3 results
Complete in vitro Dissolution of Valbenazine as Either Whole Capsules or Crushed Capsule Contents
- Mello Hebert, Richard Moore, Eric Jen, Scott Siegert
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- Journal:
- CNS Spectrums / Volume 28 / Issue 2 / April 2023
- Published online by Cambridge University Press:
- 14 April 2023, p. 227
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Introduction
Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with exposure to antipsychotics and other dopamine receptor blocking agents. Three valbenazine capsule strengths (40 mg, 60 mg, 80 mg) are approved for the once-daily treatment of TD. However, some patients with TD, especially in elderly populations, have trouble swallowing due to orolingual movements. This study was conducted to evaluate two different dissolution methods for valbenazine: whole intact capsules versus crushed capsule contents.
MethodsSamples were prepared using two commercial lots (Lot-A, Lot-B) for two doses (40 mg, 80 mg), with six replicate samples per lot and dose. The whole capsules were weighed, put into a sinker, and added to a dissolution bath containing 900 mL of 0.1N HCl at 37±0.5° Celsius. Testing on the crushed capsule contents commenced after opening the capsules, weighing and crushing the contents, and transferring the contents to the dissolution bath. Samples were collected (at 10, 15, 20, 30, 45, and 60 min) with a paddle speed of 50 rpm and analyzed using high performance liquid chromatography. Standards were prepared at nominal concentrations of 0.044 mg/mL (for 40 mg) and 0.089 mg/mL (for 80 mg).
ResultsCapsules were opened easily by manual manipulation, and contents were crushed easily between spoons. Very rapid (>85% in 15 min) and complete drug release was observed in all samples, independent of capsule strength (40 mg, 80 mg) or preparation (whole intact capsule or crushed capsule contents). For 40-mg capsules, average percent release at first and last collection timepoints were as follows (whole vs crushed): 10 min (98.4% vs 98.6% [A], 93.7% vs 97.6% [B]); 60 min (102.3% vs 100.5% [A], 100.9% vs 100.6% [B]). Results for 80-mg capsules were as follows: 10 min (98.2% vs 99.6% [A], 99.4% vs 97.9% [B]); 60 min (102.0% vs 101.6% [A], 103.2% vs 100.9% [B]).
ConclusionsCrushing the capsule contents did not impact the in vitro dissolution performance of valbenazine. Many patients with TD, particularly elderly patients, have difficulty swallowing and may benefit from alternative delivery methods for valbenazine, especially if other TD medications cannot be crushed. More research is needed to better understand if and how crushing the capsule contents of valbenazine affects their stability when mixed with food or delivered through a feeding tube.
FundingNeurocrine Biosciences, Inc.
Sustained Treatment Response With Long-Term Valbenazine in Patients With Tardive Dyskinesia
- Christoph U. Correll, Jean-Pierre Lindenmayer, Khody Farahmand, Eric Jen, Scott Siegert, Eduardo Dunayevich
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- Journal:
- CNS Spectrums / Volume 28 / Issue 2 / April 2023
- Published online by Cambridge University Press:
- 14 April 2023, p. 240
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Background
Valbenazine is a once-daily VMAT2 inhibitor approved for the treatment of tardive dyskinesia (TD), a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics, antiemetics, and other dopamine receptor blocking agents. The efficacy, safety, and tolerability of valbenazine has been established in several phase 3 trials, including a long-term study (KINECT 4 [NCT02405091]) in which participants received open-label valbenazine (40 or 80 mg) for 48 weeks. Post hoc analyses of KINECT 4 data were conducted to assess patterns of treatment response.
MethodsData from KINECT 4 treatment completers (participants who reached the Week 48 visit and had the longest duration of treatment) were analyzed post hoc. TD was assessed using the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1–7, as rated by the study investigator), the Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD), and the Patient Global Impression of Change (PGIC). Analyses were conducted at Week 8 (first study visit after the valbenazine dose-optimization period) and Week 48 using the following definitions of response: ≥50% and ≥70% improvement from baseline in AIMS total score; rating of “much improved” or “very much improved” (score ≤2) on the CGI-TD and PGIC.
ResultsOf the 167 participants who entered KINECT 4, 103 (62%) were treatment completers and included for analysis. Of these 103 participants, 39% and 86% met the ≥50% AIMS response threshold at Weeks 8 and 48, respectively. The percentages of participants who met the highly rigorous AIMS ≥70% response threshold at Weeks 8 and 48 were 17% and 52%, respectively. Of the 40 participants with AIMS ≥50% total score improvement at Week 8, 95% also met this threshold at Week 48 (“sustained response”). Of the 63 participants with <50% AIMS improvement at Week 8, 81% achieved the ≥50% response threshold by end of treatment at Week 48. The proportion of participants meeting the threshold for CGI-TD response also increased over time, from 50% at Week 8 to 92% at Week 48. PGIC results were similar, with response rates of 53% and 88% at Weeks 8 and 48, respectively.
ConclusionsPost hoc analyses of data from a 48-week, open-label study of once-daily valbenazine showed that the proportion of participants meeting rigorous treatment response thresholds increased over time. By the end of treatment at Week 48, >80% of participants demonstrated robust improvements in TD, as assessed using the AIMS (≥50% improvement), CGI-TD (score ≤2), and PGIC (score ≤2).
FundingNeurocrine Biosciences, Inc.
Test–retest reliability and sensitivity to change of the dimensional anxiety scales for DSM-5
- Susanne Knappe, Jens Klotsche, Franziska Heyde, Sarah Hiob, Jens Siegert, Jürgen Hoyer, Anja Strobel, Richard T. LeBeau, Michelle G. Craske, Hans-Ulrich Wittchen, Katja Beesdo-Baum
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- Journal:
- CNS Spectrums / Volume 19 / Issue 3 / June 2014
- Published online by Cambridge University Press:
- 08 November 2013, pp. 256-267
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Objective
This article reports on the test–retest reliability and sensitivity to change of a set of brief dimensional self-rating questionnaires for social anxiety disorder (SAD-D), specific phobia (SP-D), agoraphobia (AG-D), panic disorder (PD-D), and generalized anxiety disorder (GAD-D), as well as a general cross-cutting anxiety scale (Cross-D), which were developed to supplement categorical diagnoses in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5).
MethodsThe German versions of the dimensional anxiety scales were administered to 218 students followed up approximately 2 weeks later (Study 1) and 55 outpatients (23 with anxiety diagnoses) followed-up 1 year later (Study 2). Probable diagnostic status in students was determined by the DIA-X/M-CIDI stem screening-questionnaire (SSQ). In the clinical sample, Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnoses were assessed at Time 1 using the DIA-X/M-CIDI. At Time 2, the patient-version of the Clinical Global Impression—Improvement scale (CGI-I) was applied to assess change.
ResultsGood psychometric properties, including high test–retest reliability, were found for the dimensional scales except for SP-D. In outpatients, improvement at Time 2 was associated with significant decrease in PD-D, GAD-D, and Cross-D scores.
DiscussionMajor advantages of the scales include that they are brief, concise, and based on a consistent template to measure the cognitive, physiological, and behavioral symptoms of fear and anxiety. Further replication in larger samples is needed. Given its modest psychometric properties, SP-D needs refinement.
ConclusionIncreasing evidence from diverse samples suggests clinical utility of the dimensional anxiety scales.