Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of Vixotrigine in Healthy Volunteers.

Neuropathic pain affects ~ 6.9-10% of the general population and leads to loss of function, anxiety, depression, sleep disturbance, and impaired cognition. Here, we report the safety, tolerability, and pharmacokinetics of a voltage-dependent and use-dependent sodium channel blocker, vixotrigine, currently under investigation for the treatment of neuropathic pain conditions. The randomized, placebo-controlled, phase I clinical trials were split into single ascending dose (SAD) and multiple ascending dose (MAD) studies. Healthy volunteers received oral vixotrigine as either single doses followed by a ≥ 7-day washout period for up to 5 dosing sessions (SAD, n = 30), or repeat doses (once or twice daily) for 14 and 28 days (MAD, n = 51). Adverse events (AEs), maximum observed vixotrigine plasma concentration (Cmax ), area under the concentration-time curve from predose to 24 hours postdose (AUC0-24 ), time to Cmax (Tmax ), and terminal half-life (t1/2), among others, were assessed. Drug-related AEs were reported in 47% and 53% of volunteers in the SAD and MAD studies, respectively, with dizziness as the most commonly reported drug-related AE. SAD results showed that Cmax and AUC increased with dose, Tmax was 1-2 hours, and t1/2 was ~ 11 hours. A twofold increase in accumulation was observed when vixotrigine was taken twice vs. once daily (MAD). Steady-state was achieved from day 5 onward. These data indicate that oral vixotrigine is well-tolerated when administered as single doses up to 825 mg and multiple doses up to 450 mg twice daily.

Effects of a State- and Use-Dependent Nav1.7 Channel Blocker on Ambulatory Blood Pressure: A Randomized, Controlled Crossover Study.

Vixotrigine is a state- and use-dependent Nav1.7 channel blocker being investigated for the treatment of neuropathic pain conditions. This randomized, double-blind, placebo-controlled crossover trial was designed to evaluate changes in blood pressure with the administration of vixotrigine using ambulatory blood pressure monitoring (ABPM). Eligible participants were healthy adults 18 to 65 years of age without evidence of baseline systolic blood pressure (SBP) persistently > 140 mm Hg or diastolic blood pressure (DBP) persistently > 90 mm Hg. Vixotrigine (400 mg [men], 300 mg [women]) or placebo was administered orally twice daily for 36 days. Following a 7-day washout period, participants crossed over to the other treatment. Each dosing period was preceded by 1 inpatient visit and 1 outpatient baseline visit. Two 14-hour inpatient ABPM sessions occurred on days 14 and 35, with a return to the clinic the morning of days 15 and 36 for initiation of outpatient ABPM, which assessed blood pressure and heart rate every 15 minutes. Adverse events were collected throughout the study. The primary end point was the change from baseline in 24-hour mean SBP and DBP on day 36. Sixty participants were enrolled; 10 withdrew from the study owing to adverse events, investigator discretion, or withdrawal of consent. From baseline to day 36, mean changes in average SBP and DBP (vixotrigine treated) were -0.33 and 0.20 mm Hg, respectively. Adverse event rates were comparable for vixotrigine and placebo; the most common adverse events were headache, dizziness, and nausea. Vixotrigine administration is not associated with a clinically important increase in blood pressure.

Investigation of the Brain Biodistribution of the Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitor [18F]GSK2647544 in Healthy Male Subjects.

PURPOSE: GSK2647544 is a potent and specific inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2), which was in development as a potential treatment for Alzheimer's disease (AD). In order to refine therapeutic dose predictions and confirm brain penetration, a radiolabelled form of the inhibitor, [18F]GSK2647544, was manufactured for use in a positron emission tomography (PET) biodistribution study. PROCEDURES: [18F]GSK2647544 was produced using a novel, copper iodide (Cu(I)) mediated, [18F]trifluoromethylation methodology. Healthy male subjects (n = 4, age range 34-42) received an oral dose of unlabelled GSK2647544 (100 mg) and after 2 h an intravenous (iv) injection of [18F]GSK2647544 (average injected activity and mass were 106 ± 47 MBq and 179 ± 55 µg, respectively) followed by dynamic PET scans for 120 min. Defined regions of interest (ROI) throughout the brain were used to obtain regional time-activity curves (TACs) and compartmental modelling analysis used to estimate the primary outcome measure, whole brain volume of distribution (VT). Secondary PK and safety endpoints were also recorded. RESULTS: PET dynamic data were successfully obtained from all four subjects and there were no clinically significant variations of the safety endpoints. Inspection of the TACs indicated a relatively homogenous uptake of [18F]GSK2647544 across all the ROIs examined. The mean whole brain VT was 0.56 (95 % CI, 0.41-0.72). Secondary PK parameters, Cmax (geometric mean) and Tmax (median), were 354 ng/ml and 1.4 h, respectively. Metabolism of GSK2647544 was relatively consistent across subjects, with 20-40 % of the parent compound [18F]GSK2647544 present after 120 min. CONCLUSIONS: The study provides evidence that GSK2647544 is able to cross the blood brain barrier in healthy male subjects leading to a measurable brain exposure. The administered doses of GSK2647544 were well tolerated. Exploratory modelling suggested that a twice-daily dose of 102 mg, at steady state, would provide ~80 % trough inhibition of brain Lp-PLA2 activity. TRIAL REGISTRATION: Clintrials.gov: NCT01924858.

