Population Pharmacokinetics of Vixotrigine in Healthy Volunteers and Subjects with Trigeminal Neuralgia, Painful Lumbosacral Radiculopathy and Erythromelalgia.

BACKGROUND: Vixotrigine is a voltage and use dependent sodium channel blocker currently under development for treatment of various neuropathic pain indications. OBJECTIVE: The objective of this work was to develop a population pharmacokinetic model and assess effects of various covariates on pharmacokinetic parameters of vixotrigine. METHOD: Plasma concentration-time data from 12 Phase 1 or 2 studies were included in the analyses. The data were obtained following administration of single or multiple doses of vixotrigine in healthy volunteers and patients. One- and two-compartment pharmacokinetic models were evaluated as base structural pharmacokinetic models. The inclusion of selected covariates was assessed using a stepwise backward elimination approach (α = 0.001) once the base/full model was developed. The predictive ability of the model was evaluated using a visual predictive check (VPC). The final model was used to evaluate effect of covariates on exposure of vixotrigine. RESULTS: A total of 10,263 pharmacokinetic samples collected from 465 subjects were included in the analyses. The pharmacokinetics of vixotrigine was adequately described by a two-compartment model with two transit absorption compartments and first-order elimination. Predictability of the model was also established by VPC. The final model included covariates of age, weight and carbamazepine co-administration on clearance, weight on central volume of distribution, food on absorption rate constant and formulation and Japanese race on bioavailability. None of the covariates identified had a clinically relevant effect, as impact on area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) was within ± 25%. CONCLUSION: The model characterizes the pharmacokinetics of vixotrigine well, and the exposure of vixotrigine was comparable between healthy subjects and patients. None of the covariates evaluated have a clinically relevant impact on the pharmacokinetics of vixotrigine.

Efficacy and safety of a premixed versus a basal-plus insulin regimen as intensification for type 2 diabetes by timing of the main meal.

OBJECTIVE: To describe the efficacy and safety of premixed insulin lispro protamine suspension 75%/insulin lispro solution 25% (LM25) twice daily (bid) versus basal insulin glargine plus prandial insulin lispro (IGL), both once daily, according to main meal timing. METHODS: Data were obtained post hoc from a 24 week, randomized, open-label study comparing LM25 and IGL as insulin intensification in patients with type 2 diabetes inadequately controlled with once daily basal insulin glargine plus metformin and/or pioglitazone (ClinicalTrials.gov identifier: NCT01175824). Patients administered LM25 bid before breakfast and the evening meal, insulin glargine at bedtime and insulin lispro before the day's main meal (meal with the highest 2 hour postprandial glucose level during screening). Patients were grouped by main meal. Changes in glycosylated hemoglobin (HbA1c) and bodyweight were summarized using likelihood-based mixed models; hypoglycemia incidence was compared between treatments using Fisher's exact test. RESULTS: Overall, 476 patients (LM25, n = 236; IGL, n = 240) were randomized. In all main meal groups, with both insulin regimens, mean HbA1c significantly decreased from baseline to 24 weeks (p < 0.0001). Patients whose main meal was in the evening had a greater bodyweight increase with LM25 than with IGL (p = 0.015), and a smaller proportion of these patients experienced total (p = 0.027) and nocturnal (p = 0.006) hypoglycemia with LM25 compared with IGL. Patients whose main meal was lunch experienced more nocturnal hypoglycemia with LM25 than with IGL (p = 0.030). Study limitations include that this was a post hoc analysis and no assessments ensured that: SMBG results determined timing of the main meal, each patient's main meal remained unchanged throughout the study, or patients administered insulin lispro with that meal. CONCLUSIONS: Glycemic control improved in patients receiving either LM25 or IGL, irrespective of main meal timing. Both regimens can be used in patients with inadequate glycemic control who are in need of insulin intensification.

