Background and Objective
Vixotrigine is a voltage- and use-dependent sodium channel blocker in development for neuropathic pain management. This study evaluated the effect of coadministration of ...vixotrigine (metabolized primarily via uridine diphosphate-glucuronosyltransferases) and an oral contraceptive containing ethinyl estradiol (uridine diphosphate-glucuronosyltransferase inducer) and levonorgestrel on the pharmacokinetics and safety of all three compounds.
Methods
In this phase I, open-label, fixed-sequence, multiple-dose study, 36 healthy women received oral vixotrigine 150 mg three times daily for 6 days and once on day 7. This was followed by a washout period, days 8–11. The oral contraceptive was administered alone on days 12–25 and with vixotrigine 150 mg three times daily on days 26–32. Serial blood samples were collected for pharmacokinetic analysis. Safety was assessed.
Results
The geometric least-squares mean ratios (90% confidence intervals) for the area under the concentration-time curve over 8 h and maximum concentration of vixotrigine co-administered with an oral contraceptive vs vixotrigine alone were 0.85 (0.82–0.89) and 0.91 (0.87–0.96), respectively. The geometric least-squares mean ratios (90% confidence interval) for area under the concentration-time curve over 24 h and maximum concentration of ethinyl estradiol with vixotrigine vs ethinyl estradiol alone were 0.94 (0.91–0.97) and 0.89 (0.84–0.94), respectively; the ratios for levonorgestrel with vixotrigine vs levonorgestrel alone were 1.06 (0.98–1.16) and 1.05 (0.98–1.13), respectively. No adverse events occurring with vixotrigine alone were deemed related to the study drug by the investigators.
Conclusions
Coadministration of vixotrigine and an oral contraceptive containing ethinyl estradiol and levonorgestrel had no clinically relevant effect on exposure of all three compounds.
Trial Registration
ClinicalTrials.gov registration number: NCT03324685 (registered 25 October, 2017).
Clinical trial participants often require additional instruction to prevent idiosyncratic interpretations regarding completion of patient-reported outcomes. The Analgesic, Anesthetic, and Addiction ...Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership developed a training system with specific, standardized guidance regarding daily average pain intensity ratings. A 3-week exploratory study among participants with low-back pain, osteoarthritis of the knee or hip, and painful diabetic peripheral neuropathy was conducted, randomly assigning participants to 1 of 3 groups: training with human pain assessment (T+); training with automated pain assessment (T); or no training with automated pain assessment (C). Although most measures of validity and reliability did not reveal significant differences between groups, some benefit was observed in discriminant validity, amount of missing data, and ranking order of least, worst, and average pain intensity ratings for participants in Group T+ compared with the other groups. Prediction of greater reliability in average pain intensity ratings in Group T+ compared with the other groups was not supported, which might indicate that training produces ratings that reflect the reality of temporal pain fluctuations. Results of this novel study suggest the need to test the training system in a prospective analgesic treatment trial.
This study characterizes the tolerability of ziprasidone in children and adolescents with bipolar mania, schizophrenia, or schizoaffective disorder.
Sixty-three subjects (aged 10-17 years) entered an ...open-label study consisting of a 3-week fixed-dose period (Period 1) and a subsequent 24-week flexible-dose period (Period 2). In Period 1, subjects received ziprasidone 80 or 160 mg/d in two divided doses, titrated over 10 days. In Period 2, subjects received flexible doses (20-160 mg/d). Tolerability was evaluated using movement rating scales, laboratory tests, and electrocardiograms. Clinical response was assessed using the Young Mania Rating Scale, the Brief Psychiatric Rating Scale-Anchored Version, and the Clinical Global Impressions-Severity scale.
Adverse events (AEs) occurred mostly during dose titration and in the high-dose (160 mg/d) group. The most common AEs during Period 1 were sedation (32%), somnolence (30%), and nausea (25%) and during Period 2 were sedation (30%), somnolence (30%), and headache (25%). The incidence of movement disorder AEs was 22% and 16% during Periods 1 and 2, respectively. Six percent of study participants discontinued study participation due to AEs during Period 1 and 20% discontinued in Period 2. Thirty-three percent of subjects gained >or=7% of their baseline weight. No Fridericia-corrected QT (QTcF) intervals of >450 ms were observed during Period 1 and only one occurred during Period 2. No QTcF increase >or=60 ms from baseline was observed. Symptom reductions were observed in all patient groups.
No unexpected tolerability findings were observed in this prospective trial of ziprasidone in children and adolescents with bipolar mania, schizophrenia, or schizoaffective disorder. On the basis of the results, a starting dose of 20 mg/d titrated to between 80 and 160 mg/d over 1-2 weeks appears optimal for most patients.