Evaluation of the safety, pharmacokinetics, pharmacodynamics, and drug-drug interaction potential of a selective Lp-PLA2 inhibitor (GSK2647544) in healthy volunteers
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OBJECTIVE: To evaluate in healthy volunteers the safety, pharmacokinetics (PK), pharmacodynamics (PD), and drug-drug interaction (DDI) potential of GSK2647544, (a selective lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor). METHODS: Study 1 was a single-blind, randomized, placebo-controlled, crossover study with healthy male volunteers randomized to receive single escalating oral doses (0.5 - 750 mg) of GSK2647544. Study 2 was a single-blind, randomized, placebo-controlled study with healthy volunteers randomized to receive repeat doses (80 mg) of GSK2647544. The drug-drug interaction of GSK2647544 with simvastatin was also evaluated in study 2. RESULTS: Across both studies GSK2647544 doses were generally well tolerated with no GSK2647544-related clinically significant findings. GSK2647544 was readily absorbed and its plasma concentration declined bi-exponentially with a terminal half-life ranging from 8 to 16 hours. Plasma exposure of GSK2647544 increased approximately dose-proportionally. There was GSK2647544 dose-dependent inhibition of plasma Lp-PLA2 activity, with a trough inhibition (12 hours after dose) of 85.6% after 7-day twice daily dosing. The administration of simvastatin concomitantly with GSK2647544 increased the overall exposure (area under the plasma concentration-time curve and maximum plasma concentration) of simvastatin and simvastatin acid by 3.6- to 4.3-fold and 1.5- to 3.1-fold, respectively. CONCLUSIONS: GSK2647544 was generally well tolerated and had a reasonable PK-PD profile. The clinically significant drug-drug interaction led to an early termination of study 2.
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Safety of alitretinoin for severe refractory chronic hand eczema: Clinical studies and postmarketing surveillance.

BACKGROUND: Alitretinoin is approved for the treatment of adults with severe chronic hand eczema (CHE) refractory to potent topical steroids. In the 6 years since launch, approximately 250 000 patients have been treated with alitretinoin. OBJECTIVE: To compare the postmarketing safety surveillance experience of alitretinoin with data from clinical trials and key safety issues with other retinoids. METHODS: An integrated safety analysis of the pivotal studies of alitretinoin and postmarketing adverse event (AE) reports received since approval for alitretinoin were analyzed. RESULTS: In the pivotal trials, headache, erythema, nausea, increased blood triglycerides and increased blood creatinine phosphokinase were the most frequently reported AEs. Headache, hyperlipidemia and nausea were also frequently reported postmarketing AEs, but depression was relatively more frequently reported than in the pivotal trials. Inflammatory bowel disease and benign intracranial hypertension were rare, and very few cases have been reported in postmarketing surveillance. There have been no reports of teratogenicity in humans consequent to fetal exposure. CONCLUSIONS: Safety data collected in pivotal trials and postmarketing surveillance suggest that alitretinoin is well tolerated by patients with CHE with a relatively low incidence of serious reactions. The adverse reaction profile is congruent with reported effects of other marketed oral retinoids.

Meta-analysis of efficacy and treatment-emergent suicidality in adults by psychiatric indication and age subgroup following initiation of paroxetine therapy: a complete set of randomized placebo-controlled trials.