Impacto de las herramientas «Mapas de Conversaciones™» sobre el conocimiento de la diabetes en pacientes españoles con diabetes mellitus tipo 2: un estudio aleatorizado y comparativo / Impact of the «Conversation Map™» tools on understanding of diabetes by Spanish patients with type 2 diabetes mellitus: A randomized, comparative study

ANTECEDENTES Y OBJETIVO: Este artículo presenta los resultados de la subpoblación española de un estudio que compara una formación usando Mapas de Conversaciones (TM) (MC) con la atención habitual (AH) en pacientes con diabetes mellitus tipo 2. PACIENTES Y MÉTODOS: A pacientes adultos con diabetes mellitus tipo 2 que se consideró que no tenían un manejo ideal de su enfermedad se les asignó aleatoriamente a recibir MC o AH, realizando una evaluación inmediatamente después (visita 2) y otra a los 6 meses (visita 3) de la sesión final de los MC. La variable principal de valoración fue el conocimiento adquirido sobre la diabetes en la visita 3. RESULTADOS: Participaron 310 pacientes a los que se asignó aleatoriamente a recibir una formación con MC (n = 148) o AH (n = 162). La mediana de la puntuación de conocimiento fue significativamente más elevada en el grupo MC que en el grupo AH tanto en la visita 2 como en la visita 3. No se identificaron diferencias significativas en las variables clínicas o de otra índole entre intervenciones, excepto en la satisfacción con el cuidado (visita 2, p < 0,001; visita 3, p = 0,055) y la percepción de consecución del objetivo (p < 0,001 y p = 0,046 respectivamente) que fueron ambas más elevadas en el grupo MC. CONCLUSIONES: En estos pacientes españoles, los MC fueron superiores a la AH en términos del conocimiento sobre la diabetes 6 meses después de completar la formación, por lo que los MC podrían ser una herramienta a considerar en pacientes que requieran una educación diabetológica

BACKGROUND AND AIM: This paper presents results from the Spanish subpopulation of a study comparing Conversation Maps (TM) (CM)-based education with regular care (RC) in type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: Adult patients with T2DM who were considered as not demonstrating ideal disease management were randomly assigned to CM or RC with assessments following (Visit 2), and at follow-up 6 months after (Visit 3), the final CM session. The primary endpoint was diabetes knowledge at Visit 3. RESULTS: 310 patients were randomised to receive CM education (n=148) or RC (n=162). Median knowledge scores were ranked significantly higher in the CM group than the RC group at Visit 2 and Visit 3 (p < 0.001). No significant differences in clinical and other outcomes were identified between the interventions, except satisfaction with care (p < 0.001, Visit 2; p = 0.055, Visit 3) and perception of goal attainment (p < 0.001 and p = 0.046, respectively) that were both higher in the CM group. CONCLUSIONS: In these patients from Spain, CM was superior to RC in terms of diabetes knowledge 6 months after education was completed, suggesting that CM should be considered for use in patients requiring diabetes education

Impact of the «Conversation Map™¼ tools on understanding of diabetes by Spanish patients with type 2 diabetes mellitus: a randomized, comparative study.

BACKGROUND AND AIM: This paper presents results from the Spanish subpopulation of a study comparing Conversation Maps™ (CM)-based education with regular care (RC) in type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: Adult patients with T2DM who were considered as not demonstrating ideal disease management were randomly assigned to CM or RC with assessments following (Visit 2), and at follow-up 6 months after (Visit 3), the final CM session. The primary endpoint was diabetes knowledge at Visit 3. RESULTS: 310 patients were randomised to receive CM education (n=148) or RC (n=162). Median knowledge scores were ranked significantly higher in the CM group than the RC group at Visit 2 and Visit 3 (p<0.001). No significant differences in clinical and other outcomes were identified between the interventions, except satisfaction with care (p<0.001, Visit 2; p=0.055, Visit 3) and perception of goal attainment (p<0.001 and p = 0.046, respectively) that were both higher in the CM group. CONCLUSIONS: In these patients from Spain, CM was superior to RC in terms of diabetes knowledge 6 months after education was completed, suggesting that CM should be considered for use in patients requiring diabetes education.

