Comparison of Safety and Tolerability of Deutetrabenazine During Titration and Maintenance in Patients with Tardive Dyskinesia

BackgroundDeutetrabenazine is approved to treat tardive dyskinesia (TD) in adults and is titrated weekly by 6 mg/day, from 12 to 48 mg/day, based on dyskinesia control and tolerability. This analysis compared the safety of deutetrabenazine during titration versus maintenance.MethodsSafety was assessed during titration versus maintenance using integrated data from two 12-week placebo-controlled studies (ARM-TD and AIM-TD) and the open-label extension study. Rates were compared for overall and serious adverse events (AEs), AEs leading to discontinuation, treatment-related AEs, common AEs (≥4%), and specific AEs (parkinsonism, suicidal ideation, akathisia, restlessness).ResultsIn titration versus maintenance, AE rates with placebo (n=130) were: overall, 43.1% vs 25.4%; serious, 4.6% vs 2.3%; leading to discontinuation, 3.1% vs 0; treatment-related, 26.9% vs 10.0%. For placebo, common AEs during titration were somnolence, headache, nausea, fatigue, and dry mouth; none occurred during maintenance. In titration versus maintenance, AE rates in fixed-dose deutetrabenazine 12–36 mg (n=216) were: overall, 33.3–38.9% vs 22.2–29.2%; serious, 2.8–6.9% vs 0–1.4%; leading to discontinuation, 2.8–5.6% vs 0; treatment-related, 8.3–16.7% vs 8.3–13.9%. For fixed-dose deutetrabenazine, common AEs during titration were headache, diarrhea, nasopharyngitis, depression, hypertension, and dry mouth; headache was the only common AE during maintenance. In titration versus maintenance, AE rates with flexible-dose deutetrabenazine (n=168) were: overall, 49.4% vs 32.7%; serious, 3.6% vs 2.4%; leading to discontinuation, 2.4% vs 0.6%. For flexible-dose deutetrabenazine, the only common AE during titration was somnolence; none occurred during maintenance. Rates of parkinsonism, suicidal ideation, akathisia, and restlessness were low and comparable in titration and maintenance.ConclusionsDeutetrabenazine was well-tolerated, with AE rates similar to placebo during both phases; AE rates were higher during titration and decreased during maintenance.FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel

Two randomized, double-blind, placebo-controlled trials and one open-label, long-term trial of brexpiprazole for the acute treatment of bipolar mania

Background: Brexpiprazole is a dopamine/serotonin receptor partial agonist (D2, 5-HT1A) and antagonist (5-HT2A) approved for treatment of schizophrenia and major depressive disorder (adjunct to antidepressants). Aims: This study aimed to investigate brexpiprazole as monotherapy in acute mania (bipolar I disorder) in two short-term (ST) studies (study 080 and study 081) and one open-label (OL) extension (study 083). Methods: ST studies were three-week randomized, double-blind, flexible dose (2–4 mg/day), placebo-controlled studies. The primary endpoint was mean change in Young Mania Rating Scale (YMRS) total score from baseline to day 21. The OL study was a 26-week flexible dose (2–4 mg/day) study for patients completing the ST studies. Results: A total of 164 and 158 (study 080) and 170 and 162 (study 081) inpatients with DSM-5 mania with/without mixed features were randomized to placebo or brexpiprazole, respectively. The primary analyses did not show a statistically significant difference between brexpiprazole and placebo: study 080: least squares mean difference (95% confidence limits): 0.14 (−1.74, 2.03), p = 0.8797; study 081: −1.62 (−3.56, 0.32), p = 0.1011. OL study patients ( n = 381) demonstrated a gradual improvement in YMRS total score. Akathisia was the only adverse event, with an incidence of ⩾5% with brexpiprazole and more than placebo in the ST studies, or ⩾5% in the OL study. Brexpiprazole was more efficacious in patients with impaired or no insight (predominantly EU patients) than in patients with excellent insight (predominantly US patients). Conclusions: Further studies are necessary to address the potential efficacy of brexpiprazole in acute mania, which should ensure that the study sample is severe enough (especially with regard to insight), and that the dose/titration schedule is not too modest.