OBJECTIVE: This meta-analysis of placebo-controlled paroxetine trials examines suicidality incidence in adults, focusing on disorder and age as potential risk factors. The findings are put in context with an efficacy meta-analysis of the same trial datasets. DATA SOURCES: GlaxoSmithKline paroxetine clinical trial database(s). STUDY SELECTION: All double-blind, randomized, placebo-controlled, parallel-group studies of paroxetine therapy in adults enrolling at least 30 patients total were included in the analysis. The dataset comprised 14,911 patients from 61 trials. DATA EXTRACTION: Possible cases of suicidality were identified and blindly categorized by an expert panel, using methodology previously used by the US Food and Drug Administration. Incidences of suicidal behavior (preparatory act, suicide attempt, or completed suicide) and any suicidality (suicidal behavior or ideation) were compared between paroxetine and placebo. Efficacy assessments were based on standard depression rating scales (eg, Hamilton Depression Rating Scale or Montgomery-Asberg Depression Rating Scale) and Clinical Global Impressions Improvement scale (CGI-I) scores. RESULTS: In the primary dataset, ie, all disorders combined, there were no significant differences between paroxetine and placebo for overall suicidality (suicidal behavior or ideation: n/n = 83/8,958 [0.93%] vs n/n = 65/5,953 [1.09%], respectively; OR = 0.9 [95% CI, 0.7-1.3]; P = .649) or for suicidal behavior specifically (n/n = 50/8,958 [0.56%] vs n/n = 40/5,953 [0.67%], respectively; OR = 1.2 [95% CI, 0.8-1.9]; P = .483). However, in patients with major depressive disorder (MDD), a greater incidence of suicidal behavior occurred in paroxetine-treated patients than in placebo-treated patients (n/n = 11/3,455 [0.32%] vs n/n = 1/1,978 [0.05%], respectively; OR = 6.7 [95% CI, 1.1-149.4]; P = .058). Across all indications, a higher incidence of suicidal behavior occurred in paroxetine-treated versus placebo-treated adults aged 18 to 24 years (n/n = 17/776 [2.19%] vs n/n = 5/542 [0.92%], respectively; OR = 2.4 [95% CI, 0.9-7.3]). In older age groups, no increase in suicidality was observed. Efficacy was demonstrated in all disorders evaluated, including MDD. CONCLUSIONS: Across all disorders, overall suicidality incidence was similar between paroxetine and placebo. However, a higher frequency of suicidal behavior occurred with paroxetine in MDD, which was largely explained by the higher incidence in young adults. These data support the efficacy of paroxetine therapy; however, they also highlight the need for careful monitoring of suicidality during antidepressant therapy, particularly in younger adults.

Clinical features of patients with treatment-emergent suicidal behavior following initiation of paroxetine therapy.

BACKGROUND: Understanding suicidal behavior is an important component of assessing suicidality in psychiatric patients. GlaxoSmithKline (GSK) conducted a meta-analysis of randomized, placebo-controlled trials to compare suicidality in adult patients treated with paroxetine vs. placebo. The goal was to identify emergent clinical characteristics of patients with definitive suicidal behavior (DSB: preparatory act, suicide attempt, completed suicide). METHODS: The dataset comprised 14,911 patients from 57 placebo-controlled paroxetine trials. Possible cases of suicidality were identified and were blindly reviewed by an expert panel, which categorized cases as suicidal or non-suicidal. DSB incidences were compared between paroxetine and placebo. Clinical narratives and case report forms for major depressive disorder (MDD) and anxiety disorder patients with DSB were reviewed. For MDD, rating scale items relating to suicidality, insomnia, agitation, and anxiety were examined. RESULTS: Overall (all indications) there were no differences between paroxetine and placebo for DSB (50/8958 [0.56%] vs. 40/5953 [0.67%], respectively; OR=1.2 [CI 0.8, 1.9]; p=0.483). However, in patients with major depressive disorder (MDD), the incidence of DSB was greater for paroxetine (11/3455 [0.32%] vs. 1/1978 [0.05%], OR=6.7 [CI 1.1, 149.4]; p=0.058). Review of the 11 paroxetine MDD cases revealed common clinical features: symptomatic improvement; younger age (18-30 years); psychosocial stressors; overdose as method; and absent/mild suicidal ideation at the visit prior to the event. There was no evidence for a consistent adverse event profile or onset of akathisia/agitation or a manic/mixed state. Anxiety disorder patients with DSB had a heterogeneous clinical picture. LIMITATIONS: Limitations to the study include the relatively small number of cases and the retrospective nature of the study. CONCLUSIONS: DSB incidence was similar between paroxetine and placebo overall, but a higher frequency of DSB was found for paroxetine in MDD patients, driven by young adults aged < or =30 years. Most MDD patients with DSB improved prior to the attempt and experienced a psychosocial stressor. Patients should receive careful monitoring for suicidality during paroxetine therapy.

Paroxetine treatment in children and adolescents with major depressive disorder: a randomized, multicenter, double-blind, placebo-controlled trial.