Glucagon-like peptide 1 receptor agonist or bolus insulin with optimized basal insulin in type 2 diabetes.

OBJECTIVE: Mealtime insulin is commonly added to manage hyperglycemia in type 2 diabetes when basal insulin is insufficient. However, this complex regimen is associated with weight gain and hypoglycemia. This study compared the efficacy and safety of exenatide twice daily or mealtime insulin lispro in patients inadequately controlled by insulin glargine and metformin despite up-titration. RESEARCH DESIGN AND METHODS: In this 30-week, open-label, multicenter, randomized, noninferiority trial with 12 weeks prior insulin optimization, 627 patients with insufficient postoptimization glycated hemoglobin A1c (HbA1c) were randomized to exenatide (10-20 µg/day) or thrice-daily mealtime lispro titrated to premeal glucose of 5.6-6.0 mmol/L, both added to insulin glargine (mean 61 units/day at randomization) and metformin (mean 2,000 mg/day). RESULTS: Randomization HbA1c and fasting glucose (FG) were 8.3% (67 mmol/mol) and 7.1 mmol/L for exenatide and 8.2% (66 mmol/mol) and 7.1 mmol/L for lispro. At 30 weeks postrandomization, mean HbA1c changes were noninferior for exenatide compared with lispro (-1.13 and -1.10%, respectively); treatment differences were -0.04 (95% CI -0.18, 0.11) in per-protocol (n = 510) and -0.03 (95% CI -0.16, 0.11) in intent-to-treat (n = 627) populations. FG was lower with exenatide than lispro (6.5 vs. 7.2 mmol/L; P = 0.002). Weight decreased with exenatide and increased with lispro (-2.5 vs. +2.1 kg; P < 0.001). More patients reported treatment satisfaction and better quality of life with exenatide than lispro, although a larger proportion of patients with exenatide experienced treatment-emergent adverse events. Exenatide resulted in fewer nonnocturnal hypoglycemic episodes but more gastrointestinal adverse events than lispro. CONCLUSIONS: Adding exenatide to titrated glargine with metformin resulted in similar glycemic control as adding lispro and was well tolerated. These findings support exenatide as a noninsulin addition for patients failing basal insulin.

Resource utilisation and clinical data before and after switching between short-acting human insulin and rapid-acting insulin analogues in patients with type 2 diabetes: the SWING study.

AIM: SWING was a prospective, observational study conducted in nine European countries primarily to assess direct treatment costs when switching from short-acting human insulins to rapid-acting insulin analogues (H-A) or vice versa (A-H) in patients with type 2 diabetes. METHODS: Data were collected at a baseline visit (time of switch) and at approximately 3, 6 and 12 months post-switch. RESULTS: In total, 2389 patients switched from H-A (n=2203) or A-H (n=186); another 603 were enrolled but ineligible. Mean (SD) direct diabetes-related costs (pro-rated to account for variable visit schedules) were €548.7 (865.8) 6 months prior to switch, €625.6 (1474.9) at 0-6 months and €568.6 (590.7) 6-12 months following switch for H-A, and €544.5 (421.0), €481.0 (301.5) and €461.6 (335.0) for A-H, respectively. Mean (SD) HbA(1c) decreased over 12 months by 1.08 (1.53)% units H-A and 1.17 (1.45)% units A-H. A small decline in hypoglycaemia occurred over time, but there were no clinically meaningful changes in mean PROs. CONCLUSIONS: There were small changes in mean direct diabetes-related costs (following adjustment for time interval) in patients switching in either direction. Improvements in mean HbA(1c) and incidence of hypoglycaemia cannot necessarily be attributed to therapeutic switch.