 reduces ethanol preference, consumption, and cue-induced reinstatement. In vivo measurement of DRD3 in the living human brain has not been possible until recently owing to a lack of suitable tools. In this study, DRD3 status was assessed for the first time in human alcohol addiction. Brain DRD3 availability was compared between 16 male abstinent alcohol-dependent patients and 13 healthy non-dependent age-matched males using the DRD3-preferring agonist positron emission tomography (PET) radioligand [(11)C]PHNO with and without blockade with a selective DRD3 antagonist (GSK598809 60 mg p.o.). In striatal regions of interest, where the [(11)C]PHNO PET signal represents primarily DRD2 binding, no differences were seen in [(11)C]PHNO binding between the groups at baseline. However, baseline [(11)C]PHNO binding was higher in alcohol-dependent patients in hypothalamus (VT: 16.5 ± 4 vs 13.7 ± 2.9, p = 0.040), a region in which the [(11)C]PHNO signal almost entirely reflects DRD3 availability. The reductions in regional receptor binding (VT) following a single oral dose of GSK598809 (60 mg) were consistent with those observed in previous studies across all regions. There were no differences in regional changes in VT following DRD3 blockade between the two groups, indicating that the regional fractions of DRD3 are similar in the two groups, and the increased [(11)C]PHNO binding in the hypothalamus in alcohol-dependent patients is explained by elevated DRD3 in this group. Although we found no difference between alcohol-dependent patients and controls in striatal DRD3 levels, increased DRD3 binding in the hypothalamus of alcohol-dependent patients was observed. This may be relevant to the development of future therapeutic strategies to treat alcohol abuse.

Growing evidence suggests that there are subpopulations of daily smokers ranging from light infrequent users to heavy daily users. In the present review we will investigate whether these differences can be explained by factors such as social context, responsiveness to environmental cues, personality traits, neurochemical and pharmacogenetic differences. We will also assess how controlled abstinence and free choice smoking paradigms in a human laboratory setting may help identify and characterize these differences and what can be learned from these models to accurately predict clinical efficacy in the later phase testing of new chemical entities for the treatment of smoking dependence.

The pharmacological properties of two NK1 antagonists were studied in comparison with a benzodiazepine during a 7% CO2 challenge in a population of healthy volunteers selected for a high sensitivity to the challenge. In total, 19 healthy subjects, pre-screened for their responsiveness to the 7% CO2 test, took part in the randomised, double-blind, cross-over, incomplete block design study. After receiving treatment or placebo, the volunteers were subjected to three 7% CO2 challenges each for a time of 20 min. The treatment consisted of the administration of the following three active drugs: a single dose of benzodiazepine alprazolam (0.75 mg) and a single dose of the NK1 antagonists vestipitant (GW597599) (15 mg) and vofopitant (GR205171) (25 mg). Anxiety during the challenge was evaluated with Visual Analogue Scale-Anxiety (VAS-A) and with Panic Symptom List (PSL III-R). Respiratory parameters, heart rate and skin conductance were also recorded. Compared with placebo, vestipitant showed a significant reduction (p<0.05) in anxiety assessed on the VAS-A scale (ΔVAS-A%) while alprazolam significantly (p<0.01) attenuated the PSL III-R total score. Vofopitant did not show any anxiolytic effect. In the comparison analysis between placebo and drugs, none of the respiratory and other physiological parameters showed a statistically significant difference.

Recent studies suggest that pharmacologic effects of anxiolytic agents can be mapped as functional changes in the fear, stress and anxiety brain circuit. In this work we investigated the effects of a standard treatment, paroxetine (20 mg/day), in subjects with Social Anxiety Disorder (SAD) versus placebo using different fMRI paradigms. The fMRI sessions, performed before and after the treatment, consisted of a public exposition of recorded performance task (PERPT), an emotional face processing task (EFPT) and a 6-min resting state followed by an off-scanner public speaking test. Paroxetine significantly improved the clinical conditions of SAD patients (n=17) vs. placebo (n=16) as measured with Clinical Global Inventory – Improvement (CGI-I) while no change was seen when using Liebowitz Social Anxiety Scale, as expected given the small size of the study population. Paroxetine reduced the activation of insula, thalamus and subgenual/anterior cingulate cortex (ACC) in PERPT. Resting-state fMRI assessment using Independent Component Analysis indicated that paroxetine reduced functional connectivity in insula, thalamus and ACC when compared with placebo. Both paradigms showed significant correlation with CGI-I in rostral prefrontal cortex. Conversely, paroxetine compared to placebo produced activation of right amygdala and bilateral insula and no effects in ACC when tested with EFPT. No treatment effects on distress scores were observed in the off-scanner Public Speaking Test. Overall this study supports the use of fMRI as sensitive approach to explore the neurobiological substrate of the effects of pharmacologic treatments and, in particular, of resting state fMRI given its simplicity and task independence.