OBJECTIVE: To assess the efficacy and tolerability of paroxetine in pediatric major depressive disorder. METHOD: Subjects 7 to 17 years old with major depressive disorder received paroxetine (10-50 mg/day) or placebo for 8 weeks from 2000 to 2001. The primary efficacy measure was change from baseline in the Children's Depression Rating Scale-Revised total score at week 8 last observation carried forward). Safety was primarily assessed by spontaneous reporting of adverse events. RESULTS: A total of 206 patients (intent to treat) were randomized to paroxetine (n = 104) or placebo (n = 102). Week 8 Children's Depression Rating Scale-Revised total score adjusted mean changes from baseline for patients receiving paroxetine and placebo were -22.58 (SE 1.47) and -23.38 points (SE 1.60), respectively (0.80, 95% confidence interval -3.09 to 4.69, p = 0.684). Increased cough (5.9% versus 2.9%), dyspepsia (5.9% versus 2.9%), vomiting (5.9% versus 2.0%), and dizziness (5.0% versus 1.0%) occurred in >or=5% of the paroxetine group and at least twice that of the placebo group. Six of 104 (5.8%) paroxetine patients reported serious adverse events compared to 1 placebo patient (1.0%). The incidence of adverse events of suicidal behavior and/or ideation while taking study medication (excluding taper) was 1.92% (2/104) for paroxetine versus 0.98% (1/102) for placebo. CONCLUSIONS: Paroxetine was not shown to be more efficacious than placebo for treating pediatric major depressive disorder.

Analysis of electrocardiographic data following use of paroxetine in pediatric depression and obsessive-compulsive disorder.

OBJECTIVE: This retrospective analysis of electrocardiographic (ECG) data investigated the cardiovascular effects of paroxetine 10-50 mg/day in pediatric patients (7-18 years of age). Data were collected from three 8- to 10-week, randomized, placebo-controlled, double-blind trials of paroxetine in pediatric patients with major depressive disorder or obsessive-compulsive disorder. METHOD: Electrocardiograms (ECGs) were retrospectively retrieved from 63 study sites in the United States and Canada. Only patients with at least one screening and one on-treatment ECG were included. ECGs were analyzed for heart rate, QT interval corrected using Bazett's formula (QTcB) and Fridericia's formula (QTcF), at screening and while being treated. PR, R-R, and QRS intervals and the maximum change in QTcB and QTcF from screening to endpoint were determined. Clinically significant thresholds were defined a priori. RESULTS: A total of 1,451 ECGs from 449 patients receiving placebo (n = 207), paroxetine (n = 200), or imipramine (n = 42) were analyzed. Treatment with paroxetine did not significantly increase QTcB or QTcF or any ECG parameters compared with placebo. Treatment with imipramine significantly increased heart rate and QTcB, R-R, and QRS intervals compared with either paroxetine or placebo. CONCLUSIONS: Data from this retrospective study indicate that paroxetine (10-50 mg/day) is unlikely to be associated with significant ECG changes in medically healthy pediatric patients.

An international, multicenter, placebo-controlled trial of paroxetine in adolescents with major depressive disorder.

OBJECTIVE: The aim of this study was to examine the efficacy, safety, and tolerability of paroxetine in adolescents with unipolar major depression. METHOD: Two hundred eighty-six (286) adolescents with unipolar major depression were randomly assigned to receive either paroxetine or placebo for 12 weeks. RESULTS: The proportion of Montgomery-Asberg Depression Rating Scale (MADRS) responders (at least 50% reduction from baseline) for paroxetine and placebo were similar and not statistically different at endpoint (p = 0.702). A similar result was obtained for change from baseline on the Kiddie-Schedule for Affective Disorders and Schizophrenia for School- Age Children (K-SADS-L) depression subscale. Among secondary endpoints, only a significantly higher Clinical Global Impression-Improvement (CGI-I) response rate was reported in paroxetine-treated patients versus placebo (69.2% versus 57.3%; p = 0.045). In general, results differed by age, with patients older than 16 years demonstrating a greater response to active treatment. This age group also reported more adverse experiences (AEs) relative to placebo than younger adolescents. Overall, paroxetine was generally well tolerated (11% discontinued owing to an AE versus 7% of placebo-treated patients). A post hoc analysis of AEs related to suicidal behavior suggested a greater incidence of these events for paroxetine than for placebo (4.4% versus 2.1%); however, this difference was not statistically significant (odds ratio, 2.15, 95% Confidence Interval 0.45, 10.33; p = 0.502). CONCLUSIONS: No statistically significant differences were observed for paroxetine compared with placebo on the two prospectively defined primary efficacy variables. Paroxetine at 20-40 mg/day administered over a period of up to 12 weeks was generally well tolerated.

Evaluation of suicidal thoughts and behaviors in children and adolescents taking paroxetine.

OBJECTIVE: The aim of this study was to summarize results of a blinded review of potential suicidal events and analyses comparing incidence rates between paroxetine- and placebo-treated pediatric patients. METHOD: One thousand one hundred ninety-one (1191) children and adolescents received paroxetine (n = 642) or placebo (n = 549) during placebo-controlled portions of all acute double-blind trials of paroxetine (n = 5). An expert panel blindly reviewed and categorized all identified cases detected by electronic and manual search of adverse events (AEs), serious AEs, and selected cases as suicidal or non-suicidal behavior. Incidence rates were calculated for suicide-related events and for rating scale items assessing suicidality. RESULTS: Suicide-related events occurred more often in paroxetine (22 of 642, 3.4%) than placebo groups (5 of 549, 0.9%); odds ratio (OR) 3.86 (95% CI 1.45, 10.26; p = 0.003). All suicide-related events occurred in adolescents of at least 12 years, except for 1 of 156 paroxetine-treated children. All suicide attempts occurred in major depressive disorder (MDD); few suicide-related events occurred in patients with a primary anxiety disorder. Suicide item analyses did not reveal significant differences between paroxetine and placebo. CONCLUSIONS: Adolescents treated with paroxetine showed an increased risk of suicide-related events. Suicidality rating scales did not show this risk difference. The presence of uncontrolled suicide risk factors, the relatively low incidence of these events, and their predominance in adolescents with MDD make it difficult to identify a single cause for suicidality in these pediatric patients.

Multiple dose pharmacokinetics of paroxetine in children and adolescents with major depressive disorder or obsessive-compulsive disorder.

The current study examined the pharmacokinetics (PK), safety, and tolerability of paroxetine after repeated multiple oral dosing in children and adolescents with major depressive or obsessive-compulsive disorder. In this 6-week, open-label, repeat dose, dose-rising study, 62 patients (27 children and 35 adolescents) were treated with paroxetine 10 mg/day for the first 2 weeks of the study, 20 mg/day for the next 2 weeks, and 30 mg/day for the final 2 weeks. Pharmacokinetic sampling and safety assessments occurred at baseline and subsequently on the final treatment day of each dosing level. Between-patient variability in PK was pronounced at the 10 mg dose level, but markedly reduced at higher doses. A supra-proportional increase in plasma concentrations with increasing dose was evident in both age groups. Data for C(max) and AUC(0-24) indicated that, at each dose level, paroxetine steady-state systemic exposure was higher in children than in adolescents. The differences between age groups, however, diminished with each increasing dose, and were virtually abolished when differences in weight among different age groups were considered. Stepwise regression analysis indicated that both oral clearance and volume of distribution were highly dependent on paroxetine dose, cytochrome P4502D6 genotype, and weight (p<0.0001), but not age or sex. Paroxetine was generally safe and well tolerated in both age groups, with the most frequently observed adverse events being largely consistent with those observed in prior paroxetine studies of adult psychiatric patients. Certain gastrointestinal and behavioral activation events (aggressive reaction and nervousness) were reported more frequently in the youngest age group.

Event-related brain potentials during auditory and visual word recognition memory tasks.

Event-related brain potentials (ERPs) recorded during presentation of a series of words or pictures show enhanced positivity between 300 and 800 ms after presentation of repeated items. However, little attention has been directed to the characterization of this ERP recognition memory effect using auditory stimuli. The present study directly compared the ERP 'old/new effect' for words presented in the visual and auditory modalities. Nose-referenced ERPs were recorded from 30 electrode sites while participants (N=16) were engaged in visual and auditory continuous word recognition memory tasks. Spatially and temporally overlapping ERP components were identified and measured by covariance-based principal components analysis. The expected old/new effect was observed in both modalities, with a comparable time course peaking at 560 ms, but having a more anterior scalp topography for visual items. This suggests a common cognitive process (i.e. successful retrieval of information from memory) associated with separable neural generators in each modality. Despite this temporal synchronization, the old/new effect overlapped ERP components having distinct scalp topographies (N2) or peak latencies (P3) for each modality. The positive-going old/new effect was preceded by an earlier negativity peaking at 370 ms that was greater across modalities for old than new words, likely reflecting semantic processing aspects of word recognition memory. A late (beyond 900 ms), broadly-distributed negativity was also greater for old than new words, prolonged for auditory items, and may represent activity of a post-retrieval process.