Long-term efficacy and safety of oral semaglutide and the effect of switching from sitagliptin to oral semaglutide in patients with type 2 diabetes: a 52-week, randomized, open-label extension of the PIONEER 7 trial

IntroductionThe PIONEER 7 trial demonstrated superior glycemic control and weight loss with once-daily oral semaglutide with flexible dose adjustment versus sitagliptin 100 mg in type 2 diabetes. This 52-week extension evaluated long-term oral semaglutide treatment and switching from sitagliptin to oral semaglutide.Research design and methodsA 52-week, open-label extension commenced after the 52-week main phase. Patients on oral semaglutide in the main phase continued treatment (n=184; durability part); those on sitagliptin were rerandomized to continued sitagliptin (n=98) or oral semaglutide (n=100; initiated at 3 mg) (switch part). Oral semaglutide was dose-adjusted (3, 7, or 14 mg) every 8 weeks based on glycated hemoglobin (HbA1c) (target <7.0% (<53 mmol/mol)) and tolerability. Secondary endpoints (no primary) included changes in HbA1c and body weight.ResultsIn the durability part, mean (SD) changes in HbA1c and body weight from week 0 were –1.5% (0.8) and –1.3% (1.0) and –2.8 kg (3.8) and –3.7 kg (5.2) at weeks 52 and 104, respectively. In the switch part, mean changes in HbA1c from week 52 to week 104 were –0.2% for oral semaglutide and 0.1% for sitagliptin (difference –0.3% (95% CI –0.6 to 0.0); p=0.0791 (superiority not confirmed)). More patients achieved HbA1c <7.0% with oral semaglutide (52.6%) than sitagliptin (28.6%; p=0.0011) and fewer received rescue medication (9% vs 23.5%). Respective mean changes in body weight were –2.4 kg and –0.9 kg (difference –1.5 kg (95% CI –2.8 to –0.1); p=0.0321). Gastrointestinal adverse events were the most commonly reported with oral semaglutide.ConclusionsLong-term oral semaglutide with flexible dose adjustment maintained HbA1c reductions, with additional body weight reductions, and was well tolerated. Switching from sitagliptin to flexibly dosed oral semaglutide maintained HbA1c reductions, helped more patients achieve HbA1c targets with less use of additional glucose-lowering medication, and offers the potential for additional reductions in body weight.Trial registration numberNCT02849080.

OVERVIEW OF FORMULATION, MANUFACTURE AND APPLICATIONS OF MINI TABLETS

Mini tablets, recent trend of solid dosage form, made remarkable contribution to avoid certain obstacles in people’s mind and offered best therapeutic benefits, flexible dose and combined released pattern. Mini tablets were developed and reported as patient friendly with increased patient acceptance. Mini tablets were made into modified release system for better dose and prolong drug release. They offer the advantage of reduced dose dumping and increased effect of drug by localization. Manufacture of mini tablets are similar to conventional tablets but need a change in tooling, equipment and specifications. Evaluation parameters found to be similar with conventional tablets but doses are variable. Mini tablets can also be encapsulated and hence different drug combinations are tried and found useful.

Manipulation of Medicinal Products for Oral Administration to Paediatric Patients at a German University Hospital: An Observational Study

Pharmacotherapy in children requires medicinal products in age-appropriate dosage forms and flexible dose strengths. Healthcare professionals often encounter a lack of licensed and commercially available formulations, which results in the need for manipulation. This study aimed to investigate the nature, frequency and preventability of the manipulation of medicinal products before oral drug administration to paediatric inpatients in Germany. A prospective, direct observational approach was used. Two thousand and three medication preparation processes (MPP) in 193 patients were included in the analysis. Medicines were manipulated in 37% of oral administrations, affecting 57% of the patients. The percentage of manipulations was highest in infants/toddlers (42%) and lowest in adolescents (31%). Antiepileptics were most frequently manipulated (27%), followed by vitamins (20%) and drugs for acid-related disorders (13%). Fifty-six per cent of all manipulations were off-label. In 71% of these, no alternative appropriate medicinal product was commercially available. These results demonstrate that the manipulation of medicinal products before oral administration is common in paediatric wards in Germany. About half of the manipulations were off-label, indicating that no suitable formulation was available. Evidence-based guidelines for manipulations are required, with the overall aim of improving the safety of paediatric drug therapy.

Redox-Mediated Post-Translational Modifications of Proteolytic Enzymes and Their Role in Protease Functioning

Proteolytic enzymes play a crucial role in metabolic processes, providing the cell with amino acids through the hydrolysis of multiple endogenous and exogenous proteins. In addition to this function, proteases are involved in numerous protein cascades to maintain cellular and extracellular homeostasis. The redox regulation of proteolysis provides a flexible dose-dependent mechanism for proteolytic activity control. The excessive reactive oxygen species (ROS) and reactive nitrogen species (RNS) in living organisms indicate pathological conditions, so redox-sensitive proteases can swiftly induce pro-survival responses or regulated cell death (RCD). At the same time, severe protein oxidation can lead to the dysregulation of proteolysis, which induces either protein aggregation or superfluous protein hydrolysis. Therefore, oxidative stress contributes to the onset of age-related dysfunction. In the present review, we consider the post-translational modifications (PTMs) of proteolytic enzymes and their impact on homeostasis.