Food is known to increase the bioavailability of ziprasidone. Therefore, we evaluated the effects of meals of differing caloric and fat content on steady-state ziprasidone exposure in a stable, ...treated group of subjects with DSM-IV diagnoses of schizophrenia, schizoaffective disorder, bipolar disorder, or psychotic disorder (not otherwise specified) who were already receiving oral ziprasidone as their standard therapy.
Patients took ziprasidone under 6 meal conditions in randomized sequences (fasted, low calorie/low fat, low calorie/high fat, medium calorie/high fat, high calorie/low fat, and high calorie/high fat); each crossover period was separated by at least 3 days for washout of the previous meal condition. Serial blood samples were obtained over the 12 hours postdose. The study was conducted from July 27 to September 28 of 2006.
Maximum ziprasidone exposures in this study were observed with high-calorie meals (1000 kcal), which were nearly twice those observed under fasting conditions. The medium-calorie meal (500 kcal) was associated with exposures similar to the high-calorie meals. Low-calorie meals (250 kcal) were associated with exposures that were approximately 60% to 90% lower than those of medium- and high-calorie meals, and approached exposures seen under fasting conditions. Fat content of the meal had no significant effect on ziprasidone absorption. The ziprasidone exposures observed with medium- and high-calorie meals had less variability than those with low-calorie meals and under fasting conditions.
These results confirm that ziprasidone should be taken with food and that a meal equal to or greater than 500 kcal, irrespective of fat content, is required for optimal and reproducible bioavailability of the administered dose.
Highlights • Adequate selection and enrollment of subjects are key to successful epilepsy trials. • Selection criteria must maximize scientific impact, safety, and ability to recruit. • Workshop ...attendees suggested guidelines for “default” criteria for epilepsy trials. • Criteria apply to regulatory trials in subjects with focal or generalized seizures.
Summary
Introduction
SEP‐432 is a triple monoamine reuptake inhibitor of norepinephrine (NE), serotonin (5‐HT), and dopamine (DA), based on in vitro binding studies. We sought evidence that SEP‐432 ...engages these monoamine systems by measuring concentrations of monoamines and/or their main metabolites in cerebrospinal fluid (CSF) and plasma and comparing results to duloxetine, a dual reuptake inhibitor of NE and 5‐HT.
Methods
Eighteen healthy normal subjects received either SEP‐432 (300 mg/day), duloxetine (60 mg/day), or placebo for 14 days in‐clinic (double blind) with CSF and plasma collections at baseline (single lumbar puncture) and Day 14 (24‐h CSF and plasma collection). Concentrations of monoamines and their metabolites, as well as pharmacokinetic concentrations of SEP‐432 and metabolite, were quantified by liquid chromatography–tandem mass spectrometry.
Results
Compared to placebo in the Day 14 area under the curve 24‐h (AUC0–24 h) analysis, SEP‐432 significantly (P < 0.05) decreased the NE metabolite dihydroxyphenylglycol (DHPG) in CSF and plasma, decreased 5‐HT in plasma, and did not affect DA metabolites, while duloxetine had significant effects on DHPG and 5‐HT. Time‐matched baseline to Day 14 biomarker comparisons confirmed these findings.
Conclusion
CSF monoamine biomarkers confirmed central NET activity for SEP‐432 and duloxetine's dual reuptake inhibition.
The aim of this study was to examine global functioning, health-related quality of life (HRQOL), and clinical outcome in children and adolescents with bipolar I disorder, schizophrenia, or ...schizoaffective disorder following ziprasidone treatment.
Sixty-three subjects (aged 10-17 years) received open-label ziprasidone, titrated from 10 to 40 mg twice a day (b.i.d.) (low-dose group) or from 20 to 80 mg b.i.d. (high-dose group); fixed doses were used until week 3, followed by flexible doses for 6 months. The Children's Global Assessment Scale (CGAS) characterized functional impairment at baseline and following treatment. The Child Health Questionnaire (CHQ) assessed HRQOL at baseline.
Baseline CHQ showed greater impairment in psychosocial functioning than in physical health. Baseline mean CGAS scores were substantially below normal (i.e., <70), indicating functional impairment. Improvement in CGAS scores occurred as early as the first week of treatment. The low correlations between both CHQ and CGAS and the efficacy measures at baseline indicate that these scales measure different constructs. Nevertheless, there was good correlation between improvements in the CGAS and changes in Brief Psychiatric Rating Scale-Anchored (BPRS-A) and Young Mania Rating Scale (YMRS) during ziprasidone treatment.
CHQ and CGAS scales may be useful together with standard efficacy measures for children and adolescents with these disorders